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Adrenal gland disorders kinara
- 1. ADRENAL GLAND DISORDERS Presenter: KINARA S. KENYORU MED/18/11 Facilitator: DR. LUSWETI
- 2. Suprarenal glands • Paired organ each weighing 5-6 grams • pyramidal • superior pole of kidneys at the level of the T12 • Enclosed by fibro elastic connective tissue capsule.
- 3. CORTEX: Zona glomerulosa 15% Mineralocorticoids (Aldosterone) Zona fasciculata 75% Glucocorticoids (Cortisol & corticosterone) Zona reticularis 10% Androgens (Dehydroepiandrosterone & androstenedione) MEDULLA: Catecholamines (Epinephrine & norepinephrine)
- 6. Increased or stimulated Gluconeogenesis Glycogen deposition Protein catabolism Fat deposition Sodium retention Potassium loss Free water clearance Uric acid production Circulating neutrophils Decreased or inhibited Protein synthesis Host response to infection Lymphocyte transformation Delayed hypersensitivity Circulating lymphocytes Circulating eosinophils
- 7. ADRENAL HYPOFUNCTION Reduction in output of glucocorticoids and/or minerallocorticoids Can be: 1. Primary insufficiency – inability of adrenal glands to produce adequate hormones 2. Secondary insufficiency –inadequate pituitary or hypothalamic stimulation of the adrenal gland
- 8. Etiology Glucocorticoid treatment Autoimmune adrenalitis Tuberculosis Meningococcal septicaemia Adrenalectomy Secondary tumor deposits Amyloidosis Haemochromatosis Histoplasmosis, tuberculosis, CMV, AIDS Adrenal haemorrhage Metabolic failure in hormone production
- 9. Addison disease Autoimmune primary hypoaldosteronism. Most likely due to cytotoxic T lymphocytes bt 50% have autoab eg 21OHAb, adrenal cortex autoab, steroid cell autoab, 17αOHAb Isolated or associated with other autoimmune disease (autoimmune polyendocrine syndrome 1 & 2, primary ovarian insufficiency, Schmidt syndrome)
- 10. Clinical presentation Skin & mucous membrane pigmentation (ACTH is melanocyte stimulating hormone - proopiomelanocortin). Scars before onset not affected Tiredness, progressive weakness N & V, diarrhoea, weight loss, dehydration, hypotension Dizziness, orthostasis Impotence, amenorrhoea Loss of body hair (F since adrenal major source of androgens) Myalgia, flaccid muscle paralysis from hyperkalemia History of medications used
- 11. Ix Aldosterone & cortisol low, high ACTH, high renin UECs: Low sodium , high potassium ACTH stimulation test Adrenal antibodies
- 14. Treatment : Hydrocortisone 100 mg IV bolus, then 300 mg/day in divided doses every 8 hours or as a continuous infusion for 48 hours. When patient stable, change to oral, 50 mg every 8 hours for 6 doses, then taper to 30 - 50 mg/day. Fludricortisone - minerallocorticoid
- 15. Management Hormone replacement Life-long replacement therapy gluco + minerallocorticoid • Hydrocortisone 20-30 mg daily PO e.g. 10 mg on waking, 5 mg at12 00h, 5mg at 1800h • Prednisolone 7.5mg daily PO e.g 5mg on waking, 2.5mg at 1800h • 9α-fludrocortisone 50-300 |jg daily Secondary adrenocortical insufficiency • Hormone replacement may also need T4 • may also require more definitive treatment e.g. surgical removal of a pituitary tumour.
- 16. Adrenal crisis Acute adrenal insufficiency Medical emergency Acute in onset; can be fatal if not promptly recognized and treated Clinical features : • Severe hypovolaemia • Dehydration • Shock • Hypoglycaemia • possible mental confusion and loss of consciousness
- 17. Causes : Precipitated by stress :infection, infarction, trauma or surgery in patients with incipient adrenal failure/treated with glucocorticoids if dosage is not increased Adrenal haemorrhage due to cx of anticoagulant treatment Meningococcal septicaemia Ix Plasma cortisol concentration • <50nmol/L at 0900H → effectively diagnostic • >550nmol/L excludes the Dx Plasma renin and aldosterone levels: