HPAA_2022 rev_student central.pptx

THE HYPOTHALAMIC PITUITARY ADRENAL AXIS Clinical Aspects Dr Anna Crown Royal Sussex County Hospital HPAA: Clinical Aspects Topics • HPAA revision • Cushing’s syndrome • Addison’s disease • Autoimmune polyendocrinopathies. • Therapeutic use of glucocorticoids and mineralocorticoids • ‘Iatrogenic Cu...

THE HYPOTHALAMIC PITUITARY ADRENAL AXIS Clinical Aspects Dr Anna Crown Royal Sussex County Hospital HPAA: Clinical Aspects Topics • HPAA revision • Cushing’s syndrome • Addison’s disease • Autoimmune polyendocrinopathies. • Therapeutic use of glucocorticoids and mineralocorticoids • ‘Iatrogenic Cushings’. Assessing cortisol production: • • • • 9 am cortisol short Synacthen test urinary free cortisol dexamethasone suppression test • insulin stress test. Broad learning outcomes • To understand the presentation, diagnosis and management of endocrine diseases, (including psychological aspects) • To appreciate how an understanding of the physiology informs the investigation of endocrine disease. Hypothalamic-pituitary axis William’s Textbook of Endocrinology Hypothalamic-pituitary-adrenal axis CRH AVP CORTISOL ACTH William’s Textbook of Endocrinology Hypothalamic-pituitary axis William’s Textbook of Endocrinology Hypothalamic-pituitary-adrenal axis William’s Textbook of Endocrinology Pituitary MRI scan Hypothalamus Optic chiasm Pituitary stalk Pituitary gland with small adenoma (lower intensity) MRI scan, coronal plane, T1 weighted HORMONES, RECEPTORS & ENZYMES • Adrenal cortex hormone production – GLUCOCORTICOID • CORTISOL – MINERALOCORTICOID • ALDOSTERONE (renin-angiotensin-aldosterone system) – SEX STEROIDS • ANDROGENS • Binding proteins – 90% cortisol bound to cortisol binding globulin (CBG) • Receptors – Intracellular glucocorticoid and mineralocorticoid receptors (GR and MR) • Enzymes – 11- -hydroxysteroid dehydrogenase (11-  -HSD) STEROID HORMONES Stewart 2003 William’s Textbook of Endocrinology EFFECTS OF GLUCOCORTICOIDS • Maintenance of homeostasis during stress – e.g. haemorrhage, infection, anxiety • Anti-inflammatory • Energy balance / metabolism – / maintain normal [glucose] • Formation of bone and cartilage • Regulation of blood pressure • Cognitive function, memory, conditioning CIRCADIAN RHYTHM • Cortisol levels: – – – – rise during the early morning peak just prior to awakening fall during the day are low in the evening Bergendahl et al, JCEM, 2000 ULTRADIAN RHYTHM ‘Pulsatility’ of hormone release Mean data: Circadian rhythm Individual data: Pulsatility Bergendahl et al, JCEM, 2000 ULTRADIAN RHYTHM • Spontaneous pulses of varying amplitude • Amplitude decreases in the circadian trough • In rats…... Windle et al, Endocrinology, 1998 ULTRADIAN RHYTHM • ….and in humans • It is hard to distinguish the stress response Young et al, 2004 Frontiers in Neuroendocrinol Renin Angiotensin Aldosterone System Stewart 2003 William’s Textbook of Endocrinology CIRCULATING ANDROGENS Adrenal glands DHEAS ANDROSTENEDIONE Testes Aromatase TESTOSTERONE 5- -reductase DIHYDROTESTOSTERONE OESTROGEN GLUCOCORTICOID RECEPTOR (Anti-inflammatory action of glucocorticoids) Kronenberg: Williams Textbook of Endocrinology ENZYMES • In vitro, the ‘mineralocorticoid receptor’ (MR) has the same affinity for aldosterone and cortisol • Specificity is conferred by a ‘pre-receptor’ mechanism • 11- -HSD-2 in the kidney inactivates cortisol, enabling aldosterone to bind the MR 11- -HSD enzymes • Tissue specificity: – ‘gating’ of GC access to nuclear