Adrenal Disorders Year 2 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Adrenal Disorders Professor O'Reilly Consultant Endocrinologist LEARNING OUTCOMES 1. Explain the pathophysiology of steroid hormone excess and deficiency​ 2. List the cardinal symptoms of steroid hormone excess and defic...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Adrenal Disorders Professor O'Reilly Consultant Endocrinologist LEARNING OUTCOMES 1. Explain the pathophysiology of steroid hormone excess and deficiency​ 2. List the cardinal symptoms of steroid hormone excess and deficiency​ 3. Explain how each symptom is caused in steroid excess and deficiency​ 4. Explain the pathophysiology of steroid excess and deficiency​ 5. Develop a differential diagnosis for steroid excess and deficiency​ 6. Outline the overarching principles of investigation and management in steroid excess and deficiency​ 7. Outline the symptoms and signs of exogenous steroid use  ADRENAL CORTEX SALT SUGAR SEX Cortex: Mineralocorticoid: - Aldosterone: increased by angiotensin II and K (RAA system) Glucocorticoid: - Cortisol: Stress response. Increases blood sugar levels ,anti-inflammatory, maintenance of BP, cardiac output, water and electrolyte imbalance. Circadian rhythm. - Responds to ACTH Adrenal Androgen/estrogen: - DHEA, estrone and estradiol 17beta, regulated by ACTH Medulla: Chromaffin cells produce catecholamines, mainly epinepherine ALDOSTERONE Acts via mineralocorticoid receptor Electrolyte and fluid balance: Reabsorbs Na and Cl, H20 will follow, increasing the blood volume and BP. K+ is excreted. Aldosterone is regulated by angiotensin II and K. It is NOT centrally regulated, therefore central pathology will have less of an impact on the zona glomerulosa ie. You will see less aldosterone effects in pituitary or ectopic pathologies, more in adrenal. Hypercortisolism Cushing's HYPERCORTISOLISM PATHOPHYSIOLOGY Cushing's Syndrome: a collection of non-specific symptoms and signs that manifest following prolonged exposure to excessive glucocorticoid hormone (cortisol) Cushing's Disease: excessive cortisol due to overproduction of ACTH form a pituitary adenoma Causes: Endogenous cortisol overproduction: 1. ACTH dependent: a. Pituitary adenoma (cushing's disease) 70% of endogenous b. Ectopic ACTH production from tumours in other parts of the body: eg lung cancer (bronchogenic and neuroendocrine tumours, small cell lung ca) 2. ACTH independent: a. Adrenal tumours, adenoma/carcinoma b. Adrenal hyperplasia Exogenous: prolonged glucocorticoid therapy, oral, topical, inhaled, intravenous steroids CUSHING'S: SYMPTOMS Weight Gain Gluconeogenesis leads to high sugar levels, which leads to high insulin levels. Insulin causes fat redistribution to central areas. Cortisol causes hyperphagia. Skin Changes Violaceous striae on the abdomen, thinning of skin, easy bruising. Due to catabolic effect of cortisol, proteolysis. Fractures Osteoporosis: catabolism Non healing Poor wound healing, catabolism, suppressed ulcers immune system. Difficulty Proximal myopathy: catabolism standing from seated position Acanthosis Hyperpigmentation of skin, particularly in Nigricans creases. Manifestation of insulin resistance. Hirsutism Abnormal hair growth: Androgen Excess Menstrual Decrease in GNRH leads to decrease in LH/FSH irregularities Psychiatric Mood disorders, psychosis. Sleep disturbance. CUSHING'S: SIGNS General Rounded face Previously termed 'moon facies', fat redistribution Inspection due to cortisol/insulin Hirsutism and acne Androgen excess Central adiposity Classic appearance is central obesity with thin lower limbs. Fat redistribution with proteolysis/catabolism Interscapular fat pad 'Buffalo hump'. Fat redistribution Hands and Thin skin Catabolism arms Hypertension Increased sensitivity to catecholamines, cortisol binding to mineralocorticoid receptors Face Plethora Cortisol increasing blood flow to face Oral candidiasis Exogenous steroid use, immunodeficiency Abdomen Striae rubrae Violaceous striae, catabolism Legs Thin extremities Muscle and skin catabolism  Buffalo hump Striae Round facies Acanthosis Nigricans