bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenal Insufficiency Masquerading as Primary Hypothyroidism Following Immune Checkpoint Inhibitors Treatment
Authors: Salim Michael , Dawahir Wafa , Gilden Janice L , Havrylyan Andriy
Published: May 2021

Background: Immune checkpoint inhibitors (ICIs) are novel immunotherapy agents that have been used to treat multiple advanced cancer. Even though they confer potential clinical advantages by regulating immune reactions, they have been linked with serious immune-mediated adverse events. Here we present a case of a patient who was treated with ICIs, Nivolumab (programmed death-1 inhibitor) and Ipilimumab (cytotoxic T lymphocyte antigen-4 inhibitor), and subsequently developed two concurrent immune-related endocrine disorders. Clinical Case: An 83-year-old man with advanced renal cell carcinoma presented with generalized weakness. He had finished four cycles of immunotherapy with Nivolumab and Ipilimumab, and Ipilimumab was discontinued afterward. Two days after the fifth cycle of immunotherapy with Nivolumab, he developed worsening fatigue, nausea, and anorexia. He appeared mildly volume depleted with borderline hypotensive (104/63 mmHg). The rest of the physical exam was unremarkable. Initial tests showed elevated levels of TSH (13.15 uIU/mL, ref 0.45–5.33 uIU/L), reduced levels of free T4 (<0.25 ng/dL, ref 0.58–1.64 ng/dL), free T3 (1.72 pg/mL, ref 2.5–3.9 pg/mL), negative thyroglobulin antibody, and elevated levels of thyroid peroxidase antibody (429 IU/mL, ref <9 IU/mL), thus suggesting primary hypothyroidism. Serum levels of sodium and potassium were unremarkable (136 meQ/L, ref 136–145 mEq/L; 3.6 meQ/L, ref 3.5–5.1 meQ/L respectively). His baseline TSH was normal three months prior to arrival (1.31 uIU/mL) and suppressed one month prior to arrival (0.01 uIU/mL). Immune-related thyroiditis with immune checkpoint inhibitors was suspected. He was given levothyroxine and observed in the hospital. After two days of hospitalization, weakness had slightly improved. However, he still had persistent nausea. He also developed low blood pressure (90/47 mmHg) and mild hyponatremia (133 mEq/L) with a normal potassium level. Further investigation showed low cortisol (1.0 ug/dL, ref 5.0–21.0), low ACTH (13 pg/mL, ref 6–50 pg/mL), cortisol level at 30 and 60 minutes post-cosyntropin stimulation test of 10.8 ug/dL (ref 13.0–30.0 ug/dL) and 14.8 ug/dL (ref 14.0–36.0 ug/dL) respectively, and negative adrenal antibodies, suggesting of secondary adrenal insufficiency due to hypophysitis. The patient was started on hydrocortisone, and his symptoms improved afterward. Conclusion: This case report highlights the common pitfall of managing immune-related endocrine disorders of ICIs. Adrenal insufficiency may present with a broad range of nonspecific symptoms, which could be attributed to hypothyroidism, underlying illness, or medications. Although a rare adverse effect, it is prudent to recognize adrenal insufficiency superimposed on primary hypothyroidism. Introducing thyroxine before replacing glucocorticoids can lead to an adrenal crisis.
Adrenoleukodystrophy and Secondary Hyperaldosteronism; A Clinical Demonstration of the Zona Glomerulosa Persistence
Authors: Boily Pascale , van Rossum Nicole , Lefebvre Marco , St-Jean Matthieu
Published: May 2021

Adrenoleukodystrophy (ALD) is a peroxisomal disorder which leads to the accumulation of very long-chain fatty acids in all tissues. Age at onset of symptoms vary depending on the phenotype severity. It can present with progressive symptoms of neurological defects and/or primary adrenal insufficiency.

We report a case of 31 yo man diagnosed in childhood with ALD and treated with hydrocortisone and fludrocortisone who eventually developed resistant hypertension due to secondary hyperaldosteronism.

He was diagnosed with ALD at 9-year-old and have received an allogenic hematopoietic cell graft 4 years later. After transplantation, he developed a bronchiolitis obliterans which was treated with high dose of glucocorticoids for 3 years.

In 2014, at first evaluation with our team, he was on hydrocortisone 10mg/m2 and fludrocortisone 0.05 mg daily. Fludrocortisone was started at 14 yo for a clinical suspicion of mineralocorticoids deficiency. At that time, the patient was normokaliemic (3.8 mmol\L), his aldosterone was, 2 days apart, 245pmol/L lying down and 68 pmol/L (N 138 - 413) sitting, his renin activity was 0.11 ng/L/s (N 0.14 - 0.31) and no orthostatic hypotension was documented.

In July 2015, high blood pressure (BP) was noticed, and fludrocortisone was decreased at 0.05 mg every other day. However, his BP continued to increase progressively, thereby fludrocortisone was discontinued in June 2018. Thereafter, amlodipine 10 mg daily, hydrochlorothiazide 12.5 mg daily and terazosin 2 mg daily were progressively introduced. Even with those three anti-hypertensive drugs his BP wasn’t controlled (190/100 mmHg) and he also developed persistent hypokalemia (3.0 - 3.3 mmol/L). Furthermore, significant aortic atheromatosis was described on abdominal computed tomography. In that context, his serum aldosterone/renin ratio was measured. The aldosterone was 632 pmol/L (N < 350) and the renin mass was 93.4 ng/L (N 3 - 16). An assessment of renal arteries was done by doppler ultrasonography, which was compatible with a hemodynamically significant right renal artery stenotic lesion. The patient had never smoke, had no diabetes (HbA1c 5.1%) or dyslipidemia (LDL 2.02 mmol/L). Based on the diagnosis of secondary aldosteronism, spironolactone was introduced in June 2020. Spironolactone was titrated to 37.5 mg daily and BP significantly improved with values around 136/75 and potassium return in normal range (3.8 mmol/L).

This interesting case illustrates 1) the persistence of a functioning zona glomerulosa in some patient with ALD and the possible development of secondary hyperaldosteronism in response to renovascular disorder and 2) the particularly high burden of atherosclerosis in this young patient, without classic risk factor, raises questions on the effect of the metabolic defect of ALD itself on the development of atheromatosis.
An Case of Poems Syndrome With Primary Adrenal Insufficiency
Authors: Sillars Anne , Cleland Stephen , Tough Jillian
Published: May 2021

POEMS syndrome is rare multi-system disorder characterised by a paraneoplastic plasma cell disorder. The acronym POEMS stands for Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes. The underlying mechanisms are poorly understood, but chronic overproduction of pro-inflammatory cytokines have an integral role in the disorder. Diagnosis of POEMS is difficult owing to the variety of clinical manifestations. Mandatory diagnostic criteria are (a) one major criterion of either polyneuropathy or monoclonal gammopathy, in association with (b) one minor criterion including, but not limited to, organomegaly, endocrinopathy or skin changes. Endocrinopathies have been identified in 67–84% of patients with POEMS [1]. While hypogonadism and hypothyroidism are relatively common, primary adrenal failure is rarely reported. We present a 54-year-old woman who was found to have a raised hemoglobin, hematocrit and thrombocytosis on routine blood testing. She was concomitantly investigated for a rapidly-ascending, bilateral peripheral motor and sensory neuropathy. Diagnosis of POEMS was made and she underwent chemotherapy with Lenalidomide and high dose dexamethasone in 2015. Since then, she has not received endogenous glucocorticoids. She had an unplanned admission in April 2020 with a likely viral illness and was found to be glucocorticoid deplete. A 250-mcg short synacthen test demonstrated an inadequate response in cortisol, from 4.31 µg/dl to 6.13 µg/dl, with a raised adrenocorticotrophic hormone (ACTH) level of 66 mU/L. Adrenal antibodies were not detected. CT scan of the abdomen reported no adrenal gland abnormalities. The patient denied symptoms of mineralocorticoid deficiency, with no postural blood pressure (BP) drop - sitting BP 123/69 mmHg and standing BP 131/74 mmHg. Serum electrolytes were normal (renin and aldosterone levels are pending) and androgen screen was within normal limits. Thyroid stimulating hormone (TSH) was 8.07 mIU/L, free thyroxine (fT4) levels 0.93 ng/dL, and thyroid receptor and thyroid peroxidase antibodies were both negative. The patient is now established on Hydrocortisone therapy: 10mg (morning), 5mg (lunchtime). In summary, we present a 54-year-old woman with POEMS syndrome with subacute primary adrenal failure, characterised by glucocorticoid deficiency and ACTH excess. Although rare, it is important for all clinicians to be aware of POEMS syndrome as a potential diagnosis if the diagnostic criteria described above are filled, and for Endocrinologists to be aware that POEMS endocrinopathies can occur in any gland, including the adrenal glands.

1.Gandhi, G.Y., et al., Endocrinopathy in POEMS syndrome: the Mayo Clinic experience. Mayo Clin Proc, 2007. 82(7): p. 836–42.
Androgen Secreting Adenoma Co- Secreting Cortisol First Diagnosed During Pregnancy
Authors: Al Ghareeb Zahra , Alwosaibi Abdulaziz , Alobaidan Hoor
Published: May 2021

Background: Pure androgen secreting adenoma is rare (1) and rarer to have an adenoma that is co-secreting androgen and cortisol, and extremely rare to have it diagnosed during pregnancy. In female, an elevated serum testosterone level with normal adrenal androgens is usually regarded as ovary origin (2). Here we report an unusual case of pregnant woman with markedly elevated serum testosterone level and elevated cortisol that first presented during pregnancy. Clinical Case: A 32-year old lady who is 32 weeks pregnant, presented with signs and symptoms of Cushing and acute hirsutism developed and advanced during pregnancy. Clinically She had hypertension, gestational diabetes with sever hirsutism and virilization. Fasting total testosterone was high (52 nmoL/L n 0.2–2.9 nmoL/L), DHEAS (1.98 umol/L n 0.51–11 umol), 24 hours urine cortisol (1343 nmoL/24 hrs n 11.8–485 nmoL/24 hrs), ACTH (0.220 pmol/L n 1.6–13.9pmol/L). Adrenal MRI without contrast showed a large right adrenal mass of 6.5 x 6.2 x 5.3 cm, of heterogenous signal in all pulse sequences, with limited assessment due to the lack of IV contrast. During admission,the patient’s liver enzymes were gradually increasing which lead to the decision of an elective C-section at 34 weeks gestation followed by right robotic adrenalectomy after ruling out pheochromocytoma. The product was viable and healthy baby boy. The immediate post-op hormonal profile showed normalization of urinary cortisol and serum total testosterone level. Histopathology report confirmed an Adrenocortical adenoma. The patient was discharged on the 3rd day post-op on hydrocortisone replacement therapy. The hydrocortisone doses were gradually tapered down tell stopped. The course of follow up was uneventful, two years following the surgery, she got another pregnancy with no obvious complications.

Conclusion: Co- existing testosterone and cortisol secreting adrenocortical adenoma is a rare tumor, diagnosis and management during pregnancy is challenging, with surgical resection being the only possible definite management.

