Chapter 16Adrenal Examination

• Metabolic: Recent unexpected weight gain, especially in central area? Has anyone noticed changes in shape of your face (re: moon facies) or enlargement of back of your neck (re: dorsal fat pad)?
• Dermatologic: Any wounds that are poorly healing, or ulcers you’ve noticed? Easy bruising? Large, purple stretch marks? Excessive hair growth or acne (re: hirsutism)? Hyper-pigmentation in areas not normally exposed to the sun (due to increased ACTH, as in Cushing’s Disease)
• Musculoskeletal:
  • Any muscle weakness, for example difficulty rising from a chair or going up stairs? (re. proximal muscle weakness – absence of proximal weakness mildly reduces likelihood of Cushing’s syndrome with LR- 0.4)
  • Any height loss (re: Osteoporosis risk, compression fractures)? Any recent fragility fracture (e.g. fracture with fall from standing height or without obvious trauma)?
• Menstrual History (see Chapter 19 – Sensitive Pelvic Exam – MF3 for more info) – Cushing’s syndrome associated with menstrual irregularities, in particular:
  • Amenorrhea: Absent menstruation (can be primary i.e. no menarche, or secondary)
  • Oligomenorrhea: uterine bleeding occurring at infrequent, irregular intervals
• Increased infection risk: Any thrush (fungal infection)? Any recurrent infections?
• Mental Health Screen (explored further in Ch 33 – Assessment of Mood and Anxiety – MF4)
  • Depression (PHQ-2):
    • In past month, have you often been bothered by feeling down, depressed or hopeless?
    • In past month, have you been bothered by little interest or pleasure in doing things?
  • Anxiety: Are you a worrier? Do you worry excessively about minor things/ Have you ever found it hard to stop worrying?
  • Panic: Have you ever experienced a sudden attack/fear where you felt extremely uncomfortable?
  • Irritability: In past month, have you often been bothered by becoming easily annoyed or irritable?
• Neurologic: Vision loss (particularly peripheral vision); blurry vision → re: Cushing’s disease with pituitary adenoma causing compression of optic chiasm
• For cisgender female patients: Noting a deepened voice? (re. virilization – androgen excess)

• Adrenal Crisis: Important cause of distributive shock. It can present with acute anorexia, nausea/vomiting, abdominal pain, lethargy, fatigue, weakness, fever, confusion or coma.
• Chronic Adrenal Insufficiency Presentations:
  • General: Fatigue; headache; dizziness; weight loss; anorexia; orthostatic dizziness
  • Gastrointestinal: Nausea/vomiting; abdominal pain; alternating diarrhea and constipation
  • Menstrual History (see Chapter 19 – Sensitive Pelvic Exam – MF3 for more info) – Adrenal insufficiency particularly associated with Amenorrhea re. Absent menstruation
  • Musculoskeletal: Any myalgia (muscle weakness) or arthralgia (joint pain)? Any trouble with straightening your legs (re. flexion contractures of leg)?
  • Mental Health Screen (explored in Ch 33 – Assessment of Mood and Anxiety – MF4):
    • Depression (PHQ-2):
      • In past month, have you often been bothered by feeling down, depressed or hopeless?
      • In past month, have you been bothered by little interest or pleasure in doing things?
    • Anxiety: Are you a worrier? Do you worry excessively about minor things/ Have you ever found it hard to stop worrying?
    • Psychosis:
      • Have you had any strange or odd experiences lately that can’t be explained?
      • Do you ever hear or see things that other people can’t hear or see?
      • Do you ever feel that people are bothering you or trying to harm you?

• Classic Triad: Headache (LR+ 1.607, LR- 0.240); Palpitations (LR+ 1.888, LR- 0.518); Diaphoresis (LR+ 2.184, LR- 0.451) –note most patients with pheochromocytoma don’t have all 3 symptoms.
• Other Symptoms: Orthostatic hypotension/dizziness; tremor and pallor (particularly episodic alongside palpitations, diaphoresis and headache – re: catecholamine excess) blurry vision; weight loss; polyuria and polydipsia (re: hyperglycemia); constipation; palpitations and tachycardia; abdominal pain; nausea
• Episodic Hypertension triggers by: Beta-blockers, Monoamine-Oxidase inhibitors, Urination, changes in abdominal pressure, surgery or anesthesia