CUSHING'S: DIFFERENTIAL DIAGNOSIS Metabolic syndrome Obesity Type 2 diabetes Primary vs Secondary hypercortisolism causes: – Pituitary adenoma – Adrenal adenoma – Ectopic- SCLC INVESTIGATION Out rule exogenous steroids: thorough history Consider appropriate elevation of cortisol, eg. Pregnancy, concurrent illness Demonstrate elevated cortisol/quantify: 24-hour urinary cortisol: >50mcgs is elevated Late night salivary cortisol: will will inversely elevated at night in Cushing's Low Dose Dexamethasone suppression test: 1mg dexamethasone at 23:00 with a serum cortisol at 8am – Steroid should suppress endogenous production of cortisol in normal physiology – >50nmol/L is positive, indicates failure of suppression of cortisol Determine if ACTH dependent/independent: Ie is the cortisol being stimulated by ACTH or is the adrenal gland functioning autonomously? Serum ACTH – Low ACTH suggests ACTH independent hypercortisolism. Rationale: if cortisol levels are high, a normally functioning pituitary should stop producing ACTH. – High ACTH suggests ACTH dependent hypercortisolism. Rationale: ACTH production is continuing despite negative feedback. Source of elevated ACTH: High dose dexamethasone suppression test: used to differentiate between ectopic vs pituitary ACTH producing tumours 8mgs dexamethasone taken at 23:00, serum ACTH and cortisol at 8am – Failure to suppress cortisol indicates ectopic secretion – Rationale: Corticotroph tumors are only relatively resistant to negative feedback regulation by glucocorticoids i.e. A pituitary tumour should respond to such high doses of steroid, as they do still possess some glucocorticoid receptors. In contrast, most nonpituitary tumors associated with the ectopic ACTH release are completely resistant to feedback inhibition (as they do not possess glucocorticoid receptors). Eg. SCLC, neuroendocrine tumours. INVESTIGATION Imaging: CT adrenals: if ACTH is low and adrenal pathology is suspected MRI pituitary: If ACTH is high, but suppressed on high dose dexamethasone suppression test, pituitary adenoma/carcinoma should be suspected. (Also correlate with your exam findings- ? any visual field disturbance) CT thorax, abdomen and pelvis: if ACTH high, and not suppressed on high dose dexamethasone test, indicates ectopic source. eg. Small cell lung cancer, or other neuroendocrine tumours. Other: IPSS: Inferior petrosal sinus sampling: – Gold standard in distinguishing between pituitary and ectopic source in ACTH dependent syndrome, but invasive Serum glucose, HbA1c CUSHING'S INVESTIGATION ALGORITHM MANAGEMENT Primary Prevention: ​Steroid awareness, steroid sparing medications​ Pituitary Adenoma: Somatostatin analogue, surgery: transsphenoidal resection, radiotherapy Ectopic ACTH producing tumours: Somatostatin analogues, surgery, chemotherapy, radiotherapy Post-operative replacement of steroid: Hydrocortisone PO 20mgs mane, 10mgs tarde (two thirds in am, one third in pm)​ Post-operative replacement of other hormones as required eg. Pituitary: levothyroxine, sex hormone replacement. Fludrocortisone with bilateral adrenalectomy. Monitor for complications: Cardiovascular risks, diabetes, osteoporosis Hypocortisolism Addison's PATHOPHYSIOLOGY Primary adrenal insufficiency: Low circulating: Cortisol: fatigue, weight loss, hypoglycaemia, hypotension, poor healing Aldosterone: hypotension, hyponatraemia, hyperkalaemia, dehydration Androgens: loss of libido (women) ACTH will rise in response, trying to stimulate the non-functioning adrenal gland. ACTH is formed from a precursor POMC- proopiomelantocortin. When POMC is cleaved to produce ACTH, MSH is also formed as a byproduct Excess of MSH (melanocyte stimulating hormone)- leads to increased skin pigmentation. This is very characteristic of addison's, a bronzed look. Can also have darkness of gums In secondary adrenal insufficiency, aldosterone release is not impacted by reduced ACTH, therefore dehydration and hypotension are less prevalent than in primary hypocortisolism. ADRENAL INSUFFICIENCY Signs and symptoms of adrenal insufficiency depend on: Rate of loss of function (eg. in bilateral adrenal infarction or pituitary infarction there is a sudden drop in cortisol, vs. an autoimmune process leading to a gradual reduction) If mineralocorticoid production is preserved Extent of loss of function Often onset of symptoms is very gradual and undetected, until an acute precipitant leads to adrenal crisis An acute stressor requiring cortisol production, eg. Infection, illness, trauma, surgery Adrenal crisis can often be the first presentation of adrenal insufficiency Adrenal crisis is a life-threatening medical emergency, which requires prompt recognition and management.  