Adrenal Pathology Week 3 PDF

Adrenal Pathologies PAT-3.04 BMS 200 Learning outcomes  Describe the pathophysiology of Cushing's syndrome and Cushing's disease and relate them to their respective clinical features.  Describe the pathophysiology of Addison's disease and compare it to adrenal insufficiency.  Describe the p...

Adrenal Pathologies PAT-3.04 BMS 200 Learning outcomes  Describe the pathophysiology of Cushing's syndrome and Cushing's disease and relate them to their respective clinical features.  Describe the pathophysiology of Addison's disease and compare it to adrenal insufficiency.  Describe the pathophysiology of Conn's disease and relate it to its clinical features.  Predict the pathological findings, clinical features, and complications associated with pheochromocytoma.  Explain the pathophysiology of adrenal neoplasms and their correlation with clinical features.  Describe the pathophysiology of congenital adrenal hyperplasia and its relationship to clinical features.  Relate the pathophysiology and clinical features of relevant endocrinologic disorders to the following diagnostic tests: insulin tolerance test, CRH test, aldosterone: renin ratio, 17-OH progesterone, serum ACTH, cortisol testing, DXM suppression test; neurologic imaging (MRI). Terminology Within many endocrine pathologies, the location of dysfunction is denoted by:  Tertiary refers to dysfunction at the hypothalamus  Secondary refers to dysfunction at the level of the pituitary gland  Primary – refers to dysfunction within the “final” endocrine organ Eg. Adrenal glands Pathologies of the Adrenal Glands - intro Can involve hyper- or hypofunction: Hyperfunction:  secondary causes are quite common (pituitary dysfunction)  Can involve increased levels of cortisol or aldosterone Disorders that are associated with elevated levels of androgens usually also involve decreased levels of glucocorticoids and/or mineralocorticoids Hypofunction:  We will focus on significant insufficiencies of the adrenal cortex  Subtle alterations of glucocorticoid levels will not be discussed today Pathologies covered today Hyperfunction: Hypofunction:  Cushing’s  Adrenocortical syndrome insufficiency Hypercortisolism  Congenital adrenal  Hyperaldosteronism hyperplasia  Pheochromocytoma Enlarged adrenal gland Cushing Syndrome Disorder caused by any condition that produces an elevation in glucocorticoid levels (cortisol) 4 common sources of excess cortisol:  Iatrogenic  majority of cases from medical sources  hypothalamic-pituitary diseases associated with hypersecretion of ACTH  Hypersecretion of cortisol by an adrenal adenoma, carcinoma or nodular hyperplasia  Secretion of ectopic (from someplace else other than pituitary gland) ACTH by a nonendocrine neoplasm – aka paraneoplastic syndrome Hypersecretion of ACTH 70 to 80% of cases of endogenous hypercorticolism  Affects women 5 times more often than men, occurs most frequently in twenties and thirties Vast majority of cases: pituitary gland contains an ACTH-producing microadenoma  Referred to as Cushing Disease  What do you think the adrenal glands would look like? Why? Ectopic ACTH production Paraneoplastic syndrome  Main tumours are small cell lung cancer and a renal adenocarcinoma  Represent about 10% of cases of endogenous Cushing syndromes  Usually involve rapid increases in the levels of ACTH and evolution of symptoms/signs What would you expect the adrenals to look like?  Enlarged ACTH-independent Cushing Syndrome Primary Cushing syndrome  10 to 20 % of cases of endogenous hypercorticolism are due to an adenoma in the adrenal glands themselves Adenomas are usually well-differentiated, more common in women, and functional (i.e. secrete cortisol) Assume the adenoma is only found in one adrenal gland – what would the rest of the adrenal tissue look like? Why?  Smaller. Adrenal Carcinoma Adrenocortical carcinoma  Uncommon cause of primary Cushing’s syndrome FYI – Cushing’s disease  No suppression => ectopic ACTH-dependent (ACTH is coming from somewhere else)  e.g. lung and kidney tumours can produce ACTH  Labs - Cushing Syndrome continued Cortisol ACTH Dexamethaso ne suppression For Cushing syndrome: test Cushing’s  Once High High (pituitary High dose: Disease Cushing syndrome is tumour established, how ACTH low, could serum ACTH levels help secreting us distinguish ACTH) Low Cortisol between primary Cushing’s disease or ACTH- dependent forms for Cushing’s syndrome? Low dose: High cortisol Adrenal High Low-normal; High dose: Adenoma because ACTH cortisol does suppressed; negative