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Endocrinology - Adrenal Disorders - Fast Facts | NEJM Resident 360

The cortex of the adrenal glands secrete three primary hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. The medulla of the adrenal glands secretes the catecholamines, epinephrine and norepinephrine.

• Glucocorticoid hormones (cortisol) are secreted by the zona fasciculata, act via glucocorticoid receptors, and mediate a range of vital body processes including immune system activity and vascular and metabolic function.

• Mineralocorticoids (aldosterone) are secreted by the zona glomerulosa, act via mineralocorticoid receptors, and regulate blood pressure, volume, and electrolyte balance.

• Adrenal androgens are steroid hormones with androgenic activity. They are secreted by the zona reticularis and provide a pool of circulating precursors for peripheral conversion to potent androgens (e.g., testosterone) and estrogens (e.g., estradiol).

• Catecholamines are neurotransmitters that help the body respond to stress, regulating blood pressure, glucose levels, and heart rate, among other processes.

Adrenal disease can encompass a whole spectrum of disorders. Patients with adrenal disease are seen in both the inpatient and outpatient settings and require specific clinical considerations. In this section we will cover assessment and management of the following adrenal conditions:

• Adrenal Adenoma

• Adrenal Insufficiency and Adrenal Crisis

• Hypercortisolism/Cushing Syndrome

• Primary Aldosteronism

• Pheochromocytoma and Paraganglioma

Adrenal Adenoma

Adrenal adenomas are often found incidentally when abdominal computed tomography (CT) is performed for an unrelated reason. The frequency of “incidentaloma” increases with age, affecting as much as 5% of the general population by the age of 70 years. In evaluating an incidentaloma, the important questions to answer are:

1. Is this incidentaloma hormonally active?
2. Could this incidentaloma be malignant?

Workup

Evaluation of hormone function involves assessing the three primary hormones: cortisol, catecholamines, and potentially aldosterone if the patient is hypertensive. Recommended biochemical testing includes:

• 1-mg overnight dexamethasone-suppression test for hypercortisolism

• 24-hour urinary metanephrine test or plasma metanephrines to screen for pheochromocytoma

• plasma renin and serum aldosterone for hyperaldosteronism (if the patient has hypertension or hypokalemia)

Evaluation for malignancy potential is based on imaging characteristics. Contrast-enhanced CT or MRI should always be performed to evaluate these lesions. The following findings are important to note:

• Enhancement >10 Hounsfield units (HUs) on noncontrast CT or washout of contrast <50% at 10 minutes should raise concern a non-adenoma lesion (adrenocortical cancer, pheochromocytoma, or metastasis).

• A lesion >4 cm in diameter raises suspicion of primary adrenal cortical carcinoma.

• A lesion <4 cm in diameter could indicate adrenal metastases.

The following algorithm provides a suggested framework for the investigation of an adrenal incidentaloma:

Algorithm for the Evaluation of Patients with an Adrenal Incidentaloma

The algorithm should be individualized according to the clinical circumstance, the imaging phenotype of the mass, the patient’s age, and the patient’s preferences. Given the strong association between the imaging features and pheochromocytoma, some advocate treatment with alpha- and beta-adrenergic blockade and tumor resection in patients with this imaging phenotype, even when the results of biochemical testing for pheochromocytoma are normal. The dashed line indicates that for some patients, on the basis of the physician’s clinical judgment, serial imaging and hormonal testing may be an alternative approach.
(Source: The Incidentally Discovered Adrenal Mass. N Engl J Med 2007.)

Adrenal Insufficiency

Adrenal insufficiency (AI) is the clinical manifestation of insufficient or ineffective endogenous glucocorticoid (more specifically, cortisol) secretion. In its most extreme form, AI can be a life-threatening medical emergency known as adrenal crisis. There are three major types of AI.

Types of AI

• Primary adrenal insufficiency (Addison disease, cortisol deficiency):

• • laboratory findings: low morning cortisol, impaired response to corticotropin stimulation testing, high adrenocorticotropic hormone (ACTH)

  • typically associated with loss of both glucocorticoid and mineralocorticoid activity

  • most commonly due to autoimmune adrenalitis but can also be caused by tuberculosis and other granulomatous infections, adrenal hemorrhage, following trauma and/or anticoagulants, bilateral adrenalectomy, or malignant infiltration from metastases

  • inborn causes of adrenal insufficiency: rare and most often due to congenital adrenal hyperplasia

• Secondary adrenal insufficiency (ACTH deficiency):

• • laboratory findings: low morning cortisol, low ACTH for cortisol concentration

  • associated with glucocorticoid deficiency only (mineralocorticoid action continues to be controlled by renin–angiotensin–aldosterone axis)

  • due to pituitary gland pathology that affects the entire hypothalamic–pituitary–adrenal axis (e.g., pituitary tumor, any infiltrative disease process affecting the pituitary [sarcoidosis], postpartum pituitary necrosis [Sheehan syndrome], hypophysitis [e.g., from immune checkpoint inhibitor use])

  • other pituitary axes usually affected; isolated pituitary ACTH deficiency exists but rare

• Exogenous glucocorticoid use:

• • prolonged glucocorticoid use leads to impaired ability to synthesize ACTH and cortisol

  • cessation of the exogenous glucocorticoid can therefore lead to a period of ACTH and cortisol deficiency (secondary adrenal insufficiency), until endogenous production recovers

  • the most common cause of adrenal insufficiency

  • affects up to 2% of the population in developed countries

Clinical Features

The features of AI can be nonspecific. In primary adrenal insufficiency, both glucocorticoid and mineralocorticoid deficiency symptoms manifest. Secondary insufficiency is characterized by symptoms of glucocorticoid deficiency only.

• Symptoms and signs of glucocorticoid deficiency include:

• • anorexia

  • fatigue

  • weight loss

  • myalgia and fever

  • abdominal pain and vomiting

  • normochromic anemia, lymphocytosis, eosinophilia (due to loss of normal suppression of inflammatory cytokines and altered immune-cell activity)

  • hypoglycemia

  • hypotension

  • hyponatremia

• Symptoms and signs of mineralocorticoid deficiency include:

• • hyponatremia

  • hyperkalemia

  • hypotension, dizziness, and postural hypotension

• Other signs and symptoms can include:

• • primary adrenal insufficiency

    • generalized hyperpigmentation due to excessive pro-opiomelanocortin–peptide secretion that is stimulated by high ACTH

    • reduced libido and muscle weakness due to adrenal androgen deficiency

  • secondary adrenal insufficiency

    • symptoms and signs suggestive of panhypopituitarism

Diagnosis

Evaluation of AI requires diagnostic testing, confirmatory testing, evaluation for primary vs. secondary AI, and determination of the underlying etiology:

1. Screening testing: early-morning cortisol blood test (at 6:00–10:00 a.m. due to diurnal variation in cortisol secretion)

• <3 μg/dL is strongly suggestive of AI.

• 10-15 µg/dL suggests the diagnosis of AI is unlikely, with increasing confidence of normal adrenal function with increasing cortisol levels within this range.

• Fluctuations in albumin and cortisol-binding globulin (CBG) concentration need to be taken into consideration when measuring cortisol, because cortisol binds with albumin and CBG.

• Note: A random plasma cortisol measurement is not helpful because of diurnal variation in cortisol secretion.

2. Confirmatory testing: cosyntropin stimulation testing (comparison of baseline serum cortisol with follow-up cortisol 30–60 minutes after administering cosyntropin [250 μg, intravenously or intramuscularly])

• Post-cosyntropin plasma cortisol concentration <18 μg/dL confirms AI; a lower cut-off (14–15 µg/dL) has been proposed due to increased specificity of newer cortisol assays

• Note: Patients with recent-onset pituitary or hypothalamic disease (within 2 to 4 weeks after pituitary surgery) may have a normal response to 250 μg of cosyntropin because the adrenal glands have not yet atrophied enough and continue to respond to high concentrations of ACTH.

3. Differentiating between primary and secondary AI: ACTH measurement

• An ACTH level more than two times the upper limit of normal is highly suggestive of primary AI.

• Normal or low ACTH suggest secondary AI.

• An elevated plasma renin level coupled with an inappropriately low or normal aldosterone may signify early primary AI.

4. Determining the etiology: testing directed at either adrenal or pituitary causes once the differentiation between primary and secondary AI has been made

• Primary AI: Measure adrenal antibodies, perform CT of abdomen and adrenal glands, and review medications.

• Secondary AI: Perform pituitary MRI, and screen other pituitary hormones.

The following flowchart outlines a suggested approach to the evaluation of AI:

Algorithm for the Diagnosis of Adrenal Insufficiency

Note: A lower cortisol threshold of 14–15 mg/dL may be reasonable
(Source: Diseases of the Adrenal Gland. Cleveland Clinic Center for Continuing Education 2015.)

Treatment

Treatment involves glucocorticoid and (when needed) mineralocorticoid replacement:

• Glucocorticoid replacement is usually given as hydrocortisone in divided doses to mimic physiological secretion of cortisol, or prednisone, which can be given once daily.

• • Adjustment of dose is based on clinical symptom control.

• Mineralocorticoid replacement is provided with fludrocortisone.

• • Adjustment of dose is based on blood pressure, volume status, sodium, potassium, and plasma renin concentration.

Sick-day management: Appropriate management of sick days is crucial to prevent adrenal crisis. It is essential to educate patients about sick-day management. The following table summarizes recommendations for glucocorticoid dose changes during intercurrent illness.

Glucocorticoid Dose Changes during Intercurrent Illness

Condition	Suggested Actions (Society for Endocrinology)
Self-management of illness with fever	If temperature >38°C, double glucocorticoid dose for duration of illness.

If temperature >39°C, triple glucocorticoid dose for duration of illness. | | Unable to tolerate oral medication | Administer subcutaneous or intramuscular hydrocortisone 100 mg.

Seek medical attention; consider hospital admission | | Minor surgery | Triple dose of glucocorticoid replacement for duration of procedure and postoperatively until discharge. | | Major surgery | Administer 100 mg of hydrocortisone intravenously at induction of surgery, followed by 50 mg every 8 hours until eating and drinking.

Double or triple dose of oral glucocorticoid when first eating and drinking until discharge. |

(Reference: Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr Connect 2016.)

AI During Acute Illness

AI due to inadequate cortisol production during periods of stress, such as septic shock, can lead to “relative adrenal insufficiency.” However, some endocrinologists debate the existence of this entity during critical illness in the absence of medical history that suggests adrenal insufficiency.

In critically ill patients, testing for adrenal function is complicated. Measuring baseline cortisol, albumin, or CBG levels and a corticotropin stimulation test can help determine the need for glucocorticoid replacement.

Adrenal Crisis

Although no definition is universally accepted for adrenal crisis, it typically refers to acute deterioration in health status and hypotension in patients with AI. Symptoms and signs of adrenal crisis usually improve within 1–2 hours of glucocorticoid administration.

Adrenal crisis can affect up to 8% of patients with AI per year and is a significant cause of mortality and morbidity. In most cases, a precipitating event can be identified, such as:

• gastrointestinal illness

• other infections (e.g., urinary tract infections or even the common cold)

• perioperative period

• inadequate medication

• use of drugs that affect the cytochrome P-450 enzyme system (by either inducing cortisol metabolism or preventing endogenous production of cortisol)

Management of adrenal crisis includes parenteral glucocorticoid replacement (hydrocortisone, 100 mg up to 4 times per day), intravenous fluid replacement, and treatment of the precipitating event. Cortisol replacement and fluid replacement can lead to rapid improvement in hyponatremia. Therefore, close monitoring of serum sodium is required.

Note: All patients with adrenal insufficiency must be appropriately educated about the risk of adrenal crisis and when to seek medical attention.

Hypercortisolism/Cushing Syndrome

Cushing syndrome refers to the characteristic constellation of signs and symptoms that develop as a result of excess glucocorticoid exposure. Glucocorticoid excess can be either primary or secondary. With the rising prevalence of obesity and metabolic syndrome, patients are increasingly assessed for Cushing syndrome. However, only a small proportion of such patients have true Cushing syndrome.

• Exogenous therapeutic glucocorticoid use is the most common cause of Cushing syndrome.

• Primary hypercortisolism (ACTH-independent, adrenal cause) represents 20%–30% of cases and is most commonly due to cortisol-secreting adrenal adenoma.

• • laboratory findings: elevated systemic measures of cortisol (midnight salivary cortisol or 24-hour urinary free cortisol), suppressed ACTH

• Secondary hypercortisolism (ACTH-dependent, called Cushing disease if pituitary cause) accounts for 70%–80% of cases and is usually due to benign ACTH-secreting pituitary tumor but can also be caused by ectopic ACTH production from malignancies.

