Olfactory Neuroblastoma Causing Cushing’s Syndrome Due to the Ectopic Adrenocorticotropic Hormone (ACTH) Secretion

Posted on March 27, 2024 by MaryO

Abstract

Cushing’s syndrome is a constellation of features occurring due to high blood cortisol levels. We report a case of a 47-year-old male with a history of recurrent olfactory neuroblastoma (ONB). He presented with bilateral lower limb weakness and anosmia and was found to have Cushing’s syndrome due to high adrenocorticotropic hormone (ACTH) levels from an ectopic source, ONB in this case. Serum cortisol and ACTH levels declined after tumor removal.

Introduction

Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare malignancy arising from neuroepithelium in the upper nasal cavity. It represents approximately 2% of all nasal passage tumors, with an incidence of approximately 0.4 per 2.5 million individuals [1]. ONB shares similar histological features with small round blue cell neoplasms of the nose. Ectopic hormone secretion is a very rare feature associated with these tumors. Five-year overall survival is reported to be between 60% and 80% [2,3]. The age distribution is either in the fifth to sixth decade of life [4,5], or in the second and sixth decades [6].

Features of Cushing’s syndrome (moon face, buffalo hump, central obesity hypertension, fragile skin, easy bruising, fatigue, muscle weakness) are due to high blood cortisol levels [7]. It can be either primary (cortisol-secreting adrenal tumor), secondary (adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, also called Cushing disease), or ectopic ACTH secretion (from a non-pituitary source). All three types share similar features [8].

Ectopic ACTH syndrome (EAS) is due to an extra pituitary tumor, producing ACTH. It accounts for 12-17% of Cushing’s syndrome cases [9]. Most cases of EAS-producing tumors are in the lungs, mediastinum, neuroendocrine tumors of the gastrointestinal tract, and pheochromocytomas [9]. Ectopic ACTH secretion from an ONB is very rare. As of 2015, only 18 cases were reported in the literature [10]. Here, we report such a case.

Case Presentation

Our patient is a 47-year-old Bangladeshi male, with a history of recurrent ONB that was resected twice in the past (transsphenoidal resection in 2016 and 2019) with adjuvant radiotherapy, no chemotherapy was given. He also had diabetes mellitus type 1 (poorly controlled) and hypertension. He presented with bilateral lower limb weakness, anosmia, decreased oral intake, loss of taste for one week, and bilateral submandibular swelling that increased in size gradually over the past two years. There was no history of fever, cough, abdominal pain, or exposure to sick contacts. The patient reported past episodes of similar symptoms, but details are unclear. The patient’s family history is positive for diabetes mellitus type 1 in both parents. Lab tests in the emergency department showed hypokalemia and hyperglycemia as detailed in Table 1. He was admitted for further workup of the above complaints.

Test Patient Results Reference Range Unit Status
Hemoglobin 14.7 13-17 g/dL Normal
White blood cell (WBC) 17.9 4-10 10*9/L High
Neutrophils 15.89 2-7 10*9/L High
Lymphocytes 1.07 1-3 10*9/L Normal
Sodium 141 136-145 mmol/L Normal
Potassium 2.49 3.5-5.1 mmol/L Low (Panic)
Chloride 95 98-107 mmol/L Low
Glucose 6.52 4.11-5.89 mmol/L Elevated
C-reactive protein (CRP) 0.64 Less than 5 mg/L Normal
Erythrocyte sedimentation rate (ESR) 2 0-30 mm/h Normal
Creatinine 73 62-106 µmol/L Normal
Uric acid 197 202.3-416.5 µmol/L Normal
Alanine aminotransferase (ALT) 33.2 0-41 U/L Normal
Aspartate aminotransferase (AST) 18.6 0-40 U/L Normal
International Normalised Ratio (INR) 1.21 0.8-1.2 sec High
Prothrombin time (PT) 15.7 12.3-14.7 sec High
Lactate dehydrogenase (LDH) 491 135-225 U/L High
Thyroid-stimulating hormone (TSH) 0.222 0.27-4.20 mIU/L Low
Adrenocorticotropic hormone (ACTH) 106 ≤50 ng/L Elevated
Cortisol (after dexamethasone suppression) 1750 Morning hours (6-10 am): 172-497 nmol, Afternoon hours (4-8 pm): 74.1-286 nmol nmol/L Elevated (failure of suppression)
24-hour urine cortisol (after dexamethasone suppression) 5959.1 <120 nmol/24 hrs nmol/24hr Elevated (failure of suppression)
Table 1: Results of blood test at the time of hospitalization. Hypokalemia and high values of adrenocorticotropic hormone and cortisol were confirmed.

On examination, the patient’s vital signs were as follows: blood pressure was 154/77 mmHg, heart rate of 60 beats per minute, respiratory rate was 18 breaths per minute, oxygen saturation of 98% on room air, and a temperature of 36.7°C. The patient had a typical Cushingoid appearance with a moon face, buffalo hump, purple striae on the abdomen, central obesity, and hyperpigmentation of the skin. Submandibular lymph nodes were enlarged bilaterally. The examination of the submandibular lymph nodes showed a firm, fixed mass extending from the angle of the mandible to the submental space on the left side. Neurological examination showed weakness in both legs bilaterally (strength 3/5) and anosmia (checked by orthonasal smell test). The rest of the neurological exam was normal.

Laboratory findings revealed (in Table 1) a marked hypokalemia of 2.49 mmol/L and hyperglycemia of 6.52 mmol/L. The serum cortisol level was elevated at 1587 nmol/L. Serum ACTH levels were raised at 106 ng/L (normal value ≤50 ng/L). Moreover, the high-dose dexamethasone suppression test failed to lower the serum ACTH levels and serum and urine cortisol. Serum cortisol level after the suppression test was 1750 nmol/L, while 24-hour urine cortisol after the test was 5959.1 nmol/24hr. Serum ACTH levels after the test also remained high at 100mg/L. This indicated failure of ACTH suppression by high-dose dexamethasone, which points towards ectopic ACTH production. Other blood tests (complete blood count, liver function tests) were insignificant.

A computed tomography scan with contrast (CT scan) of the chest, abdomen, and pelvis, with a special focus on the adrenals, was negative for any malignancy or masses. CT scan of the neck showed bilaterally enlarged submandibular lymph nodes and an enlarged right lobe of the thyroid with nodules. Fine needle aspiration (FNA) of the thyroid nodules revealed a benign nature. Magnetic resonance imaging (MRI) of the brain showed a contrast-enhancing soft tissue lesion (18x18x10mm) in the midline olfactory groove area with extension into the frontal dura and superior sagittal sinus, suggesting recurrence of the previous ONB. There was evidence of previous surgery also. The pituitary gland was normal (Figures 1–2).

A-brain-MRI-(T1-weighted;-without-contrast;-sagittal-plane)-shows-a-soft-tissue-lesion-located-in-the-midline-olfactory-groove-area.-Dural-surface-with-extension-into-anterior-frontal-dura.
Figure 1: A brain MRI (T1-weighted; without contrast; sagittal plane) shows a soft tissue lesion located in the midline olfactory groove area. Dural surface with extension into anterior frontal dura.

MRI: Magnetic resonance imaging

A-brain-MRI-(T2-weighted;-without-contrast;-axial-plane)-shows-a-soft-tissue-lesion-located-in-the-midline-olfactory-groove-area.
Figure 2: A brain MRI (T2-weighted; without contrast; axial plane) shows a soft tissue lesion located in the midline olfactory groove area.

MRI: Magnetic resonance imaging

Octreotide scintigraphy showed three focal abnormal uptakes in the submandibular cervical nodes. Additionally, there was a moderate abnormal uptake at the midline olfactory groove with bilateral extension (Figure 3).

Whole-body-octreotide-scan-(15-mCi-99mTc-Octreotide-IV)-demonstrates-three-focal-abnormal-uptakes:-the-largest-(5.2-x-2.4-cm)-in-the-left-submandibular-region,-and-two-smaller-ones-on-the-right,-suggestive-of-lymph-node-uptake.-Additional-abnormal-uptake-was-seen-along-the-midline-of-the-olfactory-groove-region-with-bilateral-extension.-No-other-significant-abnormal-uptake-was-identified.
Figure 3: Whole-body octreotide scan (15 mCi 99mTc-Octreotide IV) demonstrates three focal abnormal uptakes: the largest (5.2 x 2.4 cm) in the left submandibular region, and two smaller ones on the right, suggestive of lymph node uptake. Additional abnormal uptake was seen along the midline of the olfactory groove region with bilateral extension. No other significant abnormal uptake was identified.

On microscopic examination, an excisional biopsy after the transcranial resection surgery of the frontal skull base tumor showed nests and lobules of round to oval cells with clear cytoplasm, separated by vascular and hyalinized fibrous stroma (Figures 4A–4B). Tumor cells show mild to moderate nuclear pleomorphism, and fine chromatin (Figure 4C). A fibrillary neural matrix is also present. Some mitotic figures can be seen. Immunohistochemical stains revealed positive staining for synaptophysin (Figure 4D) and chromogranin (Figure 4E). Stains for CK (AE1/AE3), CD45, Desmin, and Myogenin are negative. Immunostaining for ACTH was focally positive (Figure 4F), while the specimen of the cervical lymph nodes showed the same staining, indicating metastases. The cytomorphologic and immunophenotypic features observed are consistent with a Hyams grade II ONB, with ectopic ACTH production.

Histopathological-and-immunohistochemical-findings-of-olfactory-neuroblastoma.
Figure 4: Histopathological and immunohistochemical findings of olfactory neuroblastoma.

A (100x magnification) and B (200x magnification) – hematoxylin and eosin (H-E) staining shows cellular nests of round blue cells separated by hyalinized stroma. C (400x magnification) – nuclei show mild to moderate pleomorphism with fine chromatin. D (100x magnification) – an immunohistochemical stain for synaptophysin shows diffuse, strong cytoplasmic positivity within tumor cells. E (200x magnification) – tumor cells are positive for chromogranin. F (400x magnification) – ACTH cytoplasmic expression in tumor cells.

ACTH: adrenocorticotropic hormone

For his resistant hypokalemia, he had to be given intravenous (IV) and oral potassium chloride (KCL) repeatedly. The patient underwent transcranial resection of the frontal skull base tumor. The patient received cefazolin for seven days, and hydrocortisone for four days. After transcranial resection, his cortisol level decreased to 700 nmol/L. Furthermore, ACTH dropped, and serum potassium also normalized. Subsequently, the patient was transferred to the intensive care unit (ICU) for meticulous monitoring and continued care. In the ICU, the patient developed one episode of a generalized tonic-clonic seizure, which aborted spontaneously, and the patient received phenytoin and levetiracetam to prevent other episodes. A right-sided internal jugular vein and left transverse sinus thrombosis were also developed and treated with enoxaparin sodium. Following surgery, his low potassium levels improved, resulting in an improvement in his limb weakness. His other symptoms also gradually improved after surgery. Three weeks following the primary tumor resection, he underwent bilateral neck dissection with right hemithyroidectomy, for removal of the metastases. The patient opted out of chemotherapy and planned for an international transfer to his home country for further management. Other treatments that he received during hospitalization were ceftriaxone, azithromycin, and Augmentin®. Insulin was used to manage his diabetes, perindopril to regulate his blood pressure, and spironolactone to increase potassium retention. Omeprazole was administered to prevent GI bleeding and heartburn/gastroesophageal reflux disease relief after discharge.

Discussion

ONB was first described in 1924, and it is a rare neuroectodermal tumor that accounts for 2% of tumors affecting the nasal cavity [11]. Even though ONB has a good survival rate, long-term follow-up is necessary due to the disease’s high recurrence rate [2]. ONB recurrence has been approximated to range between 30% and 60% after successful treatment of the primary tumor [12]. Recurrent disease is usually locoregional and tends to have a long interval to relapse with a mean of six years [12]. The first reported case of ectopic ACTH syndrome caused by ONB was in 1987 by M Reznik et al., who reported a 48-year-old woman with ONB who developed a Cushing-like syndrome 28 months before her death [13].

The occurrence of Cushing’s syndrome due to ectopic ACTH can occur either in the initial tumor or even years later during its course or after recurrence [3,6,9,14]. Similar to the case of Abe et al. [3], our patient also presented with muscle weakness due to hypokalemia, which is a feature of Cushing’s syndrome. Hypokalemia is present at diagnosis in 64% to 86% of cases of EAS and is resistant to treatment [9,14], as seen in our case. In our patient, the exact time of development of Cushing’s syndrome could not be ascertained due to the non-availability of previous records. However, according to the patient, he started developing abdominal obesity, pigmentation, and buffalo hump in 2021 about two years after his second surgery for ONB.

The distinction between pituitary ACTH and ectopic ACTH involves utilizing CT/MRI of the pituitary, corticotropin-releasing hormone (CRH) stimulation test with petrosal sinus blood sampling, high dose dexamethasone suppression test, and checking serum K+ (more commonly low in ectopic ACTH) [2,15,16]. In our case, a CRH stimulation test was not available but CT/MRI brain, dexamethasone test, low serum potassium, plus the postoperative fall in cortisol levels, all pointed towards an ectopic ACTH source.

Conclusions

In conclusion, this case highlights the rare association between ONB and ectopic ACTH syndrome, which developed after tumor recurrence. The patient’s unique presentation of bilateral lower limb weakness and hypokalemia can cause diagnostic challenges, emphasizing the need for comprehensive diagnostic measures. Surgical intervention proved crucial, with postoperative cortisol values becoming normal, highlighting the efficacy of this approach. The occurrence of ectopic ACTH production in ONB patients, although very rare, is emphasized, so that healthcare professionals who deal with these tumors are aware of this complication. This report contributes valuable insights shedding light on the unique ONB manifestation causing ectopic ACTH syndrome. The ongoing monitoring of the patient’s clinical features will further enrich the understanding of the course of this uncommon phenomenon in the medical literature.

References

  1. Thompson LD: Olfactory neuroblastoma. Head Neck Pathol. 2009, 3:252-9. 10.1007/s12105-009-0125-2
  2. Abdelmeguid AS: Olfactory neuroblastoma. Curr Oncol Rep. 2018, 20:7. 10.1007/s11912-018-0661-6
  3. Abe H, Suwanai H, Kambara N, et al.: A rare case of ectopic adrenocorticotropic hormone syndrome with recurrent olfactory neuroblastoma. Intern Med. 2021, 60:105-9. 10.2169/internalmedicine.2897-19
  4. Yin Z, Wang Y, Wu Y, et al.: Age distribution and age-related outcomes of olfactory neuroblastoma: a population-based analysis. Cancer Manag Res. 2018, 10:1359-64. 10.2147/CMAR.S151945
  5. Platek ME, Merzianu M, Mashtare TL, Popat SR, Rigual NR, Warren GW, Singh AK: Improved survival following surgery and radiation therapy for olfactory neuroblastoma: analysis of the SEER database. Radiat Oncol. 2011, 6:41. 10.1186/1748-717X-6-41
  6. Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC: Esthesioneuroblastoma. Cancer. 1979, 44:3-1087. 10.1002/1097-0142(197909)44:3<1087::aid-cncr2820440343>3.0.co;2-a
  7. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  8. Chabre O: Cushing syndrome: physiopathology, etiology and principles of therapy [Article in French]. Presse Med. 2014, 43:376-92. 10.1016/j.lpm.2014.02.001
  9. Isidori AM, Lenzi A: Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007, 51:1217-25. 10.1590/s0004-27302007000800007
  10. Kunc M, Gabrych A, Czapiewski P, Sworczak K: Paraneoplastic syndromes in olfactory neuroblastoma. Contemp Oncol (Pozn). 2015, 19:6-16. 10.5114/wo.2015.46283
  11. Finlay JB, Abi Hachem R, Jang DW, Osazuwa-Peters N, Goldstein BJ: Deconstructing olfactory epithelium developmental pathways in olfactory neuroblastoma. Cancer Res Commun. 2023, 3:980-90. 10.1158/2767-9764.CRC-23-0013
  12. Ni G, Pinheiro-Neto CD, Iyoha E, et al.: Recurrent esthesioneuroblastoma: long-term outcomes of salvage therapy. Cancers (Basel). 2023, 15:1506. 10.3390/cancers15051506
  13. Reznik M, Melon J, Lambricht M, Kaschten B, Beckers A: Neuroendocrine tumor of the nasal cavity (esthesioneuroblastoma). Apropos of a case with paraneoplastic Cushing’s syndrome [Article in French]. Ann Pathol. 1987, 7:137-42.
  14. Kadoya M, Kurajoh M, Miyoshi A, et al.: Ectopic adrenocorticotropic hormone syndrome associated with olfactory neuroblastoma: acquirement of adrenocorticotropic hormone expression during disease course as shown by serial immunohistochemistry examinations. J Int Med Res. 2018, 46:4760-8. 10.1177/0300060517754026
  15. Clotman K, Twickler MTB, Dirinck E, et al.: An endocrine picture in disguise: a progressive olfactory neuroblastoma complicated with ectopic Cushing syndrome. AACE Clin Case Rep. 2017, 3:278-83. 10.4158/EP161729.CR
  16. Chung YS, Na M, Ku CR, Kim SH, Kim EH: Adrenocorticotropic hormone-secreting esthesioneuroblastoma with ectopic Cushing’s syndrome. Yonsei Med J. 2020, 61:257-61. 10.3349/ymj.2020.61.3.257

From https://www.cureus.com/articles/226080-olfactory-neuroblastoma-causing-cushings-syndrome-due-to-the-ectopic-adrenocorticotropic-hormone-acth-secretion-a-case-report?score_article=true#!/

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Cushing Syndrome due to a CRH- and ACTH-Secreting Silent Pheochromocytoma

Posted on February 26, 2024 by MaryO

Highlights

  • EAS should be considered in patients presenting with rapid progression of ACTH-dependent hypercortisolism causing severe clinical and metabolic abnormalities.
  • Ectopic ACTH secretion by a pheochromocytoma should be suspected in cases of ACTH-dependent Cushing syndrome in the presence of an adrenal mass.
  • If required, medical management with steroidogenesis inhibitors can be initiated at the time of EAS diagnosis to control clinical and metabolic derangements associated with severe hypercortisolemia
  • In patients with ACTH-dependent Cushing syndrome from an ectopic source, inhibiting steroidogenesis should be reserved for cases where the initial diagnosis is unclear or patients who are not suitable candidates for surgery.
  • Unilateral adrenalectomy is indicated in the management of ACTH/CRH-secreting pheochromocytomas and is typically curative.
  • Catecholamine blockade should be started prior to surgical removal of catecholamines-secreting pheochromocytomas.
  • A multidisciplinary approach is required to diagnose and manage this condition.

Abstract

Background/Objective

Ectopic co-secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in silent (i.e., noncatecholamine-secreting) pheochromocytoma is a rare cause of Cushing Syndrome (CS).

