Managing Addison’s Disease Dr Ved Bhushan Arya MD PhD Consultant Paediatric Endocrinologist Kings College Hospital, London Thomas Addison 1793-1860 Guy’s Hospial Described Symptoms 1855

Hypothalamic Pituitary Adrenal Axis

Actions of Glucocorticoids (Cortisol) Maintains normal blood glucose levels during starvation Maintains normal blood pressure (role in heart contractility effectiveness and vascular tone)

Actions of Mineralocorticoids (Aldosterone) Enhances the reabsorption of sodium from kidneys – maintains blood volume and blood pressure Increases the excretion of potassium through effect on kidneys – If potassium in blood very high  cardiac arrhythmia

Adrenoleukodystrophy (ALD) Progressive accumulation of VLCFAs in the Adrenal Cortex Adrenal Cortex progressively destroyed Loss of glucocorticoid and mineralocorticoid function

Presenting signs and symptoms in patients with Primary Adrenal Insufficiency Nerup J. Acta Endocrinol. 1974; 76:27-141

Primary Adrenal Insufficiency: Confirmation of diagnosis Elevated serum ACTH Low serum cortisol (in context of clinical condition) Elevated plasma renin activity (an indicator of salt depletion and low blood volume) with inadequate aldosterone level Possibly low plasma sodium/raised plasma potassium RENIN ALDOSTERONE

Screening if diagnosed ALD first – repeated until abnormal Morning (09:00h) ACTH and cortisol may miss evolving primary adrenal insufficiency Short Synacthen (ACTH stimulation) test Plasma Renin Activity

Frequency of Primary Adrenal Insufficiency in X-ALD phenotypes Estimated Relative Frequency Adrenocortical Insufficiency Childhood Cerebral 31-35% 79% Adolescent 4-7% 62% Adult Cerebral 2-3% >50% Adrenomyeloneuropathy 40-46% 50-70% Addison only Varies with age; Up to 50% in childhood 100% Asymptomatic Common before 4 years of age > 50% (with testing)

J Clin Endocrinol Metab, February 2016, 101(2): 364-389

Management Aims Family to understand the underlying condition and lifelong importance of adequate treatment. Replace Glucocorticoid: Hydrocortisone (10-12mg/m2/d) (potency = 1.0) 2-3 divided doses Prednisolone (potency 4.0) Replace Mineralocorticoid (salt retention) Fludrocortisone (synthetic equivalent of aldosterone) No restriction of dietary salt

Cortisol concentrations in healthy volunteers Cortisol concentrations measured by immunoassay on thee times daily immediate-release hydrocortisone 20 – 40 mg in adrenal insufficiency patients

Monitoring and Adjusting Treatment Growth Height, Weight 3 – 6 monthly – aim to avoid excessive weight gain or growth suppression Mineralocorticoid dose: Blood Pressure Plasma Renin Activity (PRA) Glucocorticoid dose: various options Primarily symptoms e.g. tiredness, headache – deficiency Blood/Salivary profile: cortisol 2-4 hourly day profile

Drug Interactions:

Treatment problems Some children don’t like hydrocortisone taste: try “Corlan” tablets - GPs like as cheap! But for buccal ulcer treatment – not GI absorption. Hydrocortisone requires frequent doses to mimic natural cortisol diurnal rhythm ; prefer x3 /day in chidhood ? x2 /day from teenage 3) Prednisolone lasts longer (used more in teenagers & adults) but increased risks of: Growth suppression Weight gain / obesity Osteoporosis Possible Future Solution(s): Delayed release hydrocortisone formulation – under development Continuous subcut. Hydrocortisone infusion – like insulin for diabetics – expensive but feasible.

Sick day management Treat the underlying illness if systemic with fever or vomiting (GP / hospital as necessary) Hydrocortisone (oral) dose increase x 2 or 3 Fludrocortisone dose unchanged Maintain adequate fluid and glucose / carbohydrate source (Dioralyte alone = insufficient glucose) Provide : “Hypostop” Dextrose gel Subcut. Glucagon (to correct hypoglycaemia) IM / (rectal) Hydrocortisone Hospital (TWIMC letter with instructions) – don’t be shy! Ambulance service registration as steroid dependent patient Home/School Pack

Extra Precautions Ensure routine immunisations in infancy not delayed (“because child on steroids……”) MedicAlert or similar identification tag +/- steroid card Steroid cover for elective surgery/anaesthetics Carry 2 separate sets of tablets and emergency pack when travelling on holiday (especially overseas) Extra Immunisations (for patients on steroid replacement) Pneumococcal Hepatitis A/B (e.g. “Twinrix”) Influenza

30 year experience – single centre Primary Adrenal Insufficiency (Addison’s) – 5.2 AC episodes/100 patient years (111 pts) Secondary Adrenal Insufficiency (Hypopituitary) – 3.6 AC episodes/100 patient years (319 pts) Tertiary Adrenal Insufficiency (Glucocorticoid induced) – 15.1 AC episodes/100 patient years (28 pts) Most precipitated by infection and in patients with co-morbidities

Cortisol concentrations in healthy volunteers Newer Developments Cortisol concentrations in healthy volunteers Cortisol concentrations on once daily Plenadren 20 - 40mg in patients with adrenal insufficiency

Cortisol concentrations in healthy volunteers Newer Developments Cortisol concentrations in healthy volunteers Cortisol concentrations on twice daily Chronocort 20mg at 23:00h and 10mg at 07:00h in patients with congenital adrenal hyperplasia

Capsules containing 0.5mg, 1mg, 2mg and 5mg doses of immediate release multipariculate granules

Thank You