References: (1) L. Barzon, N. Sonino, F. Fallo, G. Palù, and M. Boscaro, “Prevalence and natural history of adrenal incidentalomas,” European Journal of Endocrinology, vol. 149, no. 4, pp. 273–285, 2003.(2) Zhou, Wb., Chen, N. & Li, Cj. A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman. BMC Endocr Disord19, 14 (2019). https://doi.org/10.1186/s12902-019-0342-y
Cushing Syndrome in Carney Complex: Unilateral or Bilateral Adrenalectomy?
Authors: Vitellius Géraldine , Donadille Bruno , Decoudier Bénédicte , Deguelte Sophie , Bertherat Jérôme , Delemer Brigitte
Published: May 2021

Carney Complex (CNC) is a rare multiple endocrine syndrome dueto PRKR1A germline mutations. Primary pigmented nodular adrenal disease (PPNAD), the most frequent manifestation of the disease is responsible for non-ACTH dependent Cushing syndrome and bilateral adrenalectomy is the recommended treatment. We had followed up a CNC family with mainly Cushing syndrome disease secondary to PPNAD for more than 40 years over 2 generations. Six members carry the disease and present a germline mutation of PRKR1A, 4 women and 2 men. One patient accidently died one year after surgery and the others 5 patients were regularly followed up. The index case, a 25 years woman, was diagnosed with Cushing syndrome in 1972 with hyperandrogenism, short stature and mild manifestations of hypercortisolism. Unilateral adrenalectomy was performed on the side of a nodular adrenal and pathology described PPNAD. Her sister was subsequently diagnosed and treated the same way. The 2 sisters did well, with pregnancies for both of them but different post surgery hormonal results. The index case had partial cortisol deficiency with persistent low cortisol level at 108 nmol/L. Her sister presented a moderate increase in cortisol in the evening or after dexamethasone at 306 nmol/L at last evaluation. The only events possibly associated to hypercortisolism in this patient were central overweight and three episodes of spontaneous pulmonary embolism and veinous thrombosis. Their 2 brothers were evaluated at 17 and 39 years while they developed cushing syndrome signs (round face, HTA, amyotrophy and fatigability). As CNC have been recognized at this time by Dr Carney, bilateral adrenalectomy was performed in one patient who died accidentally a few months later. His brother chose unilateral adrenalectomy on the side of the macronodular gland, recovered hypercortisolism signs and still needs adrenal substitution. The daughter of the index case demonstrated at 21 years old a mild Cushing syndrome and chose unilateral adrenalectomy like her mother. Symptoms resumed without any recurrence during 20 years follow up. The daughter of the patient II.2 was diagnosed earlier at seven years of age because she developed hyperandrogenism, central weight gain and growth arrest due to Cushing syndrome. Bilateral adrenalectomy was successfully performed and adrenal substitution was prescribed. Surprisingly, adrenal function seemed to recover 5 to 6 years post surgery and treatment was decreased then stopped. Adrenal CT scan did not show any residual gland but noriodocholesterol scintigraphy confirmed bilateral adrenal uptake. She is now mother of 2 and present a near normal cortisol circadian rythm without any treatment. Finally, we showed in this long-term study that unilateral adrenalectomy in PPNAD could be an option for the treatment of mild Cushing syndrome in adults. Recovery after bilateral adrenalectomy occurred in one patient.
Endocrinopathies Associated With High Dose Methadone
Authors: Farmer Charles C , Agarwal Monica
Published: May 2021

Introduction: The opioid epidemic is a public health crisis and clinicians should be aware of the many under-recognized endocrinopathies associated with opioids. Herein, we present a case that exemplifies the endocrine-related adverse effects of methadone therapy.

Clinical Case: A 43-year-old Caucasian female with chronic back pain with opioid dependence, high dose methadone use (195 mg daily), and diabetes presented with refractory hypoglycemia. She was diagnosed with ketone prone diabetes eight months prior. She had since been weaned off insulin and her most recent HbA1c was 4.2%. During this time, she had an intentional weight loss of 60 pounds. On examination, she had bilateral lower extremity pitting edema with scaly plaques on the extremities. Laboratory tests showed C-peptide of 0.8 (0.9–7.1 ng/mL), insulin level of < 2 (3–25 mcIntUnits/mL), proinsulin of 4.6 (<18.8 pMol/L) with concurrent glucose of 48 mg/dl. She failed the ACTH stimulation test with 60 minute cortisol of 16.8 mcg/dL and was started on prednisone for adrenal insufficiency (AI). The pituitary and adrenal were normal on imaging. Her albumin was 1.5 (3.7–5.5 gm/dL) and she had vitamin and micronutrient deficiencies including copper, zinc, thiamine, selenium, and vitamin A. The insulin antibody test, paraneoplastic panel, celiac panel, A1 antitrypsin test, EGD, and colonoscopy were all non-revealing. A liver biopsy showed glycogenic hepatopathy. She improved clinically after prednisone initiation and treatment of malnutrition. The hypoglycemia improved but did not resolve as she refused to reduce methadone dose.

Discussion: The proposed mechanism of opioid-induced AI is the inhibitory effect on the hypothalamic-pituitary-adrenal axis, similar to the effect on the gonadal axis which causes hypogonadism. The risk for hypoglycemia is increased in patients taking more than 40 mg of oral methadone per day, and although the mechanism remains unclear, it is independent of adrenal function. Our patient had adrenal insufficiency and hypoglycemia related to methadone, which was further complicated by malnutrition. The glycogenic hepatopathy is a benign reversible condition that is believed to be a consequence of fluctuation in glucose levels.

Conclusion: Given the life-threatening nature of adrenal crisis and the overlap in symptomatology with opiate overdose, clinicians should be prompt in evaluating for endocrinopathies in patients on chronic high dose opiates, and patients should be appropriately counseled on the potential consequences of methadone use.

References: 1.Flory, J. H., et al. (2016). Methadone use and the risk of hypoglycemia for inpatients with cancer pain. JPSM, 51(1), 79–87.2.Li, T. et al. (2020). Prevalence of Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids. JCEM, 105(10), dgaa499.
Giant Adrenal Pheochromocytoma Presenting With Stroke
Authors: Alsaud Arwa , Karuppasamy Gowri , Al-Owainati Buthaina , Al-Janahi Ibrahim
Published: May 2021

Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from the adrenal medulla or from paravertebral ganglia of the sympathetic chain(1). The tumours commonly produce one or more catecholamines: epinephrine, norepinephrine, and dopamine leading to a classic triad of presentation with pounding headache, profuse sweating, and palpitations occurs in spells; However, one in 10 patients may be completely asymptomatic and the diagnosis of PPGL is frequently missed(2).

Care Report: A 29 years old African female presented with one-month history of throbbing headache, palpitations, profuse sweating, and unintentional weight loss. Her previous medical history and family history was unremarkable. She was found to have accelerated hypertension and a small lacunar infarct and some suspected subarachnoid hemorrhage on MRI head but was clinically silent. Investigation for secondary causes of hypertension revealed high metanephrine in urine and her imaging showed giant adrenal mass suggestive of pheochromocytoma.

CT Abdomen of large left adrenal necrotic solid mass lesion with heterogenous enhancement of its solid components measuring 6.5 x 6.1 x 7 cm in maximum AP, TR and CC dimensions respectively.

She was scheduled for open resection and left adrenalectomy after approximatly10 day and was treated with high-sodium diet, alpha blockers, and beta blockers perioperatively. Histopathology examination revealed Pheochromocytoma measuring 8 x 7 x 5 cm with diffuse growth >10% of tumor volume with central necrosis; PASS =4, which has malignant potential. She recovered well post operatively and required no further antihypertensive therapy or hormonal replacement, follow up hormonal profile and imaging with Iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy were negative for remnants or metastasis,

further evaluation with gallium DOTATATE PET CT and molecular genetic testing was considered, but it was not available.

Conclusion: Pheochromocytoma is a rare cause of secondary hypertension with a variable clinical presentation. Episodes of tumoral catecholamine release, are thought to be responsible for the high prevalence of cardiovascular emergencies, such as myocardial infarction, heart failure, and stroke as a complication of hypertensive crisis. Timely diagnosis and treatment are crucial to prevent life-threatening complications.
Graves’ Disease Presenting as Adrenal Crisis in a Patient With Congenital Adrenal Hyperplasia
Authors: Ibraheem Hamad Mohammad Khair Ahmad , Karuppasamy Gowri , Abdalrubb Abeer , Baagar Khaled Ahmed
Published: May 2021

Background: Adrenal crisis (AC) is a life-threatening condition that occurs either as the initial presentation of adrenal insufficiency or in patients who are known to have hypoadrenalism, when a precipitating acute stressor outweighs the mineralocorticoid and glucocorticoid supply. It is known that exposure to high levels of thyroid hormones in the presence of hypoadrenalism may precipitate AC.Graves’ disease (GD), as a precipitant of AC in patients with congenital adrenal hyperplasia (CAH), has been rarely described in the literature. Clinical Case: A 15-year-old male with classic CAH diagnosed since birth when he had vomiting and darkly pigmented skin. He was on regular follow-up with his endocrinologist in his home country. For an unclear reason, he was on hydrocortisone 40 mg daily in divided doses. The patient presented to the emergency department with nausea, vomiting, loose stool, dizziness, and fatigue for 5 days. On examination, he was conscious and oriented but looked tired. He had a temperature of 36.8°C, blood pressure (supine) 132/78 mmHg (standing blood pressure could not be taken because the patient was dizzy), pulse rate 130/minute, and respiratory rate 17/minute. Otherwise, the physical exam was unremarkable. Initial laboratory investigations showed sodium 114 (136–145 mmol/L), potassium 6.0 (3.5–5.1 mmol/l), chloride 83 (102–104 mmol/L) and Bicarbonate 14 (22–29 mmol/L). Serum creatinine, complete blood count, C-reactive protein (CRP) and procalcitonin levels were within normal. He was treated for AC with stress doses of hydrocortisone intravenously, and normal saline intravenous infusion. He showed a gradual improvement of his symptoms with normalization of the electrolytes. Thus, he was switched to oral hydrocortisone replacement 15 mg am and 10 mg in the afternoon. Nevertheless, his pulse rate was 105 -110 / min. Therefore, thyroid function test (TFT) was done and revealed TSH 0.3 (0.5–4.3 mIU/L) and FT4 30.6 (12.9–20.6 pmol/L). Thyroid uptake scan showed a mildly enlarged thyroid gland with homogeneous and slightly increased radiotracer uptake suggestive of GD. Thus, propranolol and carbimazole were prescribed in addition to hydrocortisone. Then, the patient was discharged after proper education about precipitating factors of AC. Later on, the patient appeared for his clinic appointment, he was clinically well with normal vital signs, serum electrolytes, and TFT. Propranolol was stopped, carbimazole dose was adjusted, and he was maintained on hydrocortisone.

Conclusion: Unrecognized Graves’ disease was the precipitating factor of the adrenal crisis in this patient with CAH. Despite the rarity of the association, a high index of clinical suspicion for unusual acute stressors is very important for proper management of AC and to prevent future recurrence.
Hypertension and Hirsutism in a Young Female: A Rare Form of Congenital Adrenal Hyperplasia?
Authors: Polavarapu Preethi , Kotwal Anupam
Published: May 2021

Background: Rare forms of congenital adrenal hyperplasia (CAH) especially can be a diagnostic and management challenge. We present a case of hypertension and hirsutism with elevated mineralocorticoid and sex steroid precursors concerning for non-classic rare form of CAH.

Clinical Case: A 22 y/o female was evaluated in our endocrinology clinic for primary hypertension and hirsutism (modified Ferriman-Gallwey score of 12) but without menstrual irregularity, clitoromegaly or deepening of voice. Family history was significant for hypertension and hirsutism in her mother. Renal and pelvic ultrasonographies were normal. CT abdomen showed thickened bilateral adrenal glands. Case detection testing was positive with PAC/PRA of 19.4/0.4 however intravenous saline suppression test suppressed aldosterone to 5 ng/dL, hence ruled out primary aldosteronism. Cortisol suppressed to 0.6 mcg/dL after 1 mg overnight Dexamethasone, hence ruled out Cushing’s syndrome; prolactin and TSH were normal, serum HCG was undetectable. This prompted work up for other endocrine causes of hypertension and hirsutism which revealed follicular phase elevated dehydroepiandrosterone-sulfate of 772 mcg/dL (35–430), pregnenolone of 603 ng/dL (15–132), 17-hydroxypregnenolone of 1516 ng/dL (<226), 11-deoxycortisol of 39.4 ng/dL (<32); but normal 17-hydroxyprogesterone of 36.8 ng/dL (15–70), androstenedione of 1.12 ng/mL (0.26–2.14) and free testosterone of 26 ng/dL (9–44). 250-mcg ACTH administration stimulated cortisol to 24.6 mcg/dL, pregnenolone to 1478 ng/dL, 17-hydroxypregnenolone to 1716, 11-deoxycortisol to 64.2 ng/dL but 17-hydroxyprogesterone only stimulated to 59.9 ng/dL. We initiated spironolactone at 12.5 mg increased to 25 mg daily, which normalized her blood pressure. She was counseled regarding its teratogenicity but is she declined birth control, as she was not engaging in heterosexual intercourse. Urinary steroid analysis and genetic testing were pending.

Conclusions: Hypertension and hirsutism accompanied by elevated pregnenolone, 17-hydroxypregnenolone, 11-deoxycortisol and dehydroepiandrosterone-sulfate, however, normal baseline as well as stimulated 17-hydroxyprogesterone, raise concern for co-occurrence of partial 3-betahydroxysteroid dehydrogenase deficiency in addition to non-classic 11-betahydroxylase deficiency. Management with mineralocorticoid receptor antagonist helped control hypertension.
Large Invasive Adrenal Cortical Carcinoma in a Patient With Neurofibromatosis Type I
Authors: Sandoval Brenda G , Morales Maria Del Mar Felix , Wortham Joy , Koops Maureen , Granda-Rodriguez Ramona , Bruder Jan M
Published: May 2021

Background: Adrenal cortical carcinoma is a rare neoplasm. Adrenal cortical carcinoma has previously been reported in less than 10 cases of patients with Neurofibromatosis Type I. Clinical Case: A 44-year-old Hispanic man with Neurofibromatosis Type I (NF1) presented with progressive hypoxia, tachypnea and abdominal pain. Intubation was required with 100% FiO2. CT angiogram of the chest and abdomen showed a 9.5 cm left adrenal mass with tumor thrombus in the left adrenal vein, distal left renal vein, IVC extending into the right atrium, suggestive of an adrenocortical carcinoma. Café-au-spots, neurofibromas and Lisch nodules were seen on physical exam but no signs suggestive of a functional adrenal cortical carcinoma. Transthoracic echocardiogram demonstrated a large well circumscribed echo-dense mass filling the right atrial cavity. Hemodynamically he was unstable with labile blood pressures due to right atrium thrombus burden. He was supported pending pheochromocytoma investigation. Biochemical work up revealed an elevated 24-hour free cortisol concentration of 95.9 ug/d (<=60ug/d) with a normal 24-hour urine metanephrine and normetanephrine [140ug/d (55-320ug/d) and 448 ug/d (114-865ug/d]. Plasma free metanephrine level was normal 0.43 (0.00-0.49nmol/L) and the normetanephrine levels was increased at 2.7 (0.00-0.89nmol/L) consistent with stress response. Serum aldosterone level and renin activity with potassium and DHEA-S levels were normal. Once pheochromocytoma was ruled out, he successfully underwent a left nephrectomy, left adrenalectomy, IVC thrombectomy, right atrium thrombectomy under a multidisciplinary team of surgeons. Surgery was well tolerated and he was discharged home 11 days later. Pathology confirmed adrenal cortical carcinoma, stage 4, with involvement of endocardium and left renal vein with mitotic count greater than 20/50 high-power fields, consistent with a high-grade tumor. Summary: Patients with NF1 have a higher predilection to develop tumors including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumor. NF1 association with adrenal tumors is well known, most commonly pheochromocytomas which occur in 0.1–5.7% of patients with NF1. However, based on a literature search there have been less than 10 case reports which postulate an association between NF1 and ACC. Genetic analysis of these reported cases suggest a loss of heterozygosity at the NF1 locus as a possible explanation of development of ACC in patients with NF1. Conclusion: Adrenal cortical carcinoma is rare but should be considered in a patient with NF1 and adrenal mass when plasma/urine metanephrines are not suggestive of pheochromocytoma.
Nivolumab Induced Multiple Endocrinopathies; Adrenal Insufficiency and Primary Hypothyroidism in a Patient With Stage IV Gastric Cancer - A Case Report
Authors: Abdelmasih Randa , Abdelmaseih Ramy , Gandhi Rima , Faya Marines , Vesely Josef James Karl
Published: May 2021

Introduction: Nivolumab is a revolutionary immune check point inhibitor (ICI) that changed the world of oncology. It prevents interaction of Program Death Receptor-1 (PD-1) and Program Death Ligand-1 (PD-L1) releasing a cascade of anti-tumor response. However, it has been associated with wide range of autoimmune side effects including gastrointestinal, hepatic, and endocrine side effects. The incidence of nivolumab induced endocrinopathies is relatively rare but increasingly reported. Adrenal insufficiency occurring in <1% of patients, hyperthyroidism in 15.3% and subclinical hypothyroidism in 4.2%. Case Presentations: 81 year old male with stage IV stomach cancer treated with Nivolumab. Prior to immunotherapy initiation, a set of baseline hormones was obtained and was within normal range. 6 months after, routine monitoring showed elevated thyroid stimulating hormone 6.33 mU/L and low FT4 0.59 ng/dL and FT3 0.1 ng/dL. Patient was started on thyroid replacement therapy. After 1 year of Nivolumab therapy, he presented with dizziness and orthostatic hypotension. Laboratory testing was remarkable for low sodium 130 mEq/L, which raised concerns for adrenal insufficiency. Subsequently, ACTH stimulation test showed low cortisol level 15 mcg/dL. Morning cortisol was also low 1.3 mcg/dL. Other pituitary hormones were normal. Patient was started on hydrocortisone with subsequent improvement of symptoms. Discussion: Nivolumab is a human monoclonal antibody that blocks PD-1 and turns off the tumor mediated immune system inhibition. In the meanwhile, ICI also disrupt normal immune signaling mechanisms that lead to decrease immune tolerance and autoimmune diseases. The mechanism of thyroid dysfunction due to ICI remains unclear. PD-1/PD-L1 blockade could induce thyroiditis by diminishing regulatory T cells function. Disruption of interaction between PD-1-expressing lymphocytes and PD-L-expressing thyrocytes –which protects the thyroid gland from autoimmunity– leads to infiltration of the thyroid with autoreactive T and B lymphocytes. Nivolumab induced Adrenal insufficiency is an extremely rare and unclear event, currently, there is no clear evidence that pituitary cells express PD-1. Recently, it was found that the PD-L1 and PD-L2 are expressed in mouse anterior and intermediate pituitary gland, but not the posterior pituitary. This suggests the possibility that specific injury can take place affecting only certain anterior pituitary cells, such as those producing ACTH. Awareness of such endocrinopathies is crucial. Patients should have certain baseline of laboratory data prior to therapy initiation and over the course of treatment. The risk of endocrinopathies is greater at the start of treatment, justifying closer monitoring every visit over the first 6 months, followed by regular monitoring every second visit over the next 6 months and less frequently thereafter.
Persistent Fatigue After Pregnancy: A Case Report
Authors: Naha Sowjanya , Parimi Joseph Theressa Nehu , Gundluru Rajani , Liu John Chen , Syed Hasan , Gusov Timur
Published: May 2021

Background: Pregnancy is characterized by physiologic immunosuppression and the postpartum period is often associated with rebound autoimmunity leading to unmasking of latent autoimmune disorders. Clinical Case: A thirty-one-year-old Caucasian female presented with generalized fatigue, myalgias and arthralgias that started three months after the birth of her first child. She was seen at a local hospital on multiple occasions and was treated symptomatically. She was noted to have orthostatic hypotension during these visits and was initiated on midodrine and fludrocortisone for presumed postural orthostatic tachycardia syndrome. When her symptoms did not abate, she was referred to our center for further care. At the time that we saw her, she reported nausea and vomiting in addition to the aforementioned symptoms. On careful questioning she also admitted to salt craving and unintentional weight loss of about 20 lbs over the past three months. She did not have a past history of autoimmune or endocrine disorders, but family history was positive for Grave’s disease and celiac disease in her aunt and mother respectively. Physical examination revealed hyperpigmentation of the face, knuckles, toes and abdominal scars. Random serum cortisol level was low (1.06 mcg/dL) with no perceptible response to ACTH stimulation (1.10 mcg/dL and 1.04 mcg/dL at 30 and 60 mins respectively). Serum aldosterone was undetectable (<4 ng/dL) and dehydroepiandrosterone sulfate level was low (19 mcg/dL, n: 45–295 mcg/dL). The patient was immediately initiated on corticosteroid replacement therapy. Her symptoms rapidly resolved and she was discharged on maintenance dosing of hydrocortisone and fludrocortisone. ACTH was grossly elevated (577 pg/mL) and 21-Hydroxylase antibodies were positive, confirming a diagnosis of autoimmune adrenalitis. Conclusion: Symptoms of adrenal insufficiency are often non-specific and can overlap with physiological symptoms of pregnancy. Persistence of these symptoms after delivery should raise concerns for autoimmune adrenalitis precipitated by immune reconstitution in the postpartum period.
Pheochromocytoma as the Etiology of Cushing Syndrome Through Paracrine ACTH Signaling
Authors: Jaju Amruta , Williams Vanessa , Ali Mariam Murtaza , Rehman Anis , Imtiaz Sonaina , Jakoby Michael G
Published: May 2021

