Adrenocortical insufficiency, more commonly referred to as Addison’s disease, is a condition that results from the inadequate production of certain hormones by the adrenal glands. This insufficiency can be attributed to damage to these glands or a congenital defect that impairs their function. Adrenal glands can be compromised for several reasons, including infections like tuberculosis, infiltration by malignant cells, or an autoimmune process where the body’s immune system mistakenly attacks the adrenal glands. Tuberculosis-induced adrenal damage remains the most prevalent cause worldwide, despite being considerably rare in countries like the United States today.

Addison’s disease, named after Thomas Addison, who first identified this condition nearly two centuries ago, refers to the acquired form of adrenocortical insufficiency.

Mechanisms Underlying Adrenal Crisis

Adrenal crisis, or Addisonian crisis, is a severe and potentially fatal condition characterized by an acute insufficiency of adrenal gland hormones, primarily cortisol and aldosterone.

Cortisol, classified as a glucocorticoid, profoundly influences multiple physiological processes. It modulates the body’s stress response, regulates metabolic pathways, and mediates anti-inflammatory responses. Aldosterone, a mineralocorticoid, plays an indispensable role in maintaining the body’s electrolyte and fluid balance, thus contributing to blood pressure regulation.

A sudden decrease in cortisol and aldosterone levels typically precipitates an adrenal crisis. The resultant cortisol deficiency compromises the body’s ability to respond appropriately to stress, interferes with metabolic processes, and impairs immunoregulatory mechanisms, specifically those related to inflammation.

Concurrent aldosterone insufficiency disrupts electrolyte homeostasis, leading to hyponatremia and hyperkalemia. This electrolyte imbalance can result in fluid depletion, hypotension, and potentially precipitate shock.

The consequences of an adrenal crisis are particularly severe in situations of increased physiological stress, such as during an injury, severe illness, or surgery, wherein the demand for adrenal hormones escalates. If the adrenal glands are unable to augment hormone production to meet this heightened demand, it can culminate in an adrenal crisis.

Precipitating Factors and Clinical Manifestations of Adrenal Crisis

Various factors can instigate an adrenal crisis, including severe physical stressors (like surgery or significant injury), systemic infections, dehydration, or abrupt discontinuation of glucocorticoid medication without appropriate dose tapering.

Adrenal crisis often presents with acute symptoms, including severe pain in the lower back, abdomen, or legs, profuse vomiting and diarrhea, hypotension, syncope, and severe dehydration. This condition necessitates immediate medical intervention, and the management approach typically involves rapid administration of hydrocortisone, fluids, and electrolytes to restore hormone levels and blood volume swiftly.

When the adrenal glands cease to produce adequate amounts of cortisol and aldosterone, it leads to significant physiological alterations. The fall in blood pressure is one of the immediate effects accompanied by changes in the concentrations of key electrolytes in the blood. The sodium levels tend to drop while potassium levels rise.

Simultaneously, a decrease in circulating cortisol disrupts the negative feedback mechanism on the hypothalamo-pituitary axis, leading to an escalation in Proopiomelanocortin (POMC) synthesis and a subsequent increase in Adrenocorticotropic hormone (ACTH). The rise in ACTH is mirrored by an increase in Melanocyte-stimulating hormone (MSH), a derivative of POMC. Over time, the increased MSH levels trigger hyperpigmentation, manifesting as a distinct tan in individuals suffering from adrenal insufficiency.

Symptoms and Diagnostic Processes

Apart from the drop in blood pressure, inadequate cortisol production can lead to vague symptoms such as persistent fatigue and a sense of exhaustion. Routine tests may show slightly decreased sodium and elevated potassium levels in the blood.

One standard diagnostic method involves drawing blood at 9:00 AM when cortisol levels are expected to be at their peak. A significantly lower cortisol value could signal adrenocortical insufficiency, warranting further evaluation by an endocrinology specialist. It’s crucial to understand that cortisol levels fluctuate throughout the day, and a lower level later in the evening might be considered normal. Shift workers, in particular, might show alterations in this diurnal rhythm.

In suspected cases, a more comprehensive dynamic investigation is recommended. The ACTH stimulation test is a widely accepted diagnostic procedure for assessing Addison’s disease.

The Process of Diagnosing Addison’s Disease

The diagnosis of Addison’s disease involves an initial collection of a blood sample for the measurement of cortisol and Adrenocorticotropic hormone (ACTH) levels. In individuals suffering from Addison’s disease, baseline cortisol levels are usually low, while ACTH levels are elevated.

The subsequent step in the diagnosis involves the administration of an injection containing 250 mcg of synthetic ACTH, also known as Synacthen. Blood samples are then collected at intervals of 30 and 60 minutes post-injection for the evaluation of cortisol levels.

In individuals with Addison’s disease, there is a minimal increase in cortisol levels, despite the large dose of ACTH. In contrast, healthy individuals display a significant surge in cortisol levels, usually increasing to a minimum of 18mcg/dL (Or >15mcg/dL with recent ultrasensitive assays). It’s important to note that these numerical values may exhibit slight variations across different healthcare facilities due to variations in the specific assay techniques employed.

Updated diagnostic tests and protocols can be accessed from our dynamic tests database.

Treatment for Addison’s Disease

Once the diagnosis of Addison’s disease is established, lifelong treatment with specific types of corticosteroids becomes necessary. Typically, hydrocortisone and fludrocortisone are the choice of drugs for replacement therapy, standing in for glucocorticoids and mineralocorticoids, respectively.

Treatment management and dosage adjustments should be handled by specialists in endocrinology to ensure the optimal control of symptoms. It’s crucial for patients to carry a steroid card, informing medical personnel of their condition in case of emergencies or unexpected medical events, signaling the need for additional steroid administration.

Many patients manage their condition with a daily dose of hydrocortisone, usually around 20mg. This dose is typically split into portions throughout the day: 10mg upon waking, 5mg around lunchtime, and a final 5mg dose in the early afternoon. Night-time dosing is not recommended as it can disrupt sleep patterns. The last dose should ideally be administered by 5:00 PM or at the latest, by 6:00 PM for those who wish to maintain normal sleep cycles. In addition to hydrocortisone, patients also require a daily intake of fludrocortisone, generally ranging between 50 and 100 mcg.

Treatment of Adrenal crisis

Individuals with Addison’s disease who are not receiving treatment with hydrocortisone and fludrocortisone, either due to an undiagnosed condition or accidental cessation of their medication, are at risk of a critical condition known as an Addisonian crisis. This life-threatening situation manifests as a salt-depleting, hypotensive crisis. If not promptly diagnosed and treated with steroids, patients may not recover from an Addisonian crisis.

A noticeable feature of this condition includes nausea and vomiting, which can exacerbate the crisis by hindering the ingestion and retention of necessary steroids. This necessitates prompt medical attention and warrants the classification of an Addisonian crisis as a medical emergency.

In such cases, patients need to be rapidly transported to a hospital for immediate parenteral (intravenous or intramuscular) administration of hydrocortisone, typically a dose of 100mg. This prompt action serves to provide both glucocorticoid and enough mineralocorticoid activities crucial to preserving the patient’s life.

These patients are often significantly salt-depleted, a condition stemming from a combination of excessive vomiting and the loss of sodium via the kidneys due to the lack of mineralocorticoids. Thus, they also require rehydration with saline to compensate for this loss.

Once the crisis is managed, and patients’ blood pressure returns to normal, the routine administration of their regular hydrocortisone and fludrocortisone replacement medications can be resumed.

What are steroid alert precautions?

Patients with adrenal insufficiency are at risk of an adrenal crisis, which is a life-threatening condition. Hence, the following steroid alert precautions should be followed:

1. Medic Alert Identification: Patients should wear a medical alert bracelet or necklace or carry a card that identifies their condition. This ensures that, in the event of an emergency, healthcare providers are immediately aware of their adrenal insufficiency.
2. Always Carry Medication: Patients should always have a supply of their steroid medication on hand. This is particularly important when traveling or going to locations where access to pharmacies may be limited.
3. Emergency Injection Kit: Patients should consider carrying an emergency hydrocortisone injection kit, especially for situations where oral medication cannot be taken, or immediate administration of hydrocortisone is required.
4. Double Dosing During Illness or Stress: During periods of stress or illness, particularly when fever is present, patients may need to take a “stress dose” or increase their medication under their doctor’s guidance.
5. Educate Close Contacts: Family members, friends, and coworkers should be aware of the patient’s condition and what to do in case of an emergency, including how to administer an emergency injection if necessary.
6. Regular Medical Check-ups: Regular appointments with an endocrinologist or another healthcare provider are essential for monitoring the disease and adjusting medication if necessary.
7. Proper Hydration and Salt Intake: Due to the role of aldosterone in regulating the body’s salt and water balance, patients may need to ensure they are properly hydrated and may need to increase salt intake during periods of intense physical activity or hot weather.
8. Avoid Abrupt Discontinuation of Steroids: Sudden stoppage of steroid medication can trigger an adrenal crisis. Always consult with a healthcare provider before making any changes to medication regimens.
9. Emergency Care Plan: Having a clear plan of action for emergencies, including knowing when to go to the emergency room, who to contact, and what medications to take, can save crucial time and improve outcomes.

Hypertension is a significant and prevalent cardiovascular risk factor that is amenable to treatment. When managed correctly, the risk for cardiovascular diseases, including stroke, ischemic heart disease, and heart failure, is lowered.¹ This entails accurate diagnosis and classification of hypertension and lifestyle modifications and pharmacotherapy to lower blood pressure to optimal levels.² Secondary hypertension can be effectively reversed or controlled to normotensive levels through early diagnosis and treatment of the underlying cause of high blood pressure. Endocrine hypertension, which is an uncommon form of secondary hypertension, is reversible in most cases when the cause is discovered and treated early. This requires expert evaluation of patients and specialist care. The most common endocrine pathology associated with hypertension is primary aldosteronism and less common endocrine causes are pheochromocytoma and Cushing’s syndrome.³ This article will briefly discuss current treatment options for endocrine causes of hypertension.

Primary Hyperaldosteronism

Hypertensive patients with primary hyperaldosteronism (PHA) experience higher rates of cardiovascular morbidity and mortality compared to patients with essential hypertension.⁴ Screening, early diagnosis and prompt treatment of PHA in hypertensive patients can thus improve clinical outcomes. The treatment is established after accurate identification of the cause of adrenal gland dysfunction through imaging and adrenal vein sampling. These causes include unilateral adrenal adenoma, unilateral/bilateral adrenal hyperplasia, familial hyperaldosteronism syndrome, and adrenocortical carcinoma.^3,5 Surgery is recommended in the case of unilateral PHA, whereas bilateral forms are treated with pharmacological therapy and lifestyle interventions.⁶ Unilateral adrenalectomy through a laparoscopic approach is the choice of surgical intervention.⁷ A mineralocorticoid receptor antagonist and potassium supplements are given to control hypertension and hypokalemia, respectively, before surgery and are discontinued after surgery.⁸ Most patients treated surgically for adrenal adenoma, hyperplasia or carcinoma have markedly improved blood pressure, plasma aldosterone-to-renin ratio, and potassium values.^3,8 Remission of hypertension after surgery depends on patient characteristics. Persistent high blood pressure may be observed in older patients, those with a  longer duration of hypertension, coexistent essential hypertension, or other risk factors for hypertension.^3,4,9

Lifelong pharmacological therapy with mineralocorticoid receptor antagonists (MRAs), usually spironolactone, is an alternative approach to PHA. It is recommended for patients with idiopathic PHA, bilateral adrenal hyperplasia, those who are unable or unwilling to undergo surgery, and when it is unclear whether PHA is unilateral or bilateral.^6,7 In addition, patients are advised to make lifestyle modifications to improve blood pressure, including minimizing sodium intake, avoiding tobacco use, and regular exercise.⁸ MRAs inhibit the actions of aldosterone by binding to the mineralocorticoid receptor, thus correcting sodium and water retention, hypokalemia, and hypertension.⁹ The use of spironolactone is limited by its side effects, like painful gynecomastia, erectile dysfunction, and dysmenorrhea.⁶ Eplerenone, although less potent, is an alternative MRA in patients who cannot tolerate spironolactone.^6,7 In some cases of bilateral PHA, resistant hypertension, and equivocal adrenal vein sampling, unilateral adrenalectomy may be considered to minimize the number of medications the patient requires to manage hyperaldosteronism and control blood pressure.³

Patient follow-up after medical or surgical treatment is necessary to monitor aldosterone and renin levels, blood pressure control, and potassium levels. Measurements of plasma renin activity can be used to monitor response to medical treatment.⁷ A risk for postoperative hyperkalemia exists and the patient’s serum potassium levels should be closely monitored after surgery.⁸ Evaluation of patients taking MRAs is recommended for the first two weeks to monitor tolerance and emergence of side effects.³

Pheochromocytomas

Localized adrenal and extra-adrenal pheochromocytomas, whether benign or malignant, are essentially treated with the same approach—surgical resection. ^10-12 Patient characteristics, such as suitability for surgery, and tumor characteristics, like tumor size, anatomical location, local invasion, and distant metastases, will guide the treatment approach.¹² Preoperative blood pressure control is necessary to prevent perioperative cardiovascular complications.¹⁰ Adrenergic receptor blockers are the first-line treatment for the clinical manifestations of pheochromocytomas and are given for at least 7–14 days before surgery.^11,12 An α-adrenoreceptor blocker, commonly phenoxybenzamine, is initially used to inhibit the actions of catecholamines and control blood pressure.^3,10 This is followed by a β-adrenoreceptor blocker, after achieving adequate α-blockade, if the patient experiences adverse effects such as tachycardia and postural hypotension.^10,11 The risk of postoperative hypotension caused by catecholamine-induced chronic vasoconstriction can be lowered by a high sodium diet, saline infusion or increased fluid intake to expand extracellular fluid volume before surgery.^11,12  

Laparoscopic surgery is the standard approach for the resection of abdominopelvic pheochromocytomas measuring less than 6 cm in diameter.^3,11 In contrast, open surgery may be more suitable for the resection of large tumors (>6 cm), invasive or malignant tumors, and paragangliomas.^10,11 Only a few cases of metastatic pheochromocytoma can be treated surgically; palliative care to reduce the disease burden is the choice of therapy when surgery is not possible.¹¹ Chemotherapy or radiotherapy can also be used for the treatment of aggressive metastatic tumors where surgical resection is impractical.⁶