ADRENAL CRISIS Liver production of Hypoglycaemia CORTISOL sugar decreases Low or absent Decreased Vomiting, diarrhoea, stomach digestive cramps enzymes Decreased sensitivity to Adrenal glands catecholamines Coma, death not functioning Kidney: Na and water loss Low fluid volume Hyponatraemia Shock ALDOSTERONE Hyperkalaemia Hypotension Low or absent Arrhythmia Reduced cardiac output SYMPTOMS Reduced GCS In crisis: hypoglycaemia, severe hypotension, circulatory failure Fever Infections can precipitate addisonian crisis , OR fever can be indicative of an infectious cause Constitutional Fatigue, weight loss, anorexia Tanned skin Hyperpigmentation due to MSH (byproduct of POMC, prohormone for ACTH) Salt craving Aldosterone deficiency causes hyponatraemia, which can trigger salt craving Gastrointestinal Vomiting, diarrhoea Abdominal pain: tends to be generalised, unclear cause, possibly serositis associated with autoimmune pathology. The presence of abdominal pain with fever can lead to incorrect diagnosis of a surgical abdomen, surgical exploration leads to catastrophic shock. Joint and muscle Unclear cause, tends to improve dramatically with steroids pain Loss of libido More common in men as androgen production occurs in testis Cushingoid With exogenous steroids, causing tertiary deficiency features SIGNS DIFFERENTIALS Causes of primary, secondary and tertiary Hyperpigmentation: Haemochromatosis Hyperthyroidism INVESTIGATIONS Urea and Electrolytes: Hyponatraemia, hyperkalaemia. Demonstrate Cortisol Deficiency: AM cortisol- decreased 450nmol/L is normal. Serum ACTH: Primary adrenal insufficiency: ACTH is high Secondary: ACTH is low Tertiary: ACTH is low Serum DHEA and aldosterone: Will be reduced in autoimmune (destruction of gland) but may be preserved in secondary and tertiary Plasma Renin: elevated in primary adrenal insufficiency secondary to loss of aldosterone Adrenal antibodies, 21beta hydroxylase CT/MRI adrenals: Adrenals may be atrophied in primary insufficiency, or enlarged in infection and malignancy. MRI pituitary: out rule pituitary adenoma MANAGEMENT Primary prevention: Lowest doses of steroid for shortest period of time Secondary prevention: STRESS DOSE steroids during illness, medical alert bracelet, IV hydrocortisone injection in case of emergency Acute: Addison's Crisis: MEDICAL EMERGENCY – IV HYDROCORTISONE 100mgs STAT, followed by QDS – Fluid resuscitation – Address underlying cause Chronic: – Steroid replacement: Glucocorticoid: Hydrocortisone BD, two thirds in morning, one third in evening, eg. 20mgs mane, 10mgs tarde. Mineralocorticoid if required: fludrocortisone 0.1mgs OD Stress dosing Hyperaldosteronism HYPERALDOSTERONISM HYPERTENSION: is the major clinical finding HYPOKALAEMIA Primary hyperaldosteronism: aka Conn's syndrome: – Aldosterone secreting adrenal tumours – Adrenal hyperplasia Excess production of aldosterone from the adrenal glands, leads to low levels of renin due to negative feedback loop Increased absorption of sodium and water leads to hypernatraemia and fluid retention Hypertension Metabolic alkalosis due to renal excretion of H+ ions Most common form of endocrine induced hypertension CAUSES SYMPTOMS Headaches/ changes in vision Secondary to hypertension Urinary frequency/nocturia Compensatory urination Palpitations/muscle weakness Hypokalaemia Thirst Hypernatraemia SIGNS Raised BMI Metabolic syndrome, common in primary hyperaldosteronism BP Resistant hypertension Irregular pulse Arrhythmia secondary to hypokalaemia Heart failure symptoms Due to prolonged hypertension