Adrenal disease. Dr Alan McNeil Chemical Pathologist Melbourne Pathology. Case study - 19 year old man

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1 Case study - 19 year old man Adrenal disease Dr Alan McNeil Chemical Pathologist Melbourne Pathology Tired and breathlessness Child of related parents Short stature BP 170/120 mmhg Male pattern facial hair Ambiguous genitalia not clearly male or female Internal Med J 2013 Case study - 19 year old man Low serum K+ 2.8 mmol/l ( ) Abdominal CT Enlarged adrenal glands Chromosomes Female 46 XX Case study - 19 year old man Summary Increased risk of genetic disease. Enlarged adrenal glands. Male appearance but female chromosomes and ambiguous genitalia. High blood pressure. Low serum potassium.

2 Objectives 1. Revise physiology of adrenal cortex 2. Understand Addison s and Cushing s diseases 3. Understand the mineralocorticoid diseases causing high blood pressure 4. Understand the manifestations of congenital adrenal hyperplasia (CAH) Objectives Should understand the following tests Serum cortisol, Short Synacthen test UFC, DST, salivary cortisol Renin, aldosterone 17 hydroxy progesterone Adrenal glands Adrenal anatomy and physiology The adrenal glands sit above the kidneys The medulla secretes adrenaline. The cortex makes three types of steroid hormones from cholesterol Glucocorticoids - cortisol Mineralocorticoids - aldosterone Androgens - DHEAS

3 Adrenal glands Adrenal hormones Zona Glomerulosa Zona Fasciculata Cortisol Cortisol Zona Reticularis Medulla Sex steroids Catecholamines Cortisol binding globulin (CBG) Adrenal control - glucocorticoids Decreased CBG Acute illness Nephrotic syndrome 80% of cortisol is bound to CBG. Immunoassays measure total cortisol concentration which will change if CBG changes... Increased CBG Contraceptive pill Pregnancy Hypothalamus CRH Pituitary ACTH Adrenal Cortisol Tissues Cortisol has effects on the metabolism of glucose, fat and protein as well as the immune system. ACTH and cortisol peak at 9 am and are low at midnight.

4 Adrenal control - mineralocorticoids Therapeutic uses of adrenal hormones BP K + K + Kidney Adrenal cortex K + secretion Na + reabsorption Renin Angiotensinogen Angiotensin 1, 2 Blood vessels BP Anti-inflammatory Side effects Asthma Peptic ulcer Arthritis Diabetes Transplant Thin skin & bruising Cerebral oedema Infection Replacement High blood pressure Addison s disease Muscle weakness Pituitary disease Adrenal atrophy Low blood pressure Addison s disease Addison s Adreno-cortical failure leading to deficiency of cortisol, aldosterone and adrenal androgens. disease Causes Autoimmune Malignancy Tuberculosis Bleeding Thomas Addison

5 Addison s disease Symptoms Signs Tiredness 100% Weight loss 100% Nausea 86% Pigmentation 94% Vomiting 75% Low BP 90% Constipation 33% Low sodium 88% Salt craving 16% High K + 64% Dizziness 12% Anaemia 40% Hypoglycaemia? Addison s disease Low cortisol high ACTH skin pigmentation Pigmentation may be in unusual places such as palmar creases and inside mouth. Addison s disease - diagnosis Morning serum cortisol is a simple and convenient test for Addison s disease. 9 am cortisol Probability < 100 nmol/l High nmol/l Uncertain > 500 nmol/l Low Addison s disease - diagnosis The Synacthen test is a more reliable way to diagnose Addison s disease Serum cortisol before and 30 and 60 minutes after 250 ug synthetic ACTH injection Interpretation Increase > 200 nmol/l and at least one result > 550 nmol/l

6 Addison s disease - diagnosis Synacthen test limitations 1. Anaphylaxis Some people have a life-threatening adverse reaction to Synacthen 2. Changes in cortisol binding globulin 3. Assay bias Problem with using published cut-offs Conclusions 1. Addison s disease is uncommon but it can be debilitating or fatal. 2. Diagnosis is often delayed hints include pigmentation, high serum K +, low serum Na + or low glucose 3. Morning serum cortisol is simple but the Synacthen test is more accurate. Cushing s syndrome Cushing s syndrome The changes caused by chronic excess steroid hormone. The most common cause is steroid medication given to treat another disease. Cushing s syndrome caused by endogenous production of excess steroids is uncommon.