Introduction: Pheochromocytomas are rare catecholamine-secreting tumors of the adrenal medulla that may also secrete ACTH. There are approximately 100 cases of ACTH-producing pheochromocytomas reported in the peer reviewed literature, and they typically cause Cushing syndrome by significantly raising circulating ACTH levels. We report a pheochromocytoma causing apparent ACTH-independent Cushing syndrome by paracrine action of locally produced ACTH on ipsilateral adrenal cortex. Case: A 64-year-old female was referred for an incidentally discovered left adrenal mass. The mass was 4 cm and 37 Hounsfield units on non-contrast computed tomography, and the right adrenal gland was unremarkable. The patient’s history was notable for three years of resistant hypertension, and examination revealed stigmata of Cushing syndrome including moon facies, scattered bruises, and wide, pink striae. Three measurements of plasma metanephrines ranged from 3- to 4.5-fold elevated, and 24 h urine metanephrines were 5.2-fold elevated. Urine 24 h epinephrine was 2.7-fold elevated. Three 8 AM cortisol measurements on overnight dexamethasone suppression tests were 16.3–17.4 mcg/dL (< 1.8), and 8 AM dexamethasone on one test was 494 ng/dL (140–295). Two midnight salivary cortisol measurements were 0.348 and 0.416 mcg/dL (< 0.112), and 8 AM ACTH levels on two occasions were 6.8 and 7.9 pg/mL (7.2–63.3). After adrenergic blockade, the patient underwent left adrenalectomy. Her tumor stained for synaptophysin and chromogranin consistent with pheochromocytoma, and focal staining for ACTH was also observed. Hyperplasia of the adjacent adrenal cortex was present. Hypertension resolved after adrenalectomy, and the patient developed secondary adrenal insufficiency (8 AM cortisol and ACTH 1.0 mcg/dL [> 15] and 2.9 pg/mL, respectively). Discussion: There are five published reports of pheochromocytoma and subclinical hypercortisolemia due to paracrine ACTH or IL-6 activity on ipsilateral adrenal cortex, but this case is distinguished by the occurrence of overt Cushing syndrome. Our patient had ACTH < 10 pg/mL on two measurements, her pheochromocytoma showed focal staining for ACTH, and hyperplasia of adjacent adrenal cortex was observed. In contrast, median ACTH level was 5-6x above the upper limit of normal in a recent review of 95 cases of pheochromocytomas with Cushing syndrome due to ectopic ACTH secretion. If Cushing syndrome was due to bilateral adrenal hyperplasia independent of the patient’s pheochromocytoma, cortisol excess would not have resolved after unilateral adrenalectomy. Communication between cortical and medullary circulations through venous radicles provides a mechanism for ACTH produced by the patient’s pheochromocytoma to affect the function of adjacent cortex. This case demonstrates a novel mechanism by which ACTH from a pheochromocytoma can cause Cushing syndrome.
The Case of a Glucocorticoid-Induced Myopathy & Myasthenia Gravis Combination: Is There a Border?
Authors: Dzherieva Irina , Brovkina Snezhana , Volkova Natalia , Davidenko Ilia , Reshetnikov Igor , Yudin Maxim , Plyashkevich Maria , Merenkova Maria
Published: May 2021

Introduction: Glucocorticoid-induced myopathy is the sign of Cushing’s syndrome in 83%, but can also be consequence of exogenous administration of glucocorticoids. The patients with the compromised neuromuscular system (for example, because of myasthenia gravis) have a higher risk of this complication. Differential diagnosis of glucocorticoid-induced myopathy is challenging. Clinical case. A 77-year woman complained of difficulty in the act of breathing, swallowing, weakness in the limbs, inability to self-service, ptosis. Due to the growing complaints the patient was hospitalized to ICU. From anamnesis: She was diagnosed with myasthenia gravis 2 months ago. The presence of autoantibodies to the nicotine acetylcholine receptor was confirmed. Pyridostigmine bromide 60 mg/day, Methylprednisolone 20 mg/day were prescribed for 5 days. The patient noted some improvement. After the next neurologist’s examination the dose of Methylprednisolone was doubled. (It is not known for certain whether the doctor wanted to reduce the dose and the patient misunderstood.) She noted some worsening: weakness and speech difficulties increased. She returned to the previous dose after 3 days, but there was no improvement. Objectively: hypersthenic body type, BMI 39 kg/m2, predominant deposition of adipose tissue in the abdomen and face. Breathing without a ventilator. BP 250/100 mm Hg, heart rate 87 BPM. Laboratory tests revealed hyperkalemia of 8.76 mmol/l (3.5–5), creatinine of 481 mmol/l (44–124), hyperglycemia of 16 mmol/l. Glucocorticoid-induced myopathy was suspected, the administration of methylprednisolone was cancelled. The improvement of the condition was noted in 3 days. Blood pressure, glycaemia, levels of potassium and creatinine returned to normal. A biopsy of muscle revealed: atrophy of type I and II muscle fibers. There were no signs of necrosis, regeneration or inflammation. Thereby the diagnosis of glucocorticoid-induced myopathy was confirmed. Conclusion. Glucocorticoid-induced myopathy may look like a decompensation of neuromuscular disease. Since there are no accurate diagnostic tests nowadays the main argument of diagnosis is the paradoxical reaction after increasing the dose of glucocorticoids as well in this case. Even a short period of use of these drugs can lead to the development of side effects. It is necessary to regularly monitor the dynamics of the condition of such patients.
Type 4 Renal Tubular Acidosis (RTA) Induced by Spironolactone Use in Secondary Adrenal Insufficiency
Authors: Santos Claudia Villatoro , De Rose Lisa , Proudan Nikoletta
Published: May 2021

Type 4 RTA is caused by either decreased aldosterone production or resistance. Primary adrenal insufficiency results in decreased aldosterone whereas spironolactone can cause aldosterone resistance1. We present a case of spironolactone-induced type 4 RTA in a patient with suspected primary adrenal insufficiency.