Muscle weakness Hypokalaemia Oedema Fluid retention INVESTIGATION AND MANAGEMENT Aldosterone: renin ratio. – Ratio >70 for aldosterone Fludrocortisone suppression test Saline infusion testing Oral salt loading CT adrenals Spironolactone- mineralocorticoid receptor antagonist. Surgery: unilateral or bilateral adrenalectomy  Adrenal Medulla Phaeochromocytoma PHAEOCHROMOCYTOMA Catecholamine producing tumour of chromaffin cells of adrenal medulla Rare, 0.2% of patients with hypertension 40% have familial disorder- von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), and less commonly, neurofibromatosis type 1 (NF1). Symptoms: can be paroxysmal. Relate to catecholamine release. Classic triad (paroxysmal tachycardia, headache, sweating), hypertension (a cause of secondary hypertension), palpitations, tremor, anxiety. Complications: Hypertensive consequences: cardiomyopathy, Investigations: 24 hour urinary catecholamine and metanepherine collection, CT abdomen and pelvis to assess for adrenal mass. Management: Surgical excision- adrenalectomy, requires pre- operative medical blockade to avoid lethal hypertensive crises, arrhythmias: o Alpha adrenergic blockade: Phenoxybenzamine o Beta adrenergic blockage: Propranolol o Calcium channel blockers Image source: https://www.gastroepato.it/en_feocromocitoma.htm LEARNING OUTCOME Outline the symptoms and signs of exogenous steroid use EXOGENOUS STEROIDS Used for anti-inflammatory and immunosuppressive properties Side effects are widespread, due to the presence of steroid receptors in almost all cells of the body Side effects are dose and duration dependent Side- effects of steroids: Metabolic: Iatrogenic cushing's syndrome, diabetes, weight gain Cardiovascular: Fluid retention (oedema, heart failure), hypertension, increased risk of CV events Musculoskeletal: Osteoporosis, avascular necrosis, myopathy GI: Gastritis, GI ulceration Ocular: Glaucoma, cataract Skin: Acne, impaired wound healing, thin skin, striae Immune: Increased risk of infection (consider PCP prophylaxis in long term steroid use) Psychiatric: Insomnia, emotional lability, agitation, psychosis  EXOGENOUS STEROIDS Natural adrenal production of steroid equals approximately 7.5mgs of prednisolone per day Exogenous steroid will suppress the HPA axis, reducing ACTH levels. As ACTH stimulates adrenal growth, ACTH suppression will lead to adrenal atrophy With high doses of exogenous steroids, atrophy can occur as early as 7 days into therapy and prescribers must anticipate this. Need to wean steroids gradually to allow return of native adrenal function DO NOT STOP STEROIDS ABRUPTLY or you may precipitate adrenal crisis REMEMBER: STRESS DOSE STEROIDS/ SICK DAY STEROIDS In times of intercurrent illness/stress eg. trauma or surgery, individuals on long term steroids will require double dosing of their steroid. This is to mimic the natural increase in cortisol production in stress (stress response).​ Should they not be able to tolerate steroids orally (eg. vomiting), it is essential that patients attend hospital for intravenous steroid to avoid adrenal crisis EXOGENOUS STEROIDS OTHER CONSIDERATIONS Should a prolonged/repeated course of steroid be required, consider the following: Proton pump inhibitors Monitor blood sugar levels: steroid induced hyperglycaemia Bone protection: DEXA scanning, calcium D3 supplementation, bisphosphonates etc. Prophylactic antibiotics eg. Co-trimoxazole Routine assessment for hypertension, diabetes. 1 2 3 4 5 6 7 8 ECG: slow AFIB 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 FURTHER READING / REFERENCES https://www.sciencedirect.com/science/article/pii/S0925443913001919 https://www.uptodate.com/contents/determining-the-etiology-of-adrenal-insufficiency-in- adults?search=adrenal%20insufficiency%20&source=search_result&selectedTitle=1~150&usage_ type=default&display_rank=1 https://www.uptodate.com/contents/clinical-manifestations-of-adrenal-insufficiency-in- adults?search=adrenal%20insufficiency%20&source=search_result&selectedTitle=2~150&usage_ type=default&display_rank=2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276933/