7 Cushing s syndrome Endogenous causes 65% ACTH-secreting pituitary tumour (Cushing s disease) 20% Cortisol secretion by adrenal tumour (ACTH low). 15% Ectopic ACTH secretion by a non-pituitary tumour. Harvey Cushing Cushing s syndrome Symptoms Central obesity Striae Osteoporosis Depression Bruising Diabetes High blood pressure Muscle weakness Cushing s syndrome - diagnosis 1. Serum cortisol Not a reliable test for Cushing s syndrome because non-specific increases are common. Cushing s syndrome - diagnosis 2. Urine free cortisol A good test for Cushing s syndrome as it measures the 24 hour production of cortisol. Not influenced by CBG changes. Disadvantages Inconvenience of collection Variation in laboratory methods

8 Cushing s syndrome - diagnosis 3. Midnight salivary cortisol People with Cushing s lose the diurnal variation in cortisol so their concentrations are high at midnight. Saliva can be collected at home. Disadvantages The method must be adjusted to deal with saliva and low concentrations Cushing s syndrome - diagnosis 4. Dexamethasone suppression test This test is able to differentiate the different types of Cushing s syndrome. Disadvantages The full test usually requires hospital admission. Cushing s syndrome - diagnosis Cushing s disease - treatment Normal 1 mg 2 mg 8 mg Dexa. Pituitary Cushing s Transsphenoidal surgery Stress Adrenal tumour Remove tumour Pituitary Adrenal Ectopic ACTH low ACTH high Morning serum cortisol Ectopic ACTH Some patients need drugs to suppress their adrenals if the tumour cannot be removed.

9 Mineralocorticoid hypertension Mineralocorticoid hypertension Chronic aldosterone secretion by an adrenal tumour (Conn s syndrome) or adrenal hyperplasia can cause high blood pressure through Na + retention. Some people may have low serum K +. Mineralocorticoid hypertension is underdiagnosed. Mineralocorticoid hypertension Adrenal control - mineralocorticoids The features of mineralocorticoid hypertension are increased serum aldosterone and supressed renin. Follow up tests suppression test Adrenal vein sampling BP K + K + Kidney Adrenal cortex K + secretion Na + reabsorption Renin Angiotensinogen Angiotensin 1, 2 Blood vessels BP

10 Mineralocorticoid hypertension Mineralocorticoid hypertension BP K + Kidney Adrenal cortex Renin Angiotensinogen Angiotensin 1, 2 Blood vessels Problem Excess aldosterone may be important in 1-10% of people with high blood pressure. It is impossible to do all of the tests required on so many people. K + K + secretion Na + reabsorption BP Mineralocorticoid hypertension Suggested Solutions 1. Investigate selected patients severe high blood pressure, unexplained low K + etc. 2. Treat everyone with the aldosterone blocker, spironolactone. Congenital adrenal hyperplasia

11 Congenital Adrenal Hyperplasia Congenital Present at birth Adrenal Affects the adrenal steroid pathways Hyperplasia The adrenals grow bigger as they work hard to overcome the enzyme block. Case study - 19 year old man Summary Increased risk of genetic disease. Enlarged adrenal glands. Female chromosomes but ambiguous genitalia and male hair growth. High blood pressure. Low serum potassium. Case study - 19 year old man Diagnosis An uncommon form of CAH affecting the enzyme 11 hydroxylase. The ambiguous genitalia and male facial hair in a female indicate pre- & post-natal exposure to androgens. The high blood pressure and low K + indicate excess mineralocorticoids. Adrenal hormones Cholesterol Pregnenolone 17-OH Preg DHEA Progesterone 17-OH Prog A-dione DOC Deoxycortisol Corticosterone Cortisol

12 Adrenal hormones Cholesterol Pregnenolone 17-OH Preg DHEA Progesterone 17-OH Prog A-dione DOC Deoxycortisol Corticosterone Cortisol Congenital adrenal hyperplasia Steroid hormone balance is disturbed. Serum 17 hydroxy-progesterone is usually increased. 21 hydroxylase 11 hydroxylase GC MC Andr. 11 hydroxylase Conclusions 1. Conclusions 1. Adrenal anatomy & physiology review. Adrenal hormones CBG Glucocorticoid control Mineralocorticoid control 2. Addison s disease. Serum cortisol Short Synacthen test

13 Conclusions Cushing s syndrome Salivary cortisol Urine free cortisol Dexamethasone suppression test 4. Mineralocorticoid hypertension. High BP, low renin, low potassium Conclusions Congenital adrenal hyperplasia Inherited defects in adrenal cortex enzymes can disturb the balance between different types of steroid hormones GC, MC and androgens. Increased 17 OH progesterone is a useful marker of CAH.