Cortisol still feedback high *anma says not suppressed Paraneoplastic High High (ectopic High dose Adrenocortical insufficiency Can be primary or secondary  What do these terms mean again? Anterior pituitary (2nd) or adrenal glands (1) Can also be an acute or a chronic disorder  Those with chronic adrenal insufficiency may show signs similar to acute insufficiency if their need for steroids (stress, infection) suddenly increases  Acute can be iatrogenic – people being weaned off of high doses of glucocorticoids too quickly Why would this lead to adrenal insufficiency? Adrenal Insufficiency Caused by primary adrenal disease or decreased stimulation of the adrenals due to a deficiency of ACTH Patterns of adrenal insufficiency can be considered under the following headings: – Primary acute adrenocortical insufficiency (Adrenal crisis) – Primary chronic adrenal insufficiency (Addison Disease) – Secondary adrenocortical insufficiency (also chronic) Primary Acute Adrenocortical Insufficiency Etiologies:  In patients with chronic adrenocortical insufficiency precipitated by any form of stress that requires an increased in steroid output from glands incapable of responding  In patients on exogenous corticosteroids Rapid withdrawal of steroids or failure to increase steroid doses in response to acute stress may precipitate an adrenal crisis = inability of atrophic adrenals to produce glucocorticoid hormones  Adrenal hemorrhage Next slide Acute adrenal insufficiency: adrenal hemorrhage Adrenal glands among the best-perfused tissues in body Hemorrhage can be caused by a number of different problems:  Newborns after a prolonged & difficult delivery  Anticoagulant therapy  Post-surgical disseminated intravascular coagulation (aka DIC) (problems clotting after surgery)  Waterhouse-Friderichsen syndrome (rare) Acute adrenal insufficiency Life-threatening Emergency Clinical features:  Hemodynamic instability inability to maintain blood pressure, shock, severe postural hypotension  Abdominal pain, nausea, vomiting, fever  Hypoglycemia and hyponatremia  Decreased level of consciousness, stupor Often exacerbated by concomitant illness and physiologic stress (shock, infection, surgery, trauma)  Can occur on a background of slowly progressive chronic insufficiency Addison Disease: Chronic primary Adrenal Insufficiency Addison Disease  Uncommon disorder resulting from progressive destruction of adrenal cortex  Clinical manifestations do not appear until 90% of adrenal cortex compromised 90% of all cases are attributable to one of four disorders  Autoimmune destruction of the adrenal cortex (60- 70% in developed countries)  TB (less common now, but most common cause worldwide)  AIDS  Sarcoidosis or malignancy usually lung or breast metastases Addison disease - pathogenesis Autoimmune causes:  Autoimmune polyendocrine syndrome (APS) type 1 Rare, autosomal recessive condition  FYI - mutation in an autoimmune regulator gene (AIRE) that is thought to help the immune system “ignore” normal tissue Begins in older children & adolescents several endocrine organs can be attacked  APS type 2 More common than type I begins in early adulthood (20-40s) does not have skin or dental findings often autoimmune attack of multiple endocrine organs  Idiopathic Addison Disease: Clinical Course Begins insidiously - at least 90% of cortex of both glands destroyed Initial manifestations: progressive weakness and easy fatigability GI disturbances: anorexia, nausea, vomiting, weight loss, diarrhea Hyperpigmentation Loss of potassium and sodium: Hypotension, hyperkalemia*, hyponatremia, volume depletion Stress (infection, trauma, or surgery) can cause an acute adrenal crisis Death can occur rapidly unless corticosteroid therapy begins immediately Secondary Adrenocortical Insufficiency Any disorder of hypothalamus and pituitary that reduces the output of ACTH → syndrome of hypoadrenalism  Possible etiologies include: metastatic cancer, infection, infarction, irradiation With secondary disease, hyperpigmentation of primary Addison is absent Deficient cortisol and androgen output but normal aldosterone levels (therefore no hyperkalemia, hyponatremia) Labs: In the case of suspected ACTH deficiency:  Insulin tolerance test: after insulin administration cortisol & ACTH secretion should increase  CRH administration should also show increased cortisol and ACTH plasma levels  Labs – Adrenal insufficiency For Adrenal insufficiency  Often ACTH & cortisol is measured (as 24-hour free urine cortisol and/or serum morning cortisol)  What