receptors – ‘amplification’ of GC signal in target cells Seckl & Walker, Trends in Endo & Metab, 2004 Seckl & Walker, Endocrinology, 2001 Chapman, Holmes, Seckl Physiol Rev. 2013 Jul; 93(3): 1139–1206 Too much cortisol • Cushing’s Syndrome – – – – – Weight gain Central obesity Hypertension Insulin resistance Neuropsychiatric problems – Osteoporosis CUSHING’S SYNDROME Pathogenesis Excess cortisol: – Pituitary adenoma: ACTH-secreting cells (‘Cushing’s disease’) – Adrenal tumour: adenoma (or carcinoma) – ‘Ectopic ACTH’: carcinoid, paraneoplastic – Iatrogenic: steroid treatment (‘Cushingoid’) CUSHING’S SYNDROME Clinical features – – – – – Central obesity with thin arms & legs Fat deposition over upper back (‘buffalo hump’) Rounded ‘moon’ face Thin skin with easy bruising, pigmented striae Hirsutism – – – – Hypertension Diabetes Psychiatric manifestations Osteoporosis Cushing’s syndrome patient (adrenal carcinoma) Too little cortisol: Addison’s disease • The patient – gradually falls off in general health – becomes languid & weak – indisposed to either bodily or mental exertion – the body wastes – slight pain is referred to the stomach – there is occasionally actual vomiting – discoloration of the skin – at length he gradually sinks and expires ADDISON’S DISEASE Pathogenesis – Primary adrenal insufficiency • • • • ‘Addison’s disease’ Usually autoimmune in UK Rare causes include metastases or TB Production of all adrenocortical hormones – Other causes of hypoadrenalism • Secondary to pituitary disease (rare) • ‘Iatrogenic’ – patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress ADDISON’S DISEASE Clinical features – Malaise, weakness, anorexia, weight loss – Increased skin pigmentation: • knuckles, palmar creases, around / inside the mouth, pressure areas, scars – Hypotension / postural hypotension – Hypoglycaemia Addison’s disease: increased skin pigmentation AUTOIMMUNE POLYENDOCRINE SYNDROMES • Type II 1 – Commoner Rare (still rare!) – Infancy Onset intoinfancy adulthood – Polygenic Ar (AIRE gene) – Common phenotype: • Addison’s disease • T1 Hypoparathyroidism diabetes • Autoimmue Candidiasis thyroid disease AUTOIMMUNE POLYENDOCRINE SYNDROMES • Autoimmune conditions that may occur together: – Type 1 diabetes – Autoimmune thyroid disease (hypo- or hyper-) • Also gestational / post-partum thyroiditis – – – – – – – – Coeliac disease Addison’s disease Pernicious anaemia Alopecia Vitiligo Hepatitis Premature ovarian failure Myasthenia gravis AUTOIMMUNE POLYENDOCRINE SYNDROMES • Clinical implications: – High index of suspicion for additional autoimmune endocrine disorders • T1 DM with fatigue, weight loss & hypos: – ? Addisons disease • T1 DM with non-specific GI symptoms / diarrhoea: – ? Coeliac disease – Consider screening in patients with T1 DM and/or Addison’s disease • Coeliac screen • Thyroid function tests (esp in pregnancy / post-partum) ASSESSMENT OF THE HPAA • BASAL – Blood • Cortisol • ACTH – Urine • Cortisol – Saliva • Cortisol • DYNAMIC TESTS – STIMULATED – SUPPRESSED ASSESSMENT OF THE HPAA • BASAL – Blood • Timing – circadian rhythm • Ultradian rhythm • Stress – Urine • 24 hour collection – ‘area under curve’ – Saliva • Timing • No stress! • STIMULATED – ACTH – CRH – ‘STRESS’ • Hypoglycaemia • SUPPRESSED – Dexamethasone • Synthetic glucocorticoid ASSESSMENT OF THE HPAA Cushing’s Normal diurnal profile Cortisol Addison’s 9 am 11 pm 9 am Hypothalamus Pituitary SynACTHen Adrenal Cortisol Dexamethasone (synthetic glucocorticoid) TOO MUCH CORTISOL? • 24 hour urinary free cortisol – ‘AREA UNDER THE CURVE’ • Midnight cortisol (blood / saliva) – ‘TROUGH’ • 9 a.m. ACTH (with paired cortisol) – PITUITARY / ADRENAL / ECTOPIC? • NEGATIVE FEEDBACK AT PITUITARY • DEXAMETHASONE SUPPRESSION – Sensitivity to GC negative feedback at pituitary TOO LITTLE CORTISOL? • 9 a.m. cortisol – ‘PEAK’ • SynACTHen test – Adrenal response to ACTH • Trophic effect ACTH on adrenals • Insulin tolerance test – Response to hypoglycaemic stress • Can be dangerous! • U & E ( Na,  K) in Addison’s disease – Due to mineralocorticoid deficiency – Can measure renin & aldosterone concentrations • glucose TWO GOLDEN RULES! 1. Never start investigating a patient for an endocrine condition unless their symptoms & signs suggest they may have it! Risk of false positive results 2. Never image any endocrine gland until you have established the diagnosis biochemically! Risk of discovering ‘incidentalomas’ IMAGING • Once you have confirmed that a patient has Cushing’s syndrome, consider – CXR – MRI pituitary – CT adrenals • Patients with Addison’s disease seldom need imaging unless you are concerned they may have TB / metastatic cancer CUSHING’S SYNDROME • Management – Surgical (depending on the cause) • Transphenoidal adenectomy • Adrenalectomy – Pituitary radiotherapy ADDISON’S DISEASE Management – Steroid hormone replacement therapy (‘glucocorticoid’): • Usually hydrocortisone (sometimes prednisolone) – Patients with primary adrenal insufficiency also need mineralocorticoid replacement therapy (fludrocortisone). – Patients with secondary adrenal insufficiency will often be taking other hormone replacement therapy (do not need fludrocortisone). ADDISON’S DISEASE • Dose of glucocorticoids needs to be increased to cover ‘stresses’: – Intercurrent illnesses (e.g. ‘flu) • Operations / post-op period – Recommendations depend on the procedure • Patients need IV / IM steroid if unable to take their tablets: – Vomiting – ‘Nil by mouth’ PATIENTS TAKING STEROIDS • Patients Conditions may include be treated severe with asthma long-term / COPD, hightemporal dose steroids /for arteritis polymyalgia many reasons rheumatica – Glucocorticoids These patients may look ‘Cushingoid’, especially those with – COPD Usually prednisolone • Usually the steroids are being used for their antiinflammatory / immunosuppressive effects PATIENTS TAKING STEROIDS – The endogenous adrenal function of patients on long-term high dose steroid therapy may be suppressed: • They may not mount an adequate ‘stress response’. • Their steroid treatment should not be stopped suddenly. • If they need a major procedure / an operation, they require increased steroid cover as described. • They should be given a ‘Steroid Treatment Card’ to remind them (& their doctors) about this. TOPICS • • • • • Hypothalamic pituitary adrenal axis Cushing’s syndrome Addison’s disease Autoimmune polyendocrine syndromes Therapeutic use of glucocorticoids and mineralocorticoids • Assessing the HPAA / cortisol production QUIZ! Hypothalamic-pituitary-adrenal axis: Peptide hormones or steroid hormones? 1 3 2 William’s Textbook of Endocrinology Pituitary MRI scan 2 6 3 4 5 1. Coronal, saggital or transverse plane? ADRENAL CORTEX HORMONE PRODUCTION • 3 TYPES OF HORMONE • 1 EXAMPLE OF EACH • REGULATION? CLINICAL CONDITIONS • DISEASE? • CORTISOL or  ? • 1 screening test you would recommend to a GP? AUTOIMMUNE ENDOCRINE CONDITIONS • Which autoimmune conditions may ‘cluster’ in the same individual? THANK-YOU Questions?