• Causes:
  • Exogenous corticosteroids (suppressing ACTH)
  • Cushing’s Disease (e.g. ACTH-producing pituitary adenoma)
  • Paraneoplastic Syndrome (e.g. small-cell lung cancer secreting ACTH or ACTH-like substance)
  • Adrenal Adenoma or Carcinoma (e.g. producing cortisol)
• Complications:
  • Osteoporosis: Clinically apparent Osteoporosis (e.g. history of compression fracture) greatly increases likelihood of Cushing’s Syndrome (LR+ 17.6, LR- 0.4)
  • Avascular Necrosis: Associated with osteonecrosis of femoral head, and rarely of humeral head (e.g. as complication of high-dose chronic glucocorticoid therapy)
  • Cardiovascular: Increased risk of Coronary Artery Disease, and cardiovascular risk factors including Hypertension, Diabetes Mellitus, and Sleep Apnea.
    • Glucocorticoids in excess can also bind to mineralocorticoid receptors, raising BP
  • Ophthalmology: Associated with cataracts and raised intraocular pressure, particularly as a complication of chronic glucocorticoid therapy. Pituitary tumour may present with bitemporal hemianopia (partial temporal blindness in both visual fields due to optic chiasm compression).
  • Psychiatry: Associated with anxiety, depression and mood changes.

• Primary Adrenal Insufficiency (diseases of adrenal gland):
  • Metabolic: Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (pediatric)
  • Autoimmune: Addison’s disease; Hemorrhage (e.g. anticoagulation, adrenal vein thrombus)
  • Infection: Tuberculosis, histoplasmosis, HIV, Coccidiomycosis
  • Infiltrative: Cancer metastasis, Sarcoidosis, Amyloidosis
• Secondary Adrenal Insufficiency (diseases of pituitary interfering with ACTH secretion): Panhypopituitarism (e.g. infarction, large tumor, infection e.g. tuberculosis or histoplasmosis); Traumatic brain injury; high dose progestins (e.g. megestrol acetate); opioids
• Tertiary Adrenal Insufficiency (diseases of hypothalamus interfering with corticotropin-releasing hormone): Chronic high dose glucocorticoid therapy
• Other Associated Autoimmune Diseases: Associated with T1DM, hypothyroidism, hypoparathyroidism, vitiligo, etc.

• Suspect in patients with: Hypertension refractory to usual antihypertensive therapy
• History of adrenal mass on imaging
• Neoplastic Disorders: Multiple Endocrine Neoplasia 2 (MEN2), Neurofibromatosis Type 1 (NF1)
  • MEN-2A associated neoplasms: Medullary thyroid cancer, primary hyperparathyroidism.
  • MEN-2B associated neoplasms: Medullary thyroid cancer, mucosal neuromas (commonly of lips, tongue) and intestinal ganglioneuromas.
  • NF1 associated findings: Café-au-lait spots, Peripheral neurofibromas, Optic pathway gliomas, CNS neoplasms (e.g. astrocytoma, glioma), Soft tissue sarcomas

• Pituitary surgery; Adrenalectomy (e.g. for Pheochromocytoma)

• Multiple Endocrine Neoplasia Type 2 (MEN2), Neurofibromatosis Type 1 (NF1), Von-Hippel Lindau (VHL) → ↑ risk pheochromocytoma re: catecholamine-secreting tumors.
• Multiple Endocrine Neoplasia Type 1 (MEN1) → ↑ risk of pituitary adenoma re: Cushing’s disease
• Congenital Adrenal Hyperplasia (e.g. 21-hydroxylase deficiency) → ↑ risk adrenal insufficiency

Smoking, Alcohol, IV/Illicit Drug Use, Occupation

• Exogenous Corticosteroids – Therapeutic reasons:
  • Immunosuppression (e.g. transplant patients)
  • Anti-inflammatory properties (e.g. Asthma, Inflammatory Bowel Disease, Rheumatoid Arthritis, Polymyalgia Rheumatica)
  • Exogenous corticosteroids (esp. chronic) can lead to suppression of ACTH and HPA Axis.

• High dose chronic glucocorticoids (e.g. tapering dose too quickly)
• Azole antifungals (e.g. Ketoconazole, Fluconazole)
• Anticoagulants (Heparin, Warfarin)
• Opioids (e.g. in chronic pain management)
• Antipsychotics (e.g. chlorpromazine)
• Antidepressants (e.g. Selective serotonin reuptake inhibitors = SSRIs)
• High dose progestins (e.g. megestrol acetate)

• Alpha-1 Adrenergic Blockers (always start BEFORE considering beta blockers re: risk of worsening hypertension due to unopposed alpha-receptor stimulation with beta blockade): Phenoxybenzamine; Prazosin; Terazosin; Doxazosin
• Beta-Blockers: Propranolol, Metoprolol

• Glucocorticoids: Hydrocortisone, prednisone, dexamethasone
• Mineralocorticoids: Fludrocortisone

• Blood Pressure, Heart Rate, Temp, and Orthostatic Vital Signs

Why Check:

• Blood Pressure: The presence of hypertension mildly increases the likelihood of suspected Cushing’s Syndrome (LR+ 2.3, LR- 0.8), while the absence of hypertension mildly increases the likelihood of suspected Pheochromocytoma (LR- 1.683). Hypotension is associated with Hypocortisolism.
• Orthostatic Hypotension: Mildly increases the likelihood of Pheochromocytoma (LR+ 1.885, LR- 0.792), and is associated with Hypocortisolism as well.
• Adrenal Crisis: Important cause of distributive shock (warm shock) – see Ch 9 – Volume Status – MF2. Presents with hypotension, tachycardia, and may present with fever (inflammatory response)

(Also seen in Ch 4 – Vital Signs – MF1)

AFMC level Pre-clerkship 4 · Clerkship 4

Say: Would it be alright if we measure your height, weight, hip circumference and waist circumference today?

Set-Up: Ask permission before weighing someone, and never weigh a patient in front of others. Weighing scales should be placed in private areas in clinical spaces.

Do:

13. Ask patient to remove shoes.
14. Requires a weight scale, a method of measuring height, and a tape measure.
15. Measure the patient’s weight and height using appropriate scales.
16. For waist circumference, measure circumference at a level midway between the Iliac Crest and last palpable rib (WHO guidelines)
17. For hip circumference, measure at the level with the widest portion of the buttocks.
18. Using these measurements, calculate BMI (kg /m²), Waist-Height Ratio, and Waist-Hip Ratio.

Report: The height and weight we measured today were _____, with a BMI of ______.

Why Check: With respect to obesity in connection with Cushing’s Syndrome, the distribution of obesity is important. Where central obesity (e.g. abdominal) mildly increases the likelihood of Cushing’s Syndrome (LR+ 3.0, LR- 0.2), the presence of generalized obesity significantly decreases the likelihood of Cushing’s Syndrome (LR+ 0.1, LR- 2.5). To differentiate central and generalized obesity, the Waist-Height Ratio and Waist-Hip ratio are objective measures of central (abdominal) obesity.

These calculated measures, including BMI, are imperfect, but clinically useful to monitor over time.

Differential for weight changes include Nutritional state, malignancy, chronic illness, eating disorder, hyper/hypothyroid, hyper/hypocortisolism, etc.

WHO Classification of Weight Status:

Modification for Patients with Limited Mobility:

• Height: Can be measured using the demi-span (distance from mid-sternal notch to the end of the middle finger in the coronal plane) and then calculated with the following formulas:
  • For female patients: Height (cm) = (1.35 x Demi-span) + 60.1
  • For male patients: Height (cm) = (1.40 x Demi-span) + 57.8
• Weight: The patient’s estimate of their weight is more accurate than physician’s. If the patient is unable to give an estimation, body weight can be estimated using body height, and hip and waist circumference.

Modification for Patients who are Transgender:

• Transmasculine Patients (FTM): Patients on masculinizing hormone therapy may have body fat redistribution and/or increased muscle mass.
• Transfeminine Patients (MTF): Patients on feminizing hormone therapy may have body fat redistribution and/or decreased muscle pass.

Say: I will inspect the head and neck for signs of Adrenal disorders.

Do: Look at the patient’s head shape for moon facies (round head) and hair pattern for temporal hair loss (in cis-gender female patients). Look at the patient’s eyes for conjunctival pallor. Look at the patient’s skin for facial plethora (redness), hyperpigmentation (particularly in face and neck), oily complexion, acne and diaphoresis. Inspect the patient’s mouth for Thrush (white plaques that can scrape off the tongue). Look at the patient’s neck for increased neck thickness and signs of dorsocervical fat pad.

Report: I note no moon facies, skin and hair changes of the face and neck to suggest Cushing’s syndrome, or hyperpigmentation to suggest Hypocortisolism. I note no diaphoresis or pallor to suggest Pheochromocytoma. I note no signs of temporal hair loss to suggest virilization (in cis-gender female patient)

Moon Facies¹ · Conjunctival Pallor² · Oral Candidiasis³ · Dorsocervical Fat Pad⁴

Why Check:

• Hypercortisolism (Cushing’s Syndrome): Moon facies (round head) mildly increases likelihood of suspected Cushing’s syndrome, while its absence greatly reduces its likelihood (LR+ 1.6, LR- 0.1). The likelihood of suspected Cushing’s syndrome is mildly increased by Facial plethora (LR+ 2.7, LR- 0.3) and Acne (LR+ 2.2, LR- 0.6). Hyperpigmentation can occur due to increased ACTH (as in Cushing’s disease). Note that facial plethora can be an indicator of other conditions, including dermatologic conditions such as rosacea or sunburn, hematologic conditions such as polycythemia vera, and vascular emergencies such as superior vena cava syndrome. Thrush can be an indication of immunosuppression associated with glucocorticoid excess as in Cushing’s Syndrome.
• Virilization: Alongside hirsutism (see below), deepened voice and clitoral enlargement, oily skin and temporal hair loss can be signs of virilization (androgen excess) in patients assigned female sex at birth.
• Hypocortisolism: Hyperpigmentation can be a sign of Hypocortisolism (e.g. Addison’s disease, Adrenal insufficiency) particularly in sun-exposed areas (e.g. face, neck, back of hands) and areas of chronic friction (e.g. elbows, knees, knuckles, waist on belt line, and shoulders along bra line).
• Pheochromocytoma: Conjunctival pallor mildly increases likelihood of Pheochromocytoma (LR+ 4.667, LR- 0.718), and diaphoresis mildly increases the likelihood of Pheochromocytoma (LR+ 2.184, LR- 0.451).

Modification for Transgender Patients:

• Transmasculine Patients (FTM): Patients on masculinizing hormone therapy may have oilier skin, more acne, increased facial and body hair, or ↓ scalp hair – important to normalize these changes.
• Transfeminine Patients (MTF): Patients on feminizing hormone therapy may have softening of skin/decreased skin oiliness, less acne, thinning/slowed growth of facial and body hair, or arrested progression of scalp hair loss – important to normalize these changes.

Say: I will inspect the arms and hands for signs of Adrenal disorders.

Do: Inspect at the patient’s axilla for acanthosis nigricans (hyperpigmentation re. Cushing’s syndrome). Inspect the patient’s shoulders along bra line and elbows for hyperpigmentation (re. Hypocortisolism). Inspect the patient’s dorsal surface of hands, knuckles and palmar creases for hyperpigmentation (re. Hypocortisolism). Assess palmar creases and nailbeds for pallor.

Report: I note no acanthosis nigricans, hyperpigmentation or pallor.

Acanthosis Nigricans⁵⁶

Why Check: Acanthosis nigricans (hyperpigmentation of skin in body folds e.g. axilla, intertriginous areas) can be a sign of Cushing’s Syndrome, also seen in Diabetes Mellitus. Hyperpigmentation can be a sign of Hypocortisolism (e.g. Addison’s disease, Adrenal insufficiency) particularly in sun-exposed areas (e.g. face, neck, back of hands) and areas of chronic friction (e.g. elbows, knees, knuckles, waist on belt line, and shoulders along bra line). Pallor mildly increases the likelihood of Pheochromocytoma (LR+ 4.667, LR- 0.718)

Say: I will inspect the abdomen for signs of Adrenal disorders.

Do: Inspect for red, purple or blue striae >1cm wide particularly along the abdomen and lower flanks.

Report: I note no purple striae to suggest Cushing’s syndrome.

Striae and Hirsutism¹

Why Check: Red, purple or blue striae occur as fragile skin stretches with enlarging trunk, breasts and abdomen, which mildly increases the likelihood of Cushing’s syndrome (LR+ 1.9, LR- 0.7). Note that striae distensae also occur in pregnancy – where over time, these progress to striae alba (hypopigmented with fine wrinkling) and tend to be thinner and less prominent than striae seen in Cushing’s syndrome.

Say: I will inspect the skin for hair growth and signs of Adrenal disorders.

Setup: In this exam, draping is important, with sequential exposure of examined areas after obtaining consent. For dermatological exam in sensitive areas, consider the role of a chaperone.

Do: Inspect Upper lip; Chin; Mid-sternum; Upper Arms; Upper & Lower Abdomen; Thighs; Upper & Lower Back for terminal hair growth (dark, coarse hairs). Record score of 0 (no hair) to 4 (frankly virile) for each region, as outlined in the Ferriman-Gallway Visual Scale (see right).

Report: The patient’s Ferriman-Gallwey hirsutism score is 5. There is no evidence of hirsutism.