Case Report

A 57-year-old woman rapidly developed hypercortisolism, clinically manifesting as fatigue, muscle weakness, weight gain, and worsening hypertension, and biochemically characterized by hypokalemia and marked elevation of serum cortisol and plasma ACTH. This acute presentation suggested a diagnosis of ectopic ACTH syndrome (EAS). Imaging studies revealed a right adrenal mass that enhanced after administration of the radioisotope 68Ga-DOTATATE. Plasma metanephrines were normal in two separate measurements. The possibility of a silent pheochromocytoma was considered. After controlling her hypercortisolism with metyrapone and surgical preparation with alpha blockade, the patient underwent elective right adrenalectomy. Pathology revealed a pheochromocytoma that stained focally for ACTH and CRH. Postoperatively, cortisol levels normalized, the hypothalamic–pituitary–adrenal (HPA) axis was not suppressed, and clinical symptoms from hypercortisolism abated.

Discussion

Patients who exhibit a rapid progression of ACTH-dependent hypercortisolism should be screened for ectopic ACTH syndrome (EAS). The use of functional imaging radioisotopes (such as gallium DOTA-peptides), improves the detection of ACTH-secreting tumors. Preoperative treatment with steroidogenesis inhibitors helps control clinical and metabolic derangements associated with severe hypercortisolemia, while alpha blockade prevents the onset of an adrenergic crisis.

Conclusion

We present a rare case of EAS due to a silent pheochromocytoma that co-secreted ACTH and CRH. Pheochromocytoma should be considered in patients with EAS who have an adrenal mass even in the absence of excessive catecholamine secretion.

Key words

ectopic ACTH syndrome
Cushing Syndrome
non-catecholamine-secreting pheochromocytoma

Abbreviations

EAS

ectopic ACTH syndrome
CS

Cushing Syndrome
CRH

corticotropin-releasing hormone
ACTH

adrenocorticotropic hormone
DHEA-S

dehydroepiandrosterone sulfate
UFC

urine free cortisol
PRA

plasma renin activity

Introduction

Cushing Syndrome (CS) is rare, with an estimated incidence of 0.2-5.0 per million people per year, and prevalence of 39-79 per million (1). Ectopic ACTH Syndrome (EAS), a type of CS originating from extra-pituitary ACTH-secreting tumors, is uncommon. The prevalence of CS due to ACTH-secreting adrenal medullary lesions is not well established. However, EAS is observed in approximately 1.3% of all identified cases of pheochromocytoma (2). Recognizing EAS can be challenging due to its rarity, leading to delayed diagnosis.

Neuroendocrine neoplasms can produce CRH, which can lead to the secretion of ACTH by the pituitary. In certain cases, co-secretion of ACTH and CRH by an adrenal neoplasm has been observed. Only two published cases have provided definitive biochemical and immunohistochemical evidence of exclusive CRH secretion (3).

Case Report

A 57-year-old woman with a history of well-controlled hypertension sought care due to a two-month history of 60 lb weight gain, facial rounding, easy bruising, muscle weakness, lower extremity edema and acne. Her blood pressure control had worsened, and laboratory tests showed a markedly low serum potassium level of 1.8 mmol/L while taking hydrochlorothiazide. To manage her blood pressure, she was prescribed a calcium channel blocker, an angiotensin receptor blocker, and potassium supplements. However, her symptoms worsened, and she was referred to our emergency department. Blood pressure at presentation to our hospital was 176/86 mmHg. She had characteristic features of CS, including face rounding, supraclavicular fullness, dorsocervical fat accumulation, pedal edema, oral candidiasis, multiple forearm ecchymoses, and acneiform skin eruptions. No visible abdominal striae were present. She had no family history of pheochromocytoma, or multiple endocrine neoplasia type 2.

Serum cortisol level was 128 mcg/dL (normal range: 4.6-23.4) at 5 PM, with an ACTH level of 1055 pg/mL (normal range: 6-50); serum DHEA-S level was elevated at 445 mcg/dL (normal range: 8-188). Her 24-hour urine cortisol was at 12,566 mcg (normal range: 4.0-50.0). Plasma metanephrines were normal at <25 pg/mL (normal range: <57), and plasma normetanephrine was 44 (normal range: <148). A second plasma metanephrine measurement showed similar results. Serum aldosterone level and plasma renin activity were low at 2 ng/dL (normal range: 3-16) and 0.11 ng/mL/h (normal range: 0.25-5.82), respectively. Dopamine and methoxytyramine levels were not measured. An abdominal CT revealed a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with a mean Hounsfield Unit of 68 in the non-contrast phase, and an absolute percentage washout of 30% (Fig 1A). The left adrenal gland appeared hyperplastic (Fig 1B). An Octreoscan, which was the in-hospital available nuclear medicine imaging modality, confirmed a 5.1 cm adrenal mass that was mild to moderately avid, with diffuse bilateral thickening of the adrenal glands and no other focal radiotracer avidity. A pituitary MRI did not show an adenoma, and EAS was suspected. Further evaluation with 68Ga-DOTATATE PET/CT (Fig 2) performed after her admission demonstrated an avid right adrenal mass consistent with a somatostatin receptor-positive lesion. No other suspicious tracer uptake was detected. These findings were consistent with a neuroendocrine tumor, such as pheochromocytoma.

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Fig. 1. Preoperative abdominal computed tomography scan showing a 4.8 x 4.5 x 5 cm right heterogeneously enhancing adrenal mass with irregular borders (A) and a hyperplastic left adrenal gland (B).

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Fig 2. 68Ga-DOTATATE PET/CT showing an avid right adrenal mass.

To control her symptoms while undergoing workup, the patient received oral metyrapone 500 mg thrice daily and oral ketoconazole 200 mg twice daily. Ketoconazole was stopped due to an increase in transaminases. The dosage of metyrapone was increased to 500 mg four times daily and later decreased to alternating doses of 250 mg and 500 mg four times daily. Within 3 weeks of starting medical therapy, serum cortisol level normalized at 20 mcg/dL. The 24-hour UFC improved to 246.3 mcg/24h. She experienced gradual improvement in facial fullness, acne, and blood pressure control.

The possibility of a silent pheochromocytoma was considered, and a-adrenergic blockade with doxazosin 1 mg daily was started 1 month prior surgery. She underwent surgery after two months of metyrapone therapy. With an unclear diagnosis and a large, heterogeneous adrenal mass, the surgical team elected to perform open adrenalectomy for en bloc resection due to concerns for an adrenal malignancy. The tumor was well-demarcated and did not invade surrounding structures (Figure 3A). H&E-stained sections showed classic morphologic features of a pheochromocytoma (Figure 3B), with immunohistochemistry demonstrating strong immunoreactivity for synaptophysin and chromogranin, and negative SF- I and inhibin stains excluding an adrenal cortical lesion. The sections analyzed by QuPath (4) revealed that approximately 4% of ce11s were ACTH cells, often found in isolation, and had a clear, high signal-to-noise staining (Figure 3C). CRH cells were less prevalent, comprising about 2.4% of the total analyzed cells, and tended to cluster together (Figure 3D). These cells had more background staining, resulting in a lower signal- to-noise ratio.

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Figure 3. Gross and Histopathological analysis of the patient’s pheochromocytoma. (A) Image of the gross excised specimen. (B) H&E staining (200x final magnification) demonstrates prominent vascularity and cells with finely granular, eosinophilic cytoplasm and salt-and-pepper chromatin. (C) ACTH staining (200x final magnification) shows clear and isolated positive cells, representing about 4.0% of the section analyzed by QuPath. (D) CRH staining (200x final magnification) reveals tight clusters of positive cells, accounting for 2.4% of the total cells. Positive (human placenta and hypothalamus) and negative (thyroid gland) control tissues performed as expected (data not shown).

The patient’s postoperative recovery was uneventful, with a short course of hydrocortisone which was stopped 1 week after surgery after HPA axis evaluation showed normal results. After one month, hypercortisolism had resolved, as shown by a normal 24-hour UFC at 28 mcg.

Administration of dexamethasone at 11 PM resulted in suppression of morning cortisol to 0.8 and 0.6 mcg/dL 1 and 7 months after surgery, respectively. Her liver function tests normalized, and blood pressure was well-controlled with amlodipine 10 mg daily and losartan 100 mg daily. Genetic testing for pheochromocytoma predisposition syndromes is currently planned.

Discussion

EAS accounts for 10-20% of cases of ACTH-dependent CS (5). This condition can be caused by several neuroendocrine neoplasms that produce bioactive ACTH (6) In the literature, we have found 99 documented cases of EAS caused by a pheochromocytoma. Of these, 93% showed ACTH expression. Only two cases have been reported with dual staining of ACTH and CRH (7). Exclusive CRH production has only been reported in two cases (8:9). However, the true prevalence of CRH-producing pheochromocytomas might be underestimated, as most cases testing for CRH expression was not performed.

Although the clinical presentation of EAS may be highly variable, there is often a rapid onset of hypercortisolism accompanied by severe catabolic symptoms. The diagnostic process should focus on identifying the location of a potential neuroendocrine neoplasm responsible for the ACTH secretion. Sometimes the peripheral origin of ACTH must be confirmed by inferior petrosal sinus sampling (IPSS). In this case, given the clinical presentation consistent with EAS, negative pituitary MRI, and the presence of an adrenal mass that needed to be removed independently, IPSS was not performed.

Neuroendocrine neoplasms express somatostatin receptors on their surface, which allow functional imaging using [11 lln]-pentetreotide (Octreoscan). However, Octreoscan has a low sensitivity in detecting occult EAS. In cases where the tumor is in the abdomen and pelvis, Octreoscan has limited utility in locating the source of ACTH (10). This increased risk of false negatives is caused by physiological tracer uptake by the liver, spleen, urinary tract, bowel, and gallbladder. The use of Gallium-68 labeled somatostatin receptor ligands (PET/CT 68Ga-DOTATATE) is more effective in detecting somatostatin receptors (SSTR2) than [11lln]-pentetreotide due to its higher spatial resolution and affinity (11)_ This test was performed after discharge form the hospital to rule out the presence of a second, smaller neuroendocrine tumor that the Octreoscan might have missed. A new molecular imaging technique targeting CRH receptors (68Ga CRH PET/CT) has shown potential in identifying tumors expressing CRH, but its availability remains limited (12). In our patient’s case, both the Octreoscan and 68Ga- DOTATATE successfully identified the adrenal tumor as a potential ACTH/CRH secretion source.

According to relevant guidelines, presurgical adrenergic blockade is recommended for patients with biochemical evidence of catecholamine excess (13, 14). Conversely, silent pheochromocytomas can generally be operated without alpha blockade (15). Despite this, we opted to administer pre-operative alpha blockade as a precautionary measure for this patient.

Pathology examination confirmed the diagnosis of pheochromocytoma. ACTH and CRH staining demonstrated that clear and significant populations of two separate ACTH and CRH positive cells were present in the excised pheochromocytoma. ACTH/CRH cells were dispersed throughout various regions of the pheochromocytoma rather than being well-defined, separate histological entities. As a result, there is no indication that this resulted from collision tumors, but rather random mutation and expansion of tumor cells into ACTH or CRH secreting cells. These results have limitations, including variation in ACTH and CRH expressing regions due to tumor heterogeneity, nonspecific binding of polyclonal antibodies, and normal low-rate false negative/positive detection using QuPath.

Post-surgical normal HPA activity was likely due to the de-suppression of the HPA axis by medical therapy, but it may also be explained by chronic stimulation of corticotroph cells induced by ectopic CRH secretion.

The standard approach to managing EAS involves surgical intervention. However, surgery may not be a viable option in cases where the source of ACTH production is unknown. Medical therapy to reduce or block excess cortisol can be used in such circumstances.

Conclusions

In conclusion, a pheochromocytoma causing EAS should be considered even in the absence of elevated plasma metanephrines. These tumors may simultaneously express ACTH and CRH.CRH.

References

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Sources of support: None

Permission in the form of written consent from patient for use of actual test results was obtained.

Cushing in silent pheochromocytoma

Clinical Relevance

This case highlights the importance of considering ectopic ACTH secretion by a pheochromocytoma in patients presenting with rapid progression and considerable clinical hypercortisolism concomitant with an adrenal mass and elevated plasma ACTH. This represents an unusual manifestation of a specific subtype of ACTH/CRH-secreting pheochromocytoma that did not exhibit catecholamine secretion

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

∗

These 2 authors contributed equally to this work

From https://www.sciencedirect.com/science/article/pii/S2376060524000075

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Paediatric Cushing Syndrome: Prospective, Multisite, Observational Cohort Study

Posted on January 19, 2024 by MaryO

Summary

Background

Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management.

Methods

In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants’ clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment.

Findings

Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0–3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4–13·6] vs 13·0 years [10·5–15·3] for Cushing disease vs 13·4 years [11·0–13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19–2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60–2·56] for Cushing disease vs 2·22 [1·42–2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7–18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6–5·7]) or Cushing disease (3·9 [2·3–6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease.

Interpretation

This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition.

Funding

Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.

Introduction

Paediatric endogenous Cushing syndrome is a rare disorder accounting for 5–7% of all reported cases of endogenous Cushing syndrome.1, 2, 3 In children older than 5–7 years and adolescents, endogenous Cushing syndrome is most commonly caused by corticotroph pituitary neuroendocrine tumours (PitNETs) and is termed Cushing disease. By contrast, Cushing syndrome in children younger than 5 years is often associated with adrenal disorders and is termed adrenal-associated Cushing syndrome.4 Albeit rare, a third type termed ectopic Cushing syndrome is caused by neuroendocrine tumours outside the hypothalamic–pituitary axis that secrete adrenocorticotropin or corticotropin-releasing hormone.5, 6 Thus endogenous Cushing syndrome is caused by either adrenocorticotropin-dependent sources (pituitary or ectopic) or adrenocorticotropin-independent (adrenal) hypercortisolemia.

Patients with adults-onset Cushing syndrome typically present with weight gain, skin manifestations (striae, hirsutism, acne, and easy bruising), and abnormal fat deposition.7, 8, 9 Paediatric Cushing syndrome differs from adult-onset Cushing syndrome in aspects including effects on growth (weight gain with concomitant height deceleration), atypical physical presentation (such as lack of centripetal obesity or typical striae), delayed or suppressed puberty, and variable mental health problems and neurocognitive function deficits.10 Diagnosis of paediatric Cushing syndrome is therefore challenging, and delayed evaluation is common.

Research in context

Evidence before this study

Endogenous Cushing syndrome is a rare endocrine condition. Diagnosis can be challenging and delay treatment. We searched PubMed for articles published in English on paediatric Cushing syndrome using terms “Cushing” AND “children” from database inception to May 5, 2023. Although several case series of paediatric Cushing disease were identified, only a few studies of the various causes of paediatric endogenous Cushing syndrome were available.

Added value of this study

To our knowledge, this cohort of paediatric endogenous Cushing syndrome of various causes is one of the largest sources of cumulative clinical, anthropometric, and biochemical data on the presentation, diagnosis, and management. We confirm that baseline biochemical data cannot aid differential diagnosis of Cushing syndrome subtypes. However, evidence suggests that minimally invasive stimulation tests could be a safe alternative to interventional sampling procedures such as inferior petrosal sinus sampling. We provide the prevalence of complications related to Cushing syndrome. Long-term outcomes of paediatric patients with pituitary corticotroph tumours recurrence is possible up to 8 years after initial remission.

Implications of all the available evidence

Data from this large paediatric cohort inform the evaluation, diagnosis, and long-term care of patients with paediatric Cushing syndrome. We recommend an algorithm for the diagnosis of patients and screening of complications. Screening for recurrence in patients with Cushing disease is indicated for this age group, at least for the first decade after surgery.

We have evaluated a large cohort of children and adolescents with endogenous Cushing syndrome of various causes. The aim of the study was to document anthropometric, clinical, and biochemical characteristics, complications, and outcomes of paediatric endogenous Cushing syndrome to aid clinicians in the diagnosis and management of these patients.

Section snippets

Study design and participants

In this prospective, multisite cohort study, we screened participants who, from 1995 to 2023, had enrolled in studies under protocols 97-CH-0076 (clinicaltrials.gov, NCT00001595), 95-CH-0059 (NCT00001452), and 00-CH-0160 (NCT00005927) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, Bethesda, MD, USA). Paediatric patients (18 years or younger at time of presentation) with a diagnosis of Cushing syndrome were eligible for inclusion in the study. We

Results

342 patients with paediatric Cushing syndrome were included in the study (table 1). 278 patients were referred from centres in the USA, and 64 patients were referred from centres outside of the USA. 261 (76%) patients were diagnosed with Cushing disease, 74 (22%) patients were diagnosed with adrenal-associated Cushing syndrome, and seven (2%) patients were diagnosed with ectopic Cushing syndrome. Patients with adrenal-associated Cushing syndrome were diagnosed at a younger age than patients

Discussion

We present extensive and unique data on presentation, diagnosis, and follow-up of paediatric patients with three diagnostic types of endogenous Cushing syndrome. Clinical and anthropometric characteristics were similar across subtypes of Cushing syndrome, but biochemical tests differed. We also present extensive information on complications; hypertension, insulin resistance, dyslipidaemia, and elevated ALT were common. Long-term follow-up of patients revealed excellent postoperative prognosis,

Data sharing

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of interests

CAS holds patents on the function of the PRKAR1A, PDE11A, and GPR101 genes and related issues; his laboratory had received research funding on GPR101, and on abnormal growth hormone secretion and its treatment by Pfizer. CAS receives support from ELPEN and has been consulting for Lundbeck Pharmaceuticals and Sync. CT reports receiving research funding on treatment of abnormal growth hormone secretion by Pfizer.

References (38)

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Cushing’s Syndrome Presenting as Non-Atherosclerotic Myocardial Infarction and Heart Failure

Posted on November 6, 2023 by MaryO

Abstract

Cushing’s syndrome is a rare cause of myocardial infarction and heart failure. Herein, we report a female patient who presented acute myocardial infarction and heart failure with reduced ejection fraction. The patient was found to have hypercortisolism secondary to adrenocortical adenoma and responded well to therapy. This case underlines the effects of hypercortisolism on the cardiovascular system. The clinical presentation of this patient is unique because non-atherosclerotic myocardial infarction is rarely reported in Cushing’s syndrome patients.

Introduction

Cushing’s syndrome is an endocrine condition associated with excessive secretion of cortisol. Hypertension, vascular atherosclerosis, and chronic cardiac remodelling and dysfunction are commonly recognized cardiovascular complications in Cushing’s syndrome patients.1 Herein, we report a rare case of Cushing’s syndrome patient with a primary diagnosis of non-atherosclerotic myocardial infarction and heart failure (HF).

Case Report

A 61-year-old female with a past medical history of chronic obstructive pulmonary disease was admitted with sudden onset chest pain on 6 February 2018. Electrocardiogram showed ST-segment elevation in leads V3–V5. Blood biochemical results of 1 h after the onset of chest pain: cardiac troponin I (cTnI) 0.06 ug/L↑, creatine kinase (CK) 63 U/L, creatine phosphokinase-MB (CK-MB) 22 U/L, aspartate transferase (AST) 19 U/L, and lactic dehydrogenase (LDH) 482 U/L. Myocardial injury markers were markedly elevated at the time point of 18 h after onset: cTnI 13.9 ug/L↑, CK 613 U/L↑, CK-MB 102 U/L↑, AST 112 U/L↑, and LDH 833 U/L↑. Due to the acute ECG changes and elevated myocardial injury markers, the patient was preliminarily diagnosed as ST-segment elevation myocardial infarction (STEMI) and underwent coronary angiography, which showed no stenosis, occlusion or dissection of coronary arteries (Figure 1). Echocardiography showed enlarged left atrial dimension (LAD, 55 mm) and left ventricular end diastolic dimension (LVDd, 57 mm), and reduced ejection fraction (EF, 33%). The patient was treated for STEMI and HF, and was started on aspirin, statin, diuretic of furosemide and spirolactone, metoprolol, and Sacubitril/valsartan (SV, initiated June, 2020). The patient was strictly adherent to the medication prescribed (Table 1).

Details are in the caption following the image

Coronary angiogram demonstrating no significant obstruction in coronary artery circulation.
Table 1. Echocardiography results
2020-06-22 2020-09-02 2021-03-29 2021-06-02 2021-09-01 2021-10-22 2021-12-21
LAD (mm) 55 55 46 52 47 44 41
LVDd (mm) 57 57 53 55 54 51 55
IVS (mm) 10 10 11 10 10 10 11
LVPW (mm) 11 11 11 10 11 9 10
EF (%) 33 30 31 39 47 49 52.5
  • EF, ejection fraction; IVS, interventricular septum; LAD, left atrium dimension; LVDd, left ventricular end diastolic dimension; LVPW, left ventricular posterior wall.

However, the patient’s condition was not improved despite optimized medication. On 26 January 2021, the patient was re-admitted with recurrent chest distress and oedema, with new symptoms of facial plethora, centripetal obesity, and hyperglycaemia (Figure S1). Abdominal CT scan showed a right adrenal adenoma (Figure 2). Cardiac magnetic resonance imaging revealed enlarged LVDd (62 mm), and reduced EF, with delayed myocardial enhancement and evidence of myocardial fibrosis and fatty deposits (Figure 3). Laboratory findings showed hypokalaemia: potassium 3.0 mmol/L, elevated serum cortisol level, low plasma ACTH level, and positive 1-mg overnight dexamethasone suppression test. Based on the above findings, the patient was diagnosed with Cushing’s syndrome and started treatment with the glucocorticoid receptor inhibitor mifepristone on 5 February 2021.

Details are in the caption following the image

Abdominal CT scan showed adrenal adenoma at the right.

Details are in the caption following the image

Cardiac magnetic resonance imaging revealed enlarged LVDd, reduced EF, with delayed myocardial enhancement, evidence of myocardial fibrosis and fatty deposits.

With mifepristone added to the previous medical therapy (aspirin, statin, sacubitril/valsartan, metoprolol and diuretic of furosemide and spirolactone, and mifepristone), the patient’s condition and cardiac function improved, and echocardiography (21 December 2021) showed increased EF (52.5%). The patient underwent partial adrenalectomy on 22 December 2021. Postoperative pathology confirmed adrenal cortical adenoma. At last follow-up on 29 May 2023, the patient showed marked improvement in face and body shape, with no complaints of chest distress or oedema (Figure S2).

Discussion

In this case, the patient was first evaluated for STEMI due to her symptoms of chest pain, and the elevated ST-segment on ECG, along with the moderately elevated troponin I and other cardiac enzyme levels. However, coronary atherosclerotic heart disease was ruled out by the normal cardiac catheterization. We presume that a possible reason for acute myocardial infarction (AMI) might be vasospastic angina due to abnormal hormone levels with Cushing’s syndrome, leading to increased excessive myocardial metabolic demand and relative myocardial hypoxia, which eventually induced myocardial infarction. Although coronary atherosclerotic heart disease is the main cause of AMI, many non-atherosclerotic processes can lead to an imbalance between decreased coronary blood flow and increased myocardial metabolic demand. To date, non-atherosclerotic myocardial infarction has rarely been reported in Cushing’s syndrome patients. Vieira JT et al. reported that a patient with Cushing’s disease was considered to have spontaneous coronary artery dissection, which is a rare reason for AMI.2

Cushing’s syndrome is associated with an increased risk of cardiac failure,3 with both structural alterations and functional impairment. In our case, the patient’s CMR imaging showed typical features of cardiac geometry, function, and fibrosis, in accordance with previous reports.4 The underlying mechanisms may be the enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in direct response to cortisol excess.5

Our patient responded well to the therapy of conventional anti-HF medication of sacubitril/valsartan, metoprolol, and diuretic, once mifepristone was added. This favourable response to the pharmacological regimen supports the benefits of the agents for the normalization of excess cortisol. This case indicates that early diagnosis and effective treatment of Cushing’s syndrome may be crucial in preventing irreversible cardiac dysfunction secondary to cardiovascular events and heart failure.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81900409 and 82172182) and the PLA Youth Training Project for Medical Science (19QNP037).

Conflict of interest

The authors declares that there is no conflict of interest.

From https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14548

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A Patient With a Bronchial Carcinoid Presents With Cushingoid Symptoms Due To An Atypical and Potentially Dangerous Supplement

Posted on October 11, 2023 by MaryO

Highlights

•

The most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer; however it is a relatively uncommon complication of pulmonary neoplasms.

•

The most common cause of Cushing syndrome is iatrogenic corticosteroid use and it should be considered in all patients regardless of clinical background.

•

Low urine cortisol levels may be associated with exogenous glucocorticoid exposure.

•

Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography.

•

Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

Abstract

Background

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background.

Case report

A 59 year old woman with an 11 year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Laboratory results were not consistent with an ACTH dependent Cushing Syndrome and exogenous steroids were suspected. The patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain.

Discussion

Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing.

Conclusion

Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing.

1. Introduction

Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and can rarely exhibit Cushing syndrome due to ectopic production of adrenocorticotropic hormone (ACTH). However the most common cause of Cushing syndrome is iatrogenic corticosteroid use and should be considered in all patients regardless of clinical background (see Fig. 1, Fig. 2, Fig. 3, Fig. 4).

Fig. 1

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Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake.

Fig. 2

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Fig. 2. DOTATATE PET/CT demonstrates intense uptake within a right upper lobe pulmonary nodule, consistent with biopsy-proven carcinoid tumor. There are no distant sites of abnormal uptake to suggest metastatic disease.

Fig. 3

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Fig. 3. Artri Ajo King Supplement (Source: FDA). The label claims that the product contains glucosamine, chondroitin, collagen, vitamin C, curcumin, nettle, omega 3, and methylsulfonylmethane.

Fig. 4

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Fig. 4. Artri King Supplement (Source: FDA).

2. Case report

A 59–year old woman with an 11 year history of a 1.5 cm well-differentiated bronchial carcinoid, presented with 20 lb. weight gain, facial swelling, flushing, lower extremity edema and shortness of breath over 3 months. On exam, the patient was normotensive, centrally obese with mild hirsutism, facial fullness and ruddiness with evidence of a dorsocervical fat pad. Initially there was concern for hormonal activation of her known bronchial carcinoid. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n < 15 mg/dL), elevated chromogranin A (201 ng/mL, n < 103 ng/mL), normal histamine (<1.5 ng/mL, n < 1.7 ng mL), low-normal 7 AM serum cortisol (5.1 μg/dL, n 3.6–19.3 μg/dL), normal 7 AM ACTH (17 pg/mL, n < 46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0–50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4–16.8 mcg/dL). Testosterone, IGF-1, glucose and electrolytes were appropriate. An echocardiogram showed an ejection fraction of 60% with no evidence of carcinoid heart disease. A Dotatate PET-CT was obtained to evaluate for progression of the neuro-endocrine tumor and revealed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Given low cortisol levels, ectopic Cushing syndrome was excluded and exogenous steroids were suspected, however the patient denied use of oral,inhaled, or injected steroids. A cosyntropin stimulation study yielded a pre-stimulation cortisol 6.2 μg/dL with an adequate post-stimulation cortisol 23.5 μg/dL. At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King Glucosamine supplements not listed on the product label but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and even death associated with such products. The patient’s symptoms gradually improved after discontinuation of the supplement.

3. Discussion

3.1. Ectopic ACTH syndrome

This patient’s Cushingoid features were initially suspected to be secondary to the known bronchial neuroendocrine tumor. Ectopic ACTH production accounts for about 5–10% of all Cushing Syndrome cases [1]. The most common location of ectopic ACTH is the lungs with pulmonary carcinoid tumors being the most common cause, followed by squamous cell lung cancer [2]. Despite this patient’s history of bronchial carcinoid tumor and positive chromogranin histopathological marker, her laboratory results were not consistent with an ACTH dependent Cushing Syndrome. In fact, Cushing syndrome is a relatively uncommon neuroendocrine neoplasm complication. The prevalence of ectopic ACTH production in patients with lung tumors is rare, at less than 5% in squamous cell lung cancer and about 3% in patients with lung or pancreatic (non-MEN1) neuroendocrine tumors1.

Patients with ACTH dependent Cushing syndrome not suspected to originate from the pituitary, undergo further testing to evaluate for an ectopic ACTH secreting tumor. These tests include conventional imaging of the chest, abdomen and pelvis, as well as functional imaging such as octreotide scans, fluoride 18-fluorodeoxyglucose-positron emission tomography [18F-FDG PET], and gallium-68 DOTATATE positron emission tomography-computed tomography [Dotatate PET-CT] scan [3]. In our literature review, we found that there was insufficient evidence to determine the sensitivity and specificity of nuclear medicine imaging techniques [4,5]. In this case, the patient had no laboratory evidence for ACTH dependent Cushing Syndrome, but given the known bronchial carcinoid tumor, a repeat Dotatate PET-CT scan was obtained which demonstrated no indication of growth or spread of the known bronchial tumor.

3.2. Supplement induced Cushing Syndrome

One of the most remarkable findings in this case was the patient’s low urine cortisol level in the setting of her overt Cushingoid features. In our survey of the literature, we found that low urine cortisol levels were associated with exogenous glucocorticoid use [6,7]. The low urine cortisol levels may be reflective of intermittent glucocorticoid exposure. Indeed, this patient’s Cushingoid features were determined to be secondary to prolonged use of Artri King supplement.

Occult glucocorticoid use is difficult to diagnose even after performing a thorough medication reconciliation as patients may unknowingly consume unregulated doses of glucocorticoids in seemingly harmless supplements and medications. The incidence of supplement induced Cushing Syndrome is currently unknown as supplements are not regularly tested to detect hidden glucocorticoid doses. Additionally, the likelihood of developing supplement induced Cushing syndrome is dependent on dosage and duration of use.

In our literature review we found nine published articles describing supplement induced Cushing Syndrome [[7], [8], [9], [10], [11], [12], [13], [14], [15]], one case report of tainted counterfeit medication causing Cushing Syndrome [16], and two cases of substances with probable glucocorticoid-like activity [17,18]. Of the nine published articles of supplement induced Cushing Syndrome, six were associated with supplements marketed as arthritic joint pain relief products including ArtriKing, Maajun, and AtriVid [[7], [8], [9], [10], [11], [12]]. These products later received government issued warnings in Mexico, Malaysia, and Colombia respectively [[19], [20], [21]].

To our knowledge there have been four published reports of ArtiKing supplement induced Cushing Syndrome [[7], [8], [9], [10]]. The first documented cases were reported in 2021 in Vera Cruz, Mexico; since then the Mexican medical community reported seeing a disproportionate increase in cases of iatrogenic Cushing Syndrome due to these supplements [7]. There have also been three American published articles describing a total of 4 cases of ArtriKing supplement induced Cushing syndrome [[8], [9], [10]]. In January 2022 the FDA issued a warning about Atri Ajo King containing diclofenac, which was not listed in the product label [22]. In April 2022 the FDA expanded its warning, advising consumers to avoid all Artri and Ortiga products after the FDA found these products contained dexamethasone and diclofenac [23]. In October 2022 the FDA issued warning letters to Amazon, Walmart, and Latin Foods market for distributing Artri and Ortiga products [24].

Many supplements are not regulated by the government and may contain hidden ingredients such as glucocorticoids. In these cases further evaluation of suspected products [25], medications [16], and patient serum [26] and urine [6] utilizing techniques such as liquid chromatography may be used to confirm occult glucocorticoid exposure.

This case highlights the importance of educating patients to exercise caution when purchasing health products both online and abroad. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products.

4. Conclusion

Although the most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer, it is a relatively uncommon complication of pulmonary neoplasms.

Exogenous Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. This case report emphasizes the importance of teaching patients to be vigilant and appropriately research their health supplements.

Patient consent

Formal informed consent was obtained from the patient for publication of this case report.

Declaration of competing interest

The authors (Tomas Morales and Shanika Samarasinghe) of this case report declare that they have no financial conflicts of interest. Shanika Samrasinghe is an editorial member of the Journal of Clinical and Translational Endocrinology: Case Reports, and declares that she was not involved in the peer review and editorial decision making process for the publishing of this article.

References

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