A 70-year-old female with liver cirrhosis on spironolactone and chronic bronchitis on inhaled steroids (ICS) presented for altered mental status. Laboratories showed hyponatremia 131 mmol/L (135–145 mmol/L) and hyperammonemia 113 µmol/L (11–51 µmol/L). She was successfully treated with oral lactulose for hepatic encephalopathy. However, on day 3, she developed worsening hyponatremia (126 mmol/L) and hyperkalemia 5.8 mmol/L (3.5–5.4 mmol/L). Spironolactone was discontinued, and hyperkalemia improved after medical treatment. Nonetheless, hyperkalemia recurred with worsening hyponatremia (125 mmol/L), hypoglycemia (57 mg/dL), and mild non-anion gap metabolic acidosis without other signs or symptoms of adrenal insufficiency. On day 5, her morning cortisol was 1.5 µg/dL (5–20 µg/dL), with ACTH 11 pg/mL (6–70 pg/mL). Her hyperkalemia persisted (6.3–6.8 mmol/L), and she was started on oral patiromer. Due to suspected adrenal insufficiency, she received dexamethasone 10 mg daily, and endocrinology was consulted. On day 7, an ACTH stimulation test (250 µg IV) showed a baseline ACTH <3 pg/mL, baseline cortisol 0.7 µg/dL (3–15 µg/dL), cortisol 30 minutes 9.9 µg/dL, and 60 minutes 12.2 µg/dL, consistent with incomplete response attributed to the supraphysiologic dexamethasone versus chronic ICS. On day 8, endocrinology discontinued dexamethasone and enoxaparin, and started hydrocortisone 10 mg orally in AM and 5 mg in PM. Aldosterone (measured at day 6) was 7.2 ng/dL (<= 31.0 ng/dL), renin activity 3.1 ng/mL/hr (0.5–4.0 ng/mL/hr), and aldosterone/renin ratio 2.3 (<= 25) consistent with hyporeninemic hypoaldosteronism since aldosterone and renin were inappropriately normal for the hyperkalemia. Repeat cosyntropin test on day 11 showed low ACTH (3 pg/mL), low baseline cortisol 1.1 µg/dL, cortisol 30 minutes 7.9 µg/dL, and 60 minutes 11.2 µg/dL, consistent with secondary adrenal insufficiency, ascribed to chronic ICS. Potassium level normalized seven days after spironolactone discontinuation, related to its approximate duration of action1. The patient was discharged with hydrocortisone 10 mg daily, and spironolactone was permanently discontinued.

Spironolactone use can result in type 4 RTA due to aldosterone resistance and mimic mineralocorticoid deficits characteristic of primary adrenal insufficiency.

1. O’Connell JE, Colledge NR. Type IV renal tubular acidosis and spironolactone therapy in the elderly. Postgrad Med J. 1993;69(817):887–889.
Variations in the Initial Presentation of a Rare Congenital Adrenal Hyperplasia: Steroidogenic Acute Regulatory Deficiency
Authors: Saha Priyanka , Hodax Juanita , DiVall Sara A , Kim Grace , Huang Alyssa
Published: May 2021

Background: Steroidogenic Acute Regulatory (StAR) deficiency is a rare form of congenital adrenal hyperplasia characterized by dysregulated cholesterol transport mediated by StAR enzyme across mitochondrial membranes. Adrenal dysfunction is due to the two-hit hypothesis: 1) defective StAR protein and 2) cholesterol accumulation in the adrenals and gonads. With variable cellular damage, adrenal crisis can occur early or late. Clinical cases: We present two cases of StAR deficiency with contrasting presentations. Case 1: A 9-day old ex full term female from a nonconsanguineous union presented to a rural hospital with hypothermia, lethargy, and poor feeding. She had hypoglycemia 41 mg/dL (60–105), hyponatremia 120 mEq/L (135–145), hyperkalemia 7.7 mEq/L (3.5–5.5) and cortisol < 0.4 ug/dL (4.5–23). Baby was started on hydrocortisone (HCT) 100 mg/m2 and one-time fludrocortisone (FCT). She decompensated requiring chest compressions, intubation and pressors. She was transferred to our institution. Newborn screen was normal; she had typical female external genitalia. US demonstrated a uterus; ovaries and adrenals were not identified. Upon extubation and clinical improvement, her HCT was weaned to physiologic doses. She became hyponatremic requiring FCT and salt supplements. Post-HCT wean, ACTH level was 304 pg/mL (7–63) with aldosterone < 4.0 ng/dL (6.5–86). Karyotype was 46,XX. Genetic analysis revealed a novel heterozygous likely pathogenic variant in the STAR gene, (STAR c.65-12_68del variant) without defect in the other STAR gene. Case 2: A 9-month-old ex full-term female of Iraqi descent from a nonconsanguineous union presented with fatigue, poor oral intake and weight loss from 50%-ile to 3%-ile. She had hyponatremia 122 mEq/L, hyperkalemia 8.0 mEq/L, but was normoglycemic. She was normotensive; EKG was normal. Parents noted progressive hyperpigmentation including her gums, palmar and plantar creases. She had typical external female genitalia with a hypoplastic clitoris (2 mm x 2 mm). ACTH stimulation test showed low cortisol (0.5 ug/dL) at 60 minutes. She was treated with HCT 100 mg/m2 for 5 days, then tapered to maintenance dosing, with FCT and salt supplements. Her ACTH level returned > 5000 pg/ml. Aldosterone, 17-OH-Progesterone, 17-OH-Pregnenolone, 11-Deoxycortisol and androstenedione were undetectable. Pelvic US did not identify uterus or ovaries. Pelvic MRI identified bilateral inguinal testes with enlarged adrenal glands. Karyotype was 46, XY. We suspected StAR deficiency with sex-reversal. Genetic analysis revealed a known homozygous mutation in STAR (c.545G>A). Conclusion: StAR deficiency is clinically indistinguishable from P450scc deficiency and genetic testing is needed. Both entities can present with early or delayed adrenal crisis. While classic for StAR deficiency, adrenal enlargement is inconsistent. Karyotype is vital to identify sex reversal.