Due to the uncertainty of recurrences and metastases, long-term clinical, biochemical and radiological monitoring is necessary.^9,10 Plasma or urine metanephrine measurements return to normal approximately within a week after surgery, indicating complete tumor resection.¹⁰ Measurements are obtained within the first month after surgery, again at six months, and at one year with imaging; thereafter, long-term annual follow-up is advised.¹¹ Ten-year follow-up is recommended in all patients, while those with hereditary pheochromocytoma require lifelong follow-up.¹² Monitoring is also important for assessing potential postoperative complications including tachyarrhythmias, renal impairment, hypoglycemia, and persistent hypotension.^3,10

Cushing’s syndrome

Hypertension is prevalent in patients with endogenous Cushing’s syndrome. Early diagnosis and prompt treatment of hypercortisolism will often lead to the resolution or alleviation of hypertension, among other comorbidities.^13,14 The therapeutic approach depends on a comprehensive diagnosis that distinctly identifies the underlying cause of the disease. Additionally, treatment will be based on the severity of hypercortisolism, medical history, current drug history, and patient perspectives and needs.¹⁴ Adrenocorticotropic hormone (ACTH)-producing pituitary adenomas are the most common cause of endogenous Cushing’s syndrome.¹³ Other causes are ACTH-producing ectopic tumors, cortisol-secreting adrenal tumors including unilateral adrenal adenoma and adrenocortical carcinoma, and micro- or macro-nodular adrenal hyperplasia.¹³

The treatment of choice for pituitary adenoma is conservative transsphenoidal surgical resection, with preservation of as much organ function as possible to avoid hormone replacement therapy.^9,14 If the initial surgery for pituitary adenoma is unsuccessful, a second surgery or radiation therapy may be attempted. Radiation therapy is indicated in the case of growing pituitary adenomas and post-surgical remnants.¹⁴ Surgical resection is also indicated as the first-choice treatment for other operable tumors. For instance, unilateral or bilateral adrenalectomy is used to treat adrenal adenomas, hyperplasia, and carcinoma.⁹ When surgery is not a therapeutic option, such as in the case of metastatic tumors, pharmacological therapy is the first-line treatment to reduce cortisol production. Pharmacotherapy can also be considered for disease control before surgery and adjuvant therapy after surgery or radiotherapy.¹⁴ Adrenal-directed drugs that inhibit steroidogenic enzymes (steroidogenesis inhibitors) and thus cortisol production and glucocorticoid receptor blockers are commonly used in Cushing’s syndrome. Pituitary-directed drugs, such as pasireotide and cabergoline, are less effective than steroidogenesis inhibitors but can be considered to block tumor secretion of ACTH and may lead to tumor shrinkage.¹⁴ Ketoconazole is the most common steroidogenesis inhibitor used⁹ while others include mitotane and metyrapone.^14,15 The glucocorticoid receptor antagonist mifepristone can also be used to control hypercortisolism.^14,15

In patients with complications of cortisol excess, symptomatic treatment, such as that of hypertension, is necessary before comprehensive diagnosis and definitive treatment of Cushing’s syndrome are completed.¹⁴ The treatment of hypertension is targeted at the underlying pathophysiological mechanisms and usually requires the use of more than one antihypertensive drug.¹⁶ Angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors may be initiated as first-line treatment since the renin-angiotensin system plays a major role in cortisol-induced hypertension.^13,14 Spironolactone can be used in hypokalemic hypertensive patients, alone or in combination,¹⁴ to target the mineralocorticoid receptor and block the aldosterone-like effects of excess cortisol.¹³ Calcium channel blockers or β-blockers may be used as adjuncts to improve blood pressure control.¹⁴

The complications of hypercortisolism, including hypertension, may sometimes persist despite surgical or pharmacological treatment for Cushing’s syndrome. Targeted treatment of persistent comorbidities is therefore recommended.^13,14 Follow-up of patients is also emphasized in those treated for ACTH- or cortisol-producing neoplasms due to the possibility of recurrences.¹⁴

Thyroid Disease

Conditions that cause thyroid dysfunction can be generally categorized as those that result in thyroid hormone deficiency (hypothyroidism) or excess (hyperthyroidism). Chronic autoimmune thyroid diseases are the most common causes of hypothyroidism in iodine-sufficient regions,¹⁷ with Hashimoto thyroiditis accounting for most cases.¹⁸ Other causes include iatrogenic thyroid injury after radioiodine or surgical treatment for hyperthyroidism, benign nodular thyroid disease or thyroid cancer, exposure to head and neck radiotherapy, and medications (e.g., amiodarone, lithium, and immune response modulators).^17,19 The most common causes of hyperthyroidism are autoimmune Graves’ disease and toxic multinodular goiter. Iodine-containing drugs, mainly amiodarone, excess levothyroxine therapy, and less frequently, subacute thyroiditis can also lead to hyperthyroidism. ^17,19 Disorders of the pituitary gland or hypothalamus can lead to secondary hypo/hyperthyroidism.¹⁹

The treatment of the underlying thyroid disease and restoration of euthyroidism in hypertensive patients will lead to the normalization of blood pressure in most cases. However, antihypertensive medications may be required after thyroid treatment to control blood pressure. β-adrenoreceptor blockers are used in hyperthyroidism, whereas vasodilators, such as calcium channel blockers, are the drugs of choice in hypothyroid patients.^20,21

Symptomatic primary hypothyroidism is usually treated with levothyroxine replacement therapy, a synthetic thyroxine hormone.^18,19 Treatment response is assessed by measuring the levels of thyroid-stimulating hormone (TSH) every three months until at least two similar measurements (three months apart) within the normal reference range are obtained, and then once a year. When TSH remains abnormal, additional testing of free thyroxine (T4) and/or tri-iodothyronine (T3) is required to guide further treatment decisions, after ruling out secondary causes.¹⁸ Other treatments for primary hypothyroidism include liothyronine (synthetic T3), as monotherapy or in combination with levothyroxine, and desiccated thyroid extract. Liothyronine is indicated when levothyroxine treatment fails whereas desiccated thyroid extract is currently not recommended by professional guidelines.^18,19

Antithyroid drugs (thionamides), usually carbimazole, are the first-line treatment for hyperthyroidism in Graves’ disease. However, long-term use is discouraged, and radioiodine ablation therapy or thyroidectomy may be indicated after thionamide therapy for definitive treatment.¹⁹ Radioiodine ablation of the thyroid gland is indicated when thionamide therapy fails, in recurrent Graves’ disease, and in patients who cannot tolerate thionamides.¹⁹ Thyroidectomy is preferred over radioiodine ablative therapy in patients with moderate-to-severe Graves’ orbitopathy; women who are planning to be pregnant within the next 6–12 months; large goiters with compressive symptoms or major retrosternal extension; when thyroid cancer is suspected; or when patients refuse radioiodine therapy.¹⁹

Primary Hyperparathyroidism

Parathyroidectomy is the first-line and only curative treatment for primary hyperparathyroidism (PHPT). It is indicated in all symptomatic patients without contraindications for surgery and asymptomatic patients with evidence of end-organ damage or risk of disease progression.^22,23 Normalization of calcium and parathyroid hormone levels is an indicator of PHPT cure after parathyroidectomy.²⁴ Surgical treatment improves many clinical manifestations of PHPT. However, resolution or amelioration of hypertension following parathyroidectomy has shown variable results, with some studies reporting no improvements and others showing improvements.²⁵