do we expect urine or serum cortisol & ACTH to be with Adrenal insufficiency? Low To distinguish between primary and secondary adrenal insufficiency an ACTH stimulation test can be done  Exogenous ACTH (cosyntropin) is given Cortisol ACTH ACTH stimulation test Addison’s Low High  Low cortisol disease unregulated (primary) Secondary Low Low High cortisol adrenal insufficiency Primary hyperaldosteronism Generic term for small group of closely related, uncommon syndromes  Characterized by chronic excess aldosterone secretion Causes sodium retention and potassium excretion Resulting in hypertension and hypokalemia Indicates an autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity Primary Hyperaldosteronism Where is the level of dysfunction? Etiologies:  Adrenocortical neoplasm: usually a solitary aldosterone secreting adenoma Conn Syndrome  Bilateral hyperplasia of adrenals Secondary hyperaldosteronism Aldosterone release in response to activation of the renin-angiotensin system Characterized by increased levels of plasma renin Conditions: – Decreased renal perfusion – Arterial hypovolemia and edema: CHF, cirrhosis, nephrotic syndrome – Pregnancy: due to estrogen induced increases in plasma renin substrate Clinical course of Hyperaldosteronsim Hypertension:  sodium retention increases total body sodium and expands the extracellular fluid Hypokalemia:  due to renal potassium wasting and can cause variety of neuromuscular manifestations Labs:  Serum aldosterone & renin can be measured for an aldosterone: renin ratio (ARR) What would you expect serum aldosterone to be? What about the ARR?  Small (high aldosterone: high renin) *secondary issue  Large (high aldosterone: low renin) *primary issue Congenital Adrenal Hyperplasia (CAH) Autosomal recessive defect in enzyme in cortisol synthesis pathways  Most common enzyme deficiency: 21- Hydroxylase  Results in mild to complete lack of cortisol production  How would this result in adrenal hyperplasia?  What would accumulate? Congenital Adrenal Hyperplasia (CAH) continued Types:  Classic: affects newborns Salt-wasting:  complete inactivation of 21-hydroxylase Simple virilizing:  significantly reduced function of 21- hydroxylase  Non-classic Milder & later onset (late childhood/early adulthood) Partial deficiency in 21- hydroxylase Congenital Adrenal Hyperplasia (CAH) – classic forms Salt-wasting  No synthesis of aldosterone causes hyponatremia, hyperkalemia, dehydration, hypotension, & increased renin secretion Can be fatal if not treated  Virilization of female infants Simple virilizing  Female infants often have ambiguous genitalia at birth  Male infants show no abnormalities of sexual organs at birth  Adult women typically experience infertility Adult men can be fertile or experience azoospermia Congenital Adrenal Hyperplasia (CAH) – non-classic Late-onset (aka non-classic)  Most common form of CAH  No abnormalities at birth, symptoms typically present at puberty  In women, late-onset CAH can often mimic poly cystic ovary syndrome (PCOS) Hirsutism, acne, menstrual irregularities, infertility  Men are often asymptomatic  Labs 17 hydroxyprogesterone (17-OHP) levels as assessed, what would you expect to see?  High levels Pheochromocytoma Rare tumour of chromaffin cells (medulla of adrenals)  Most of the time secretes elevated quantities of catecholamines (epinephrine/norepinephrine) Etiology:  Most often sporadic, occasionally inherited alone or as part of hereditary syndrome Pathology:  Most of the time tumours arises in the adrenal medulla FYI - (10% will arise elsewhere, i.e. carotid bodies)  In about 10% of cases they can be malignant and will invade Pheochromocytoma continued Clinical features: Dominant picture is hypertension  Many have a baseline elevated blood pressure  2/3 will experience paroxysmal hypertension enormous acute increases in blood pressure, often precipitated by stress or even posture changes Large changes in blood pressure can result in cerebrovascular accidents, heart failure, and eventual hypertrophy of the heart  Treated with surgical excision – surgically curable high blood pressure Elevated levels of what would you expect to find in the urine?  High levels of free catecholamines, which metabolize to VMA and _____ Adrenals Labs Summary Increased levels of cortisol:  Cushing disease, Cushing syndrome  Stress (physiologic or psychologic)  Hyperthyroidism (increased cortisol to meet needs of metabolism) Decreased levels of cortisol:  Congenital adrenal hyperplasia  Addison disease  Hypopituitarism, hypothyroidism