• • laboratory findings: raised systemic measures of cortisol and elevated or inappropriately normal ACTH

Clinical Features

All clinical features of Cushing syndrome relate to excess glucocorticoid activity on a range of tissues. These include:

• obesity and redistribution of adipose tissue with characteristic central adiposity and increased supraclavicular fat pads

• hypertension

• violaceous striae and skin thinning

• plethora

• hirsutism

• depression/mania and related neuropsychiatric symptoms

• osteopenia/osteoporosis

• glucose intolerance and diabetes

Diagnosis

As with all tests for cortisol, testing to establish hypercortisolism can be challenging and requires diagnostic testing, evaluating for primary vs. secondary hypercortisolism, and evaluation for underlying cause.

1. Diagnostic testing: requires documented endogenous glucocorticoid excess on at least two of the following tests:

• 24-hour urinary free cortisol (UFC): provides an integrated assessment of free unbound cortisol. Caveats are that normal values vary widely and can change depending on total urine volume (may be unreliable if urine volume >5 liters per day); cutoffs should be based on the testing available at your institution.

• 1-mg overnight dexamethasone-suppression test (1 mg dexamethasone given at 11:00 p.m., cortisol measured at 8:00 a.m. the following morning)

• • cortisol level >5 µg/L: strongly suggestive of hypercortisolism

  • cortisol level <1.8 µg/L: suggests hypercortisolism unlikely

  • high rate of false-positive results, especially when CBG is elevated (e.g., from use of estrogen, such as in the combined oral contraceptive pill)

  • consider concurrent measurement of dexamethasone level to confirm that the test was done correctly and that the patient is not a rapid metabolizer of dexamethasone

• midnight salivary cortisol

• • 550 ng/dL: likely to have hypercortisolism

  • <145 ng/dL: unlikely to have endogenous hypercortisolism

  • may be difficult to interpret in people with atypical diurnal rhythms (e.g., shift workers)

2. Differentiating between ACTH-dependent (secondary) and independent (primary) hypercortisolism:

• low or undetectable ACTH level indicates ACTH-independent

• normal or elevated ACTH level indicates ACTH-dependent

3. Evaluation of underlying cause relies on imaging studies of the adrenal glands (ACTH-independent), pituitary gland, or elsewhere (ACTH-dependent). Evaluation to differentiate between pituitary or ectopic causes of ACTH-dependent hypercortisolism requires additional investigation such as inferior petrosal sinus sampling.

Treatment

Treatment of hypercortisolism requires management of the underlying cause; this may be surgical or medical.

The following diagram summarizes an approach to evaluating and managing a patient with endogenous hypercortisolism based on whether the condition is ACTH-dependent or not.

Differential Diagnosis of Cushing Syndrome

(Source: Diagnosis and Differential Diagnosis of Cushing’s Syndrome. New Engl J Med 2017.)

See Ectopic Cushing’s Syndrome for images of Cushing syndrome and a case description. 

Primary Aldosteronism

Primary aldosteronism (PA) is the most common cause of secondary hypertension and affects an estimated 5%–10% of all patients with hypertension. PA is associated with considerable morbidity beyond the risks related to hypertension alone. Most PA cases are due to bilateral idiopathic PA (65%), followed by primary aldosterone-producing adenoma (30%). Rarely, PA is due to an aldosterone-producing adrenocortical carcinoma (1%). Increasingly, familial and hereditary causes of PA (e.g., glucocorticoid-remediable PA) are being identified, although these cases are generally rare. Recognizing and diagnosing PA provides a unique opportunity to treat and potentially cure hypertension.

Clinical Features

Hypertension is the cardinal feature of PA and may be associated with the following features:

• hypokalemia (found in up to 30% of cases)

• resistant hypertension (requires at least three drugs for treatment)

• adrenal incidentaloma

• young age (<30 years)

• suspicion for secondary hypertension

• family history of hypertension or stroke at young age (<40 years)

Diagnosis

Diagnosis of PA requires detection, confirmation, and subtype testing.

Case detection: morning plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or plasma renin concentration (PRC) and plasma aldosterone-to-renin ratio (ARR)

• ARR >20 and PAC >10 ng/dL is generally considered a positive screen.

• Patients should have serum potassium within the normal range before testing is performed.

• Certain medications (e.g., mineralocorticoid receptor antagonists such as spironolactone and antihypertensives) can interfere and give false results.

• Generally, stop medications that interfere with the renin–angiotensin–aldosterone system, however testing with these agents can be carried out in unique circumstances.

Confirmatory testing: The following confirmatory tests can be performed to demonstrate autonomous aldosterone secretion (choice of test should be guided by local expertise):

• saline suppression test

• captopril stimulation test

• fludrocortisone suppression test

• oral sodium-loading test

Confirmatory testing is not needed in patients with the following features:

• spontaneous hypokalemia

• undetectable PRA

• PAC >20 ng/dL

Subtype classification: performed to differentiate between bilateral or unilateral disease. This involves imaging studies and adrenal vein sampling.

Treatment

Treatment depends largely on underlying cause:

• unilateral disease: generally treated surgically with adrenalectomy

• bilateral disease: treated with mineralocorticoid receptor antagonist (spironolactone and eplerenone) to help control blood pressure and protect against target-organ effects independent of blood pressure

Pheochromocytoma and Paraganglioma

Pheochromocytomas and paragangliomas (PPGLs) are frequently sought — but rarely found — catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla (pheochromocytoma) or the parasympathetic ganglia (paraganglioma). Most cases are benign and at least one-third of cases are due to an underlying genetic cause. Screening for PPGLs is important because it is a curable disease when correctly diagnosed and treated. However, it can be fatal if left undiagnosed or improperly treated.

Clinical Features

Clinical features of PPGLs are due to circulating catecholamine excess:

• Hypertension is the most common sign; can be sustained or paroxysmal; a small proportion of patients are normotensive

• Classic triad (most patients do not present with all three features)

• • headache (90% of patients)

  • sweating (70% of patients)

  • tachycardia

• Tremor, pallor, and palpitations (other symptoms of catecholamine excess)

• Consider evaluating for PPGLs in the following clinical scenarios:

• • adrenal incidentaloma

  • resistant hypertension

  • positive family history

  • pressor response during procedures

  • idiopathic dilated cardiomyopathy

Diagnosis

Case detection should include measurement of plasma free metanephrines or fractionated urinary metanephrines as the initial biochemical screening tests. Patient medications also need to be taken into consideration because certain medications interfere with results, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, levodopa, amphetamines, and drugs that contain adrenergic antagonists. In general, antihypertensive medications should be continued. Mild elevations, especially of normethanephrine (rather than metanephrine), are most likely due to a false-positive result; patients with symptomatic pheochromocytomas/paragangliomas usually have metanephrine levels more than three times the upper limit of normal for the assays.

Imaging studies: used to localize the tumor. In general, if a patient is symptomatic with biochemical confirmation of disease, a tumor will be identified on imaging.

• Abdominal CT with contrast is the most frequently used modality. PPGLs have a typical imaging characteristic, which includes:

• • dense and vascular

  • precontrast radiodensity >20 HU

  • <50% washout at 10 minutes

  • heterogeneous, with areas of cystic degeneration

Treatment

Treatment of PPGLs is generally surgical. Drug therapy is mandatory in the perioperative phase to minimize the risk of intraoperative hypertensive crisis and postoperative hypotension. Both alpha- and beta-adrenergic blockade is required. Do not commence beta-blockade before alpha-blockade is established, due to risk of hypertensive crisis.

Potential Treatment Regimens for PPGLs

Regimen	Starting Time	Starting Dose	Final Dose
Regimen 1
Phenoxybenzamine
or doxazosin	10–14 d before surgery
10–14 d before surgery	10 mg twice daily
2 mg/d	1 mg/kg/d
32 mg/d
Regimen 2
Nifedipine
or amlodipine	As add-on to regimen 1 when needed
As add-on to regimen 1 when needed	30 mg/d
5 mg/d	60 mg/d
10 mg/d
Regimen 3
Propranolol
or atenolol	After at least 3–4 d of regimen 1
After at least 3–4 d of regimen 1	20 mg 3 times daily
25 mg/d	40 mg 3 times daily
50 mg/d

(Reference: Pheochromocytoma and Paraganglioma: an Endocrine Society Clinical Practice Guideline. J Clin Endo Metab 2014.)

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