Monitoring is a safe and alternative approach for PHPT in patients who cannot undergo surgery.^22,23 It comprises annual evaluation of serum calcium, vitamin D, and renal function, bone mineral density evaluation every 1 to 2 years, and 24-hour biochemical renal stone evaluation with renal imaging if calcium stones are suspected.^23,24 Patients who are being monitored are advised to stay adequately hydrated and avoid restricting dietary calcium.²² Parathyroidectomy is recommended when signs of disease progression are observed in patients who are being monitored.²³ Medical therapy, with agents such as alendronate, denosumab, cinacalcet, vitamin D, or estrogen therapy, can also be when surgery is contraindicated, unsuccessful, or rejected by the patient.^22,23 Cinacalcet has been shown to reduce serum calcium and parathyroid hormone levels.^23,24 However, medical therapy is less effective than parathyroidectomy and is non-curative.²²

References

1. Yang J, Shen J, Fuller PJ. Diagnosing endocrine hypertension: a practical approach. Nephrology. 2017 May; 22.
2. Carey RM, Jr JTW, Taler SJ, Whelton PK. Guideline-Driven Management of Hypertension: An Evidence-Based Update. Circulation Research. 2021 April; 128(7).
3. Thomas RM, Ruel E, Shantavasinkul PC, Corsino L. Endocrine hypertension: An overview on the current etiopathogenesis and management options. World J Hypertens. 2015 September; 5(2).
4. Yozamp N, Vaidya A. The Prevalence of Primary Aldosteronism and Evolving Approaches for Treatment. Curr Opin Endocr Metab Res. 2020 October; 8.
5. Charles L, Triscott J, Dobbs B. Secondary Hypertension: Discovering the Underlying Cause. American Family Physician. 2017 October; 96(7).
6. Freminville JBd, Amar L. How to Explore an Endocrine Cause of Hypertension. J Clin Med. 2022 January; 11.
7. El-Asmar N, Rajpal A, Arafah BM. Primary Hyperaldosteronism: Approach to Diagnosis and Management. Med Clin North Am. 2021 November; 105(6).
8. Jr WY. Diagnosis and treatment of primary aldosteronism: practical clinical perspectives. Journal of Internal Medicine. 2018 September; 285(2).
9. Sica DA. Endocrine Causes of Secondary Hypertension. J Clin hypertens. 2008 July; 10(7).
10. Pappachan JM, Tun NN, Arunagirinathan G, Sodi R, Hanna FWF. Pheochromocytomas and Hypertension. Curr Hypertens Rep. 2018 January; 20(1).
11. Farrugia F, Martikos G, Tzanetis P, Charalampopoulos A, Misiakos E, Zavras N, et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. J Clin Hypertens (Greenwich). 2017 July; 51(3).
12. Garcia-Carbonero R, Teresa FM, Mercader-Cidoncha E, Mitjavila-Casanovas M, Robledo M, Tena I, et al. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clin Transl Oncol. 2021 May; 23.
13. Barbot M, Zilio M, Scaroni C. Cushing’s syndrome: Overview of clinical presentation, diagnostic tools and complications. Best Pract Res Clin Endocrinol Metab. 2020 March; 34(2).
14. Ferriere A, Tabarin A. Cushing’s syndrome: Treatment and new therapeutic approaches. Best Practice & Research Clinical Endocrinology & Metabolism. 2020; 34.
15. Isidori AM, Graziadio C, Paragliola RM, Cozzolino A, Ambrogio AG, Colao A, et al. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J Hypertens. 2015 January; 33(1).
16. Cicala MV, Mantero F. Hypertension in Cushing’s Syndrome: From Pathogenesis to Treatment. Neuroendocrinology. 2010 September; 92(suppl 1).
17. Berta E, Lengyel I, Halmi S, Zríny M, Erdei A, Harangi M, et al. Hypertension in Thyroid Disorders. Front. Endocrinol. 2019 July; 10.
18. Vasileiou M, Gilbert J, Fishburn S, Boelaert K. Thyroid disease assessment and management: summary of NICE guidance. BMJ. 2020.
19. Hughes K, Eastman C. Thyroid disease: Long-term management of hyperthyroidism and hypothyroidism. Australian Journal of General Practice. 2021; 50(1–2).
20. Kalra S, Baruah M, Agrawal N, Bandgar T, Gandhi A, Mitra S. Management of hypertension in thyroid disease: results from the IMPERIAL study-1. Thyroid Research and Practice. 2010; 7(1).
21. Mazza A, Beltramello G, Armigliato M, Montemurro D, Zorzan S, Zuin M, et al. Arterial hypertension and thyroid disorders: what is important to know in clinical practice? Ann Endocrinol (Paris). 2011 September; 72(4).
22. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nature Reviews Endocrinology. 2018 September; 14.
23. Bilezikian JP, Khan AA, Silverberg SJ, Fuleihan GEH, Marcocci C, Minisola S, et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. Journal of Bone and Mineral Research. 2022 August; 37(11).
24. Islam AK. Advances in the diagnosis and the management of primary hyperparathyroidism. Ther Adv Chronic Dis. 2021 June; 11.
25. Fisher SB, Perrier ND. Primary hyperparathyroidism and hypertension. Gland Surg. 2020 Feb; 9(1).
26. NICE guidelines. Thyroid disease: assessment and management. [Online].; 2019 [cited 2023 May 6]. Available from: https://www.nice.org.uk/guidance/ng145/resources/thyroid-disease-assessment-and-management-pdf-66141781496773

Hypertension, or high blood pressure, has been established as a major modifiable risk factor for several diseases such as ischemic heart disease, heart failure, chronic kidney disease, and cerebrovascular accidents. It is the leading determinant of cardiovascular morbidity and mortality and was estimated to affect over 30% of the global adult population in 2019.¹ Characterized by chronic elevated systemic arterial blood pressure, a consensus definition of hypertension is blood pressure values of ≥140/90 mmHg.²

The American College of Cardiology/American Heart Association guidelines categorize hypertension as elevated, defined as a systolic pressure of 120 to 129 mmHg with a diastolic pressure of <80 mmHg; stage 1, defined as 130 to 139 mmHg systolic pressure or 80 to 89 mmHg diastolic pressure; and stage 2, defined as a blood pressure reading of ≥140/90 mmHg.^2-4

Hypertension is classified as primary/essential hypertension and secondary hypertension based on etiology; the former is the most common form of the condition and occurs without a discernable cause, while secondary hypertension accounts for 10% of cases.^5-7 Endocrine pathologies, including primary hyperaldosteronism, pheochromocytoma, Cushing`s syndrome, acromegaly, primary hyperparathyroidism, and thyroid disorders, account for 10% of the underlying causes of secondary hypertension.^7,8 The evaluation and diagnosis of the secondary causes of hypertension are crucial in its treatment as they guide the selection of the most appropriate therapy that could potentially lead to the complete remission of hypertension. However, extensive testing for secondary hypertension is impractical as the list of potential etiologies is wide.⁹ Nonetheless, there are suggestive clinical findings for which screening and diagnostic testing are recommended, as will be discussed in this article, with a focus on endocrinopathies.

Resistant Hypertension

Hypertensive patients may present with a form of the condition that is difficult to control despite the use of at least three antihypertensive agents, including a diuretic, in the correct combination and at the highest tolerated doses (referred to as resistant hypertension).^2,10,11 Resistant hypertension is also defined as hypertension that requires four or more antihypertensive drugs for optimum control.^10,11 The first steps in evaluating resistant hypertension are objective determination of compliance to and adequate selection and dosing of antihypertensive medications, exclusion of secondary causes of hypertension, and ambulatory blood pressure monitoring (ABPM).^10,11 Additionally, exclusion of pseudo-resistant hypertension, defined as an apparent lack of blood pressure control despite adequate doses of at least three well-selected antihypertensive medications, including a diuretic, is necessary.² Factors that lead to the development of this entity include the white-coat effect (elevated in-office blood pressure and normal or significantly lower out-of-office values); poor adherence to pharmacological therapy; periodic dietary changes (e.g., high sodium and alcohol intake); concomitant use of medications that elevate blood pressure, e.g., sympathomimetics; and rapid weight gain.^2,11

True resistant hypertension is characterized by at-home ambulatory blood pressure values of ≥135/85 mmHg during the daytime or ≥130/80 mmHg over 24 hours.^2,10

In assessing secondary causes of resistant hypertension, primary hyperaldosteronism is typically the first endocrine pathology considered as it is among the most common causes.¹⁰ Pheochromocytomas, Cushing’s syndrome, thyroid dysfunction, and hyperparathyroidism are rarer endocrine causes of resistant hypertension.¹¹

Endocrine Causes of Hypertension

Primary Hyperaldosteronism

Primary hyperaldosteronism (PHA) is the leading endocrine cause of secondary hypertension⁵ and the most common cause of resistant hypertension.^7,9 It is characterized by excessive levels of aldosterone independent of the renin-angiotensin-aldosterone system (RAAS).⁹ Aldosterone is a hormone produced by the cortex of the adrenal glands in response to activation of the RAAS and elevated serum potassium. It plays a role in the regulation of blood pressure by stimulating renal reabsorption of sodium and water, thus controlling water retention, extracellular fluid levels, and consequently blood pressure.^12,13

PHA is typically idiopathic and involves both adrenal glands.^7,12 It may also arise as a result of an adrenal adenoma, less commonly, unilateral/bilateral adrenal hyperplasia and familial hyperaldosteronism syndrome, and, rarely, adrenocortical carcinoma.^7,9 The clinical presentation is variable, with most patients developing resistant hypertension and hypokalemia (low potassium levels).⁷ The clinical suspicion of PHA-associated hypertension is high in hypertensive patients with hypokalemia, patients with resistant hypertension, hypertensive patients with an incidental adrenal mass, young patients with early onset hypertension or cerebrovascular accidents, those previously evaluated for other causes of secondary hypertension, or a family history of PHA.^7,12

When PHA is suspected, the initial recommended test performed (screening) is a morning measurement of the plasma aldosterone-to-renin ratio in the upright position.^7,9,12 As this test is highly sensitive, the diagnosis can be made, when there is a high index of clinical suspicion, after at least two measurements of plasma aldosterone >20 ng/dL and renin (activity or concentration) below detection levels.⁵ Interpretation of the plasma aldosterone-to-renin ratio is made with caution as several factors can produce false negative/positive results; these include medications (e.g., many antihypertensive drugs, oral contraceptives, and selective serotonin reuptake inhibitors), renovascular hypertension, hypokalemia, and pregnancy.^7,14 Other screening tests include plasma and urinary potassium levels and plasma aldosterone. However, they are less sensitive and not used on their own as some patients may have normal levels of potassium and aldosterone.⁹ Further investigations, such as the oral sodium loading test and saline infusion test, may be necessary for a definitive diagnosis and are typically ordered by a specialist.^7,14 The oral sodium loading and saline infusion tests aim to increase plasma volume and, in the absence of PHA, will suppress renin and thus aldosterone production.¹⁵

The oral sodium loading test, which is performed in stable and potassium-replete patients, is often used and is highly sensitive and specific. A 24-hour urine aldosterone level >12 μg/24h with a concomitant 24-hour urine sodium excretion >200 mmol/d confirms the diagnosis.^7,12,14

Imaging tests are recommended following a biochemical diagnosis of PHA to determine the underlying etiology. A computed tomography (CT) scan is the first modality of choice used to differentiate unilateral adrenal adenoma from bilateral adrenal hyperplasia and to rule out other pathologies such as adrenocortical carcinoma.¹² Magnetic resonance imaging (MRI) and scintigraphy may also be used.^7,14 Imaging may be combined with other tests, most notably adrenal vein sampling (AVS).⁷ AVS is the most reliable method used to distinguish between unilateral and bilateral hyperaldosteronism and is essential in adrenal surgical planning.^7,12 This procedure involves blood sampling from left- and right-sided adrenal and peripheral veins through femoral catheterization, followed by aldosterone/cortisol measurements in each blood sample to assess whether there is unilateral dominance of aldosterone hypersecretion.¹⁵ However, some schools of thought suggest that AVS is not required in all patients,¹² such as those below the age of 40 years with marked PHA and a distinct unilateral adrenal adenoma on CT scan, with significant surgical risk, suspected of having adrenocortical carcinoma, or with proven familial hyperaldosteronism.^16,15

Pheochromocytoma

Pheochromocytomas, often grouped with catecholamine-secreting paragangliomas, are rare neuroendocrine tumors that produce excess circulating catecholamines—epinephrine, norepinephrine, and, very rarely, dopamine.^7,17,18 Catecholamines possess both neurotransmitter and hormonal activity; their functions include the “fight or flight” response, blood pressure regulation, and glucose metabolism, to mention a few.¹⁹ Pheochromocytomas arise from neural crest-derived cells of the adrenal medulla (adrenal pheochromocytoma) and sympathetic ganglia (paraganglioma or extra-adrenal pheochromocytoma), with the former representing most cases.¹⁷ The majority are benign whereas 10–15% are malignant, mainly extra‐adrenal pheochromocytomas.^17,18 Clinically, they mimic numerous conditions of catecholamine overproduction and may manifest with the classic triad of headache, sweating, and tachycardia.^7,9 Hypertension is the most common sign associated with pheochromocytomas and is present in the majority of patients.^7 (7) It presents as sustained or paroxysmal elevations in blood pressure due to constant or episodic excess catecholamine secretion, respectively.^7,9 Patients with sustained hypertension frequently develop orthostatic hypotension, thought to result from hypovolemia as a result of persistent vasoconstriction and diminished sympathetic reflex.^7,18 Paroxysmal attacks of hypertension may be spontaneous or triggered by anesthesia, tumor manipulation, pain, trauma, postural changes, exercise, or medications such as anti-depressants, β-blockers, and opioid analgesics.^17,18 If the diagnosis or treatment is delayed, these tumors can result in severe clinical sequelae. Such complications include secondary erythrocytosis, new-onset diabetes mellitus, congestive heart failure, isolated dilated cardiomyopathy, cardiac arrhythmias, and hypertensive crisis.^7,17,18

The diagnosis of pheochromocytoma requires a high index of clinical suspicion. The clinical findings that are suggestive of pheochromocytoma include resistant hypertension; unexplained orthostatic hypotension in untreated hypertensive patients; headaches, palpitations, and sweating in a hypertensive patient; paradoxical blood pressure increases while taking β-blockers; paroxysmal attacks of hypertension triggered by anesthesia, tumor manipulation, pain, etc.; incidental finding of an adrenal tumor (adrenal incidentaloma); syndromic features suggesting hereditary pheochromocytoma; and a family history of pheochromocytoma in hypertensive patients.^7,18 The standard diagnostic procedure for pheochromocytoma is the measurement of plasma free metanephrines or 24-hour urinary metanephrines in the supine position.^7,9,18 A plasma free metanephrine test is used when the clinical index of suspicion is significant as this test provides greater sensitivity than specificity. In contrast, a 24-hour urinary metanephrine test is preferred when the clinical suspicion is lower as this test has greater specificity.^7,20  A four-fold increase in plasma free metanephrines above the upper cutoff value is highly diagnostic of pheochromocytomas.^17,18 Plasma 3-methoxytyramine (dopamine metabolite) may be performed along with free plasma metanephrines when metastatic disease is suspected, which is important for the diagnosis of malignant pheochromocytomas.^17,18 Imaging studies are recommended after biochemical confirmation of a pheochromocytoma. CT and MRI are the main imaging modalities used to identify these tumors and are useful for surgical treatment planning.^7,18   

Cushing’s Syndrome

Cushing’s syndrome is a rare and potentially life-threatening endocrine disorder caused by longstanding exposure to excess endogenous or exogenous glucocorticoids.²¹ Endogenous glucocorticoids, i.e., cortisol and corticosterone, are steroid hormones produced by the adrenal cortex in response to stimulation by the pituitary hormone, adrenocorticotropic hormone (ACTH).²² Cortisol is the main biologically active glucocorticoid in humans and exhibits anti-inflammatory and immunosuppressive properties.²² Cushing’s syndrome infrequently results from the endogenous overproduction of cortisol.²³  The majority of cases are iatrogenic, resulting from prolonged administration of exogenous glucocorticoids (i.e., systemic corticosteroids).^9,23 Endogenous Cushing’s syndrome is typically ACTH-dependent, arising from ACTH-producing pituitary (most prevalent) or ectopic tumors. Less commonly, it is ACTH-independent, in which case there is autonomous glucocorticoid overproduction by the adrenal gland.²¹ Chronic excessive cortisol levels are associated with several conditions, including but not limited to obesity, insulin resistance, impaired glucose tolerance, hypertension, cardiovascular diseases, and infections.^15,23

Hypertension is present in 80% of patients with endogenous Cushing’s syndrome,⁹  although it represents an infrequent cause of hypertension in the general population.⁸

The mechanisms by which cortisol raises blood pressure are postulated to involve an interplay between various pathophysiological pathways, including increased mineralocorticoid activity, activation of the RAAS, enhanced reactivity to vasoconstrictors, and increased sympathetic activity, among others.^23-25

An increase in mineralocorticoid activity is thought to be the major contributing factor.²⁵ Cortisol binds to the mineralocorticoid receptor with equal affinity as aldosterone; this action is normally enzymatically inhibited.

In Cushing’s syndrome, the levels of cortisol are overwhelmingly elevated, and thus, cortisol freely binds to and activates the mineralocorticoid receptor, leading to increased aldosterone-like activity and consequently hypertension.^24,25 Evidence suggests that Cushing’s syndrome can also result in hypertension through increased expression of angiotensin hormone receptors, thus implicating the RAAS system.²⁴ Additionally, it has been demonstrated that cortisol raises the levels of angiotensinogen, the angiotensin precursor.²⁵ Cushing’s syndrome is also associated with a marked increase in endothelin-1, a very potent vasoconstrictor. Furthermore, there is reduced activity of the nitric oxide vasodilatory system. Thus, hypertension may also develop due to significant vasoconstriction.^24,25

The diagnosis of Cushing’s syndrome may present challenges as patients often have nonspecific and variable clinical features like weight gain, excessive abdominal adiposity, thin skin, purple striae, increased irritability, acne, hirsutism, and menstrual irregularity.^21,23 (21) Thus, screening for hypercortisolism-induced hypertension is recommended in select clinical situations: resistant hypertension; the presence of an adrenal incidentaloma; cushingoid-like features unusual for the patient’s age, such as hypertension, uncontrolled diabetes, or female balding; the presence of multiple suggestive signs and symptoms; and weight gain with a decrease in height percentile and delayed puberty in children.^9,21,23 At least two measurements of 24-hour urinary free cortisol, a low-dose (1mg) dexamethasone suppression test, or at least two late-night salivary cortisol measurements can be performed as the initial screening procedure for Cushing’s syndrome.^9,21,23 The choice of test is individualized based on patient characteristics to circumvent false positive and false negative results, and findings are interpreted with caution based on specific limitations for each test.^7,23 The diagnosis of endogenous Cushing’s syndrome is confirmed when at least two of the initial screening tests are overtly abnormal, after excluding prolonged exogenous glucocorticoid use.²³ 24-hour urinary free cortisol values that are four-fold over the upper limit have high diagnostic accuracy.²¹ The dexamethasone suppression test involves oral intake of two 0.5 mg dexamethasone tablets at bedtime (11:00 PM) and early morning (08:00 AM) cortisol measurement the following day.¹⁵ Normal findings are a fall in cortisol levels below 50 nmol/L, whereas higher values indicate a lack of negative feedback mechanism associated with Cushing’s syndrome.^15,21 A late-night salivary cortisol test will demonstrate high cortisol levels in patients with Cushing’s syndrome due to loss of diurnal variation.²¹ Some specialists may perform further diagnostic tests such as the 48-hour 2 mg daily dexamethasone suppression test or intravenous 4 mg dexamethasone suppression test.¹⁵ After biochemical confirmation of Cushing’s syndrome, additional evaluation of patients involves investigation of the cause of cortisol hypersecretion, whether ACTH-dependent or ACTH-independent.¹⁵

Other Endocrine Causes of Hypertension

Thyroid Disease

Thyroid hormones, i.e., thyroxine (T4) and triiodothyronine (T3), are secreted by the thyroid gland in response to stimulation by the thyroid-stimulating hormone (TSH) from the pituitary gland.²⁶ They play a role in the regulation of heart rate, blood pressure, body temperature, and basal metabolic rate. Both thyroid hormone excess and deficiency have been associated with hypertension.²⁶ Hypothyroidism can cause an elevation in diastolic blood pressure, whereas hyperthyroidism can elevate systolic blood pressure.^9,26 The indications for screening are the same in hypertensive and non-hypertensive populations.^5 (5) Screening is done in individuals presenting with common clinical features of thyroid dysfunction, risk factors of thyroid disease, or a history of thyroid disease or treatment.²⁷ Plasma measurement of TSH is the first test of choice for the evaluation of thyroid disorders.²⁸ Plasma T4 measurement is necessary in acutely ill patients.²⁹ Free T4 levels are a better indicator of thyroid secretory function compared to total T4.^27,29

Primary Hyperparathyroidism

Primary hyperparathyroidism results from excessive secretion of parathyroid hormone (PTH) from one or more of the parathyroid glands. It is characterized by unexplained hypercalcemia and can affect vascular reactivity, renal function, and circadian blood pressure rhythm.⁹ The levels of PTH may be elevated, as expected, or inappropriately normal.³⁰ Primary hyperparathyroidism is most often caused by a single parathyroid adenoma. It can also arise due to hyperplasia of all four parathyroid glands and less commonly multiple adenomas and parathyroid cancer.³⁰ The diagnosis is confirmed with an elevated albumin-adjusted calcium level (hypercalcemia) along with an elevated or unexpectedly normal PTH level after excluding secondary hyperparathyroidism.³⁰

References

1. NCD Risk Factor Collaboration. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021 September; 11(398).
2. Hannah-Shmouni F, Gubbi S, Spence DJ, Stratakis CA, Koch CA. Resistant Hypertension: A Clinical Perspective. Endocrinol Metab Clin N Am. 2019; 48.
3. Wu S, Xu Y, Zheng R, Lu J, Li M, Chen L, et al. Hypertension Defined by 2017 ACC/AHA Guideline, Ideal Cardiovascular Health Metrics, and Risk of Cardiovascular Disease: A Nationwide Prospective Cohort Study. Lancet. 2022 March ; 20.
4. Alexander MR. Hypertension. [Online].; 2022 [cited 2023 April 20] Available from: https://emedicine.medscape.com/article/241381-overview
5. Freminville JBd, Amar L. How to Explore an Endocrine Cause of Hypertension. J Clin Med. 2022 January; 11.
6. Hegde S, Ahmed I, Aeddula N. Secondary Hypertension. In StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
7. Thomas RM, Ruel E, Shantavasinkul PC, Corsino L. Endocrine hypertension: An overview on the current etiopathogenesis and management options. World J Hypertens. 2015 September; 5(2).
8. Sica DA. Endocrine Causes of Secondary Hypertension. J Clin hypertens. 2008 July; 10(7).
9. Charles L, Triscott J, Dobbs B. Secondary Hypertension: Discovering the Underlying Cause. American Family Physician. 2017 October; 96(7).
10. Oliveras A, Sierra Adl. Resistant hypertension: patient characteristics, risk factors, co-morbidities and outcomes. Journal of Human Hypertension. 2014 August; 28.
11. Doroszko A, Janus A, Szahidewicz-Krupska E, Mazur G, Derkacz A. Resistant Hypertension. Adv Clin Exp Med. 2016; 25(1).
12. El-Asmar N, Rajpal A, Arafah BM. Primary Hyperaldosteronism: Approach to Diagnosis and Management. Med Clin North Am. 2021 November; 105(6).
13. Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, Inflammation, Immune System, and Hypertension. American Journal of Hypertension. 2021 January ; 34(1).
14. Chrousos GP. Hyperaldosteronism. [Online].; 2023 [cited 2023 April 20] Available from: https://emedicine.medscape.com/article/920713-workup
15. Yang J, Shen J, Fuller PJ. Diagnosing endocrine hypertension: a practical approach. Nephrology. 2017 May; 22.
16. Rossi GP, Auchus RJ, Brown M, Lenders JWM, Naruse M, Plouin PF, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014 January; 63(1).
17. Pappachan JM, Tun NN, Arunagirinathan G, Sodi R, Hanna FWF. Pheochromocytomas and Hypertension. Curr Hypertens Rep. 2018 January ; 20(1).
18. Farrugia F, Martikos G, Tzanetis P, Charalampopoulos A, Misiakos E, Zavras N, et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. J Clin Hypertens (Greenwich). 2017 July; 51(3).
19. Paravati S, Rosani A, Warrington SJ. Physiology, Catecholamines. In StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
20. Blake MA. Pheochromocytoma. [Online].; 2021 [cited 2023 April 21] Available from: https://emedicine.medscape.com/article/124059-workup
21. Barbot M, Zilio M, Scaroni C. Cushing’s syndrome: Overview of clinical presentation, diagnostic tools and complications. Best Pract Res Clin Endocrinol Metab. 2020 March; 34(2).
22. Chourpiliadis C, Aeddula N. Physiology, Glucocorticoids. In StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.
23. Savas M, Mehta S, Agrawal N, Rossum EFCv, Feelders RA. Approach to the Patient: Diagnosis of Cushing Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2022 November; 107(11).
24. Isidori AM, Graziadio C, Paragliola RM, Cozzolino A, Ambrogio AG, Colao A, et al. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J Hypertens. 2015 January; 33(1).
25. Cicala MV, Mantero F. Hypertension in Cushing’s Syndrome: From Pathogenesis to Treatment. Neuroendocrinology. 2010 September ; 92(suppl 1).
26. Berta E, Lengyel I, Halmi S, Zríny M, Erdei A, Harangi M, et al. Hypertension in Thyroid Disorders. Front. Endocrinol. 2019 July ; 10.
27. Larson J, Anderson E, Koslawy M. Thyroid disease: a review for primary care. J Am Acad Nurse Pract. 2000 June; 12(6).
28. Pappan N, Din MTU, Venkat D, Wedgeworth P, Fu S. Screening for Thyroid Disorders Among Resistant Hypertension Patients: Are We Doing Enough? Clin Med Res. 2022 June; 20(2).
29. Institute of Medicine (US) Committee on Medicare Coverage of Routine Thyroid Screening. Pathophysiology and Diagnosis of Thyroid Disease. In Medicare Coverage of Routine Screening for Thyroid Dysfunction. Washington (DC): National Academies Press (US); 2003.
30. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nature Reviews Endocrinology. 2018 September; 14.

Glucocorticoids, such as dexamethasone, methylprednisolone, and prednisone, are a class of steroid hormones that have various effects on the immune system. One notable consequence of their use is an increase in the white blood cell (WBC) count, primarily attributed to a rise in neutrophils, also known as polymorphonuclear leukocytes (PMN). This article aims to provide a comprehensive understanding of the biological processes that lead to the increase in circulating PMNs and the importance of these changes when evaluating patients receiving glucocorticoid treatment.

The Composition of White Blood Cells

A WBC count measures the total number of leukocytes present in a patient’s blood. These leukocytes consist of neutrophils (60-70%), lymphocytes (28%), monocytes (5%), eosinophils (2-4%), and basophils (0.5%). Neutrophils, being the most abundant leukocytes, play a significant role in changes observed in the WBC count. These cells, also referred to as Polymorphonuclear neutrophils (PMNs), undergo several developmental stages before maturing.

Immature neutrophils are initially released from the bone marrow and are characterized by a nonsegmented, band-like nucleus, earning them the name “bands.” An increase in circulating immature neutrophils often indicates a bacterial infection, as they are mobilized to combat the invading pathogens. This phenomenon is typically referred to as a “left shift” in a WBC differential

As the immature neutrophils become activated or exposed to bacteria, their nuclei adopt a segmented appearance. Neutrophils are found in various compartments within the body, with the marginal (neutrophils attached to blood vessel endothelium) and circulating compartments being the most relevant to this discussion.

Glucocorticoids and Their Impact on WBC Count

The administration of glucocorticoids (e.g., dexamethasone, methylprednisolone, prednisone) is known to cause an increase in WBC counts, predominantly due to elevated PMN levels. This increase can be attributed to several factors:

• Demargination of neutrophils from the endothelial surface of blood vessels.
• Delayed transmigration of neutrophils into tissues.
• Delayed apoptosis (programmed cell death).
• Increased release of neutrophils from the bone marrow.

While all these factors contribute to the rise in circulating neutrophils, demargination has the most significant impact. Some studies have reported WBC count increases greater than 20,000/mm3 within the first day of glucocorticoid administration, with maximum levels reached in approximately two weeks. On average, patients taking 40-80 mg of oral prednisone experience a WBC count increase of around 4,000/mm3. However, there is a high degree of variability, which may be partly due to differences in glucocorticoid dosage.

Key Message : What are bands? Bandemia, also known as a left shift, refers to an increase in the number of immature neutrophils called “bands” in the bloodstream. Neutrophils are a type of white blood cell (WBC) that play a crucial role in the immune system’s defense against infections, particularly bacterial infections. It is worth noting that when the body faces an infection, it responds by increasing the production of neutrophils in the bone marrow. During this rapid phase of neutrophil production, a higher number of immature neutrophils are released into the general circulation. Indeed, these immature neutrophils are characterized by their nonsegmented, band-like nuclei, hence the name “bands.” In a normal WBC differential, the percentage of bands is low, usually less than 6% of the total neutrophil count. However, when the body is fighting an infection or facing other inflammatory conditions, the percentage of bands may increase significantly. A left shift, or bandemia, is observed in a complete blood count (CBC) with a differential. This term originates from the historical practice of manually counting different types of white blood cells on a blood smear under a microscope. The various types of white blood cells were placed in columns, with the immature neutrophils (bands) on the left and the more mature neutrophils on the right. An increase in the number of bands, or immature neutrophils, was referred to as a “shift to the left.” Bandemia or left shift is an important clinical indicator, as it often suggests an ongoing infection or inflammation that requires further investigation and appropriate medical intervention.

Mechanisms of Steroid induced Leukocytosis

The main mechanisms by which steroids increase WBC count are:

First, steroids cause neutrophils to detach from the endothelial surface of blood vessels. This process, called demargination, increases the number of neutrophils circulating freely in the blood, leading to an elevated WBC count.

Also, steroids slow down the process by which neutrophils migrate from the blood vessels into the tissues. This delay in transmigration results in a higher number of neutrophils remaining in the bloodstream, contributing to the increase in WBC count.

Furthermore, steroids can prolong the life of neutrophils by delaying apoptosis or programmed cell death. As a result, the overall number of neutrophils in circulation increases.

Finally, they can stimulate the bone marrow to produce and release more neutrophils, including immature neutrophils called “bands.” This increased production and release of neutrophils lead to a higher WBC count.

Understanding the Clinical Implications of Glucocorticoid-Induced WBC Count Increase

In summary, glucocorticoids are known to increase WBC count, primarily due to a rise in PMNs. The primary factors contributing to this increase are demargination, delayed transmigration, delayed apoptosis, and an increase in the release of neutrophils from the bone marrow. A thorough understanding of these biological processes is essential for the proper interpretation of WBC count changes, especially when glucocorticoids are part of a patient’s treatment regimen.

Monitoring and Managing WBC Count in Glucocorticoid-Treated Patients

It is important to closely monitor the WBC count of patients undergoing glucocorticoid therapy, as elevated levels may be misinterpreted as an indication of infection, potentially leading to unnecessary antibiotic treatment. In some cases, however, glucocorticoid-induced leukocytosis may mask an underlying infection. Therefore, clinicians should carefully consider the patient’s clinical presentation and overall health status when evaluating changes in WBC count.

It is also essential to manage the potential side effects of glucocorticoids, such as immunosuppression, increased risk of infection, and adrenal insufficiency. Patients on long-term glucocorticoid therapy should be educated about the importance of reporting any signs of infection or other health concerns to their healthcare provider. Additionally, the healthcare team should regularly reassess the patient’s glucocorticoid dosage and consider tapering the dose or discontinuing the medication if appropriate.

Conclusion

Glucocorticoids play a significant role in increasing WBC count, primarily through the elevation of PMNs. Understanding the factors behind these changes and their clinical implications is crucial for healthcare professionals when evaluating and treating patients receiving glucocorticoids. Close monitoring of WBC count and a comprehensive understanding of the patient’s clinical presentation can ensure that the most appropriate diagnostic and therapeutic decisions are made, ultimately leading to improved patient outcomes.

References

Dale DC, Fauci AS, Guerry D IV et al. Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. J Clin Invest 1975;56:808-13.

Nakagawa M, Terashima T, D’yachkova Y et al.  Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes.  Circulation  1998;98:2307-13. 

Hereditary paraganglioma-pheochromocytoma (PPGLs) syndromes refers to paragangliomas (tumors derived from neuroendocrine tissues found along the paravertebral axis extending from the skull base to the pelvis) and by pheochromocytomas (paragangliomas of the adrenal medulla).

Although paragangliomas can produce hormones, they do not produce metanephrine (a metabolite of epinephrine) due to the lack of paracrine stimulation by PNMT (requires cortisol). Conversely, pheochromocytomas can produce either metanephrine or normetanephrine (a metabolite of norepinephrine).

Comparison of sympathetic and parasympathetic paragangliomas

Extra-adrenal parasympathetic paragangliomas	Extra-adrenal sympathetic paragangliomas
Location:  skull base, neck, and upper mediastinum	Location : lower mediastinum, abdomen, and pelvis
Majority of them are nonsecretory (95%)	Majority of them are secretory
Low malignancy risk	High malignancy risk

 

Genetic Testing of paragangliomas and pheochromocytomas

All patients with PPGLs should undergo genetic testing since hereditary PPGLs are typically inherited in an autosomal dominant fashion. Although patients usually inherit a pathogenic variant from a parent, some probands may have a de novo pathogenic variant (uninherited spontaneous mutation).  

SDHA, SDHB, SDHC and SDHD (designated as the SDHx syndrome complex) represents four nuclear genes that encode the subunits of the mitochondrial enzyme succinate dehydrogenase (SDH).

Mnemonics for SDHx

SDHB = “BAD” : A high risk of malignancy and extra-adrenal sympathetic PPGLs

SDHD = “DAD” : Parent of origin effects (Deleterious effects from Dad)

What is the meaning of Parent of origin effects?

This refers to the risk of expressing a pathogenic variant based on the parent from which a mutation is inherited. A patient with an SDHD pathogenic variant inherited from their father stands a high risk of developing PPGL. Conversely, the risk is significantly low, but not negligible, if an SDHD mutation is inherited from a mother.

Detailed instructions for sick day and emergency management of adrenal insufficiency. Refer to the table below.

Summary of Adrenal Insufficiency Sick Day Rules

Situation	Instructions
Maintenance (Usual) Doses Take these doses on a daily basis when well
Sick Day Management (“Stress Dosing”) With any physical stress such as infection or injuries, the body need higher amounts of hydrocortisone In the event of fever (above 38 Celsius or 100.4 Fahrenheit), infection that requires antibiotics, vomiting, diarrhea, or fracture, use the higher doses for 24 to 48 hours Resume usual (maintenance) doses of hydrocortisone when fever/stress has resolved	Stress dose is typically double or triple usual daily dose. Call Endocrinology Team
Emergency Management(Solu-Cortef Injection) When unable to tolerate oral medication, hydrocortisone by injection will be necessary In the event of severe illness, trauma, inability to tolerate oral hydrocortisone, unconsciousness, or repeated vomiting, administer Solu-Cortef by intramuscular injection	Solu-Cortef (100 mg in 2 mL) Age under 3 years → administer 25 mg (0.5 mL) by intramuscular injection Age 3-10 years → administer 50 mg (1 mL) by intramuscular injection Age above 10 years → administer 100 mg (2 mL) by intramuscular injection Go to the emergency Department or call 911  Call Endocrinology Team
Preparation for Surgery The stress of surgery and recovery from it necessitates higher doses of hydrocortisone during and 1-3 days after surgery This requires team approach among the healthcare professionals managing the surgery and post-operative care	Make the surgeon (or dentist) and anesthesiologist aware Diagnosis of adrenal insufficiency and medication doses Surgical team and endocrinology should communicate with each other Plan well before the date of surgery Decide on hydrocortisone doses before and after surge