Ferriman-Gallway Visual Scale⁷

Why Check: Hirsutism is defined by excess terminal hair growth (dark, coarse hairs) in androgen-dependent areas (i.e. 9 regions tested above). The presence of hirsutism mildly increases the likelihood of Cushing’s Syndrome (LR+ 1.7, LR- 0.7); other causes include Polycystic Ovary Syndrome (PCOS), Hyperprolactinemia, Thyroid disorders, Acromegaly, and drug-induced (including a number of neuroleptic medications, SSRIs, SNRIs, and corticosteroids). One way to grade Hirsutism is the Ferriman-Gallwey hirsutism score, which scores each of 9 regions from 0 (no hair) to 4 (frankly virile). This system has limitations (e.g. originally a population study of Caucasian female patients in England). It has been adapted with cut-off scores for hirsutism in female patients vary by race/ethnicity: ≥2 in Asian populations; ≥8 in Black or Caucasian populations; and ≥9 for Mediterranean, Hispanic and Middle Eastern populations. A score of <15 is considered mild hirsutism, 16-25 moderate, >25 severe. Conversely, loss of hair may indicate Hypocortisolism (e.g. Adrenal insufficiency, Addison’s Disease).

Modification for Transgender Patients:

• Transmasculine Patients (FTM): Patients on masculinizing hormone therapy may have oilier skin, more acne, increased facial and body hair, or ↓ scalp hair – important to normalize these changes, where the Ferriman-Gallwey hirsutism score would not apply here.
• Transfeminine Patients (MTF): Patients on feminizing hormone therapy may have softening of skin/decreased skin oiliness, less acne, thinning/slowed growth of facial and body hair, or arrested progression of scalp hair loss – important to normalize these changes, where the Ferriman-Gallwey hirsutism score would not apply here.

Say: I will inspect the skin for signs of coagulopathy.

Do: Assess for Hematomas: Based on size, either Petechiae (1-2 mm diameter red spot), Purpura (3-10 mm), and/or Ecchymosis (>10 mm); as well as Telangiectasias (spider veins)

Report: I note no petechiae, purpura or ecchymosis on inspection.

Petechiae⁸ · Telangiectasias⁹

Why Check: Generally, these are important signs of platelet or vascular disorders. In the context of an Adrenal exam, Ecchymosis mildly increases the likelihood of Cushing’s Syndrome (LR+ 4.5, LR- 0.5).

Say: I will measure the thickness of the skin of the hand using calipers.

Do: Using skin-safe calipers (if available in your clinical setting, ensure caliper points are dulled), hold the patient’s non-dominant hand (e.g. left hand if patient is right-handed) with palm facing down. At the 3rd digit (D3), palpate dorsal skin between the 3rd Metacarpophalangeal (MCP) and 3rd Proximal Interphalangeal (PIP) Joints. Grasp dorsal skin between your 1st an 2nd fingers to create skinfold. Measure skin thickness with calipers.

Report: I note the patient’s skin thickness is 3 millimeters, a negative test for Cushing’s Disease.

Why Check: A thin skinfold of <1.8 mm on back of patient’s hand using calipers to measure greatly increases the likelihood of Cushing’s Syndrome (LR+ 115.6, LR- 0.2). Note the population under study was young women with hirsutism and menstrual irregularities, where these findings are most applicable to similar patients¹.

(Also seen in MF1: Ch 6 – Cardiac Exam and Ch 8 – Peripheral Vascular Exam)

AFMC level Pre-clerkship 4 · Clerkship 4

Say: I will palpate for leg swelling (Sacral edema if patient immobile). Please tell me if you are in discomfort.

Do: Press firmly with pads of your thumbs on the dorsal surface of patient’s leg, just above the ankle at bony prominence. Hold for 10s, then release. Look for pitting edema – skin does not bounce back immediately (i.e. pits). How high does it go on the leg? Is it pitting (transudate) or non-pitting (exudate)?

Look at patient for signs of discomfort and stop exam signs of distress.

Grading: 0 = none; 1+ = 2mm depression; 2+ = 4mm depression; 3+ = 6mm depression; 4+ = 8mm depression

Report: I note (grade) pitting edema bilaterally, up to the level of (location e.g. ankles).

Pedal Edema¹⁰

Why Check: In the context of an adrenal exam, dependent edema mildly increases the likelihood of Cushing’s syndrome (LR+ 1.8, LR- 0.7). Edema is excess interstitial fluid accumulation causing swelling, particularly in gravity dependent areas (e.g. feet). Normally, this fluid returns through lymphatic drainage. Pitting edema = transudate (non-protein filled) – sign of increased hydrostatic pressure (e.g. congestive heart failure, decreased venous return) or decreased oncotic pressure (e.g. nephrotic syndrome, hypoalbuminemia). Non-pitting edema = exudate (protein) filled, or an issue with lymphatic drainage (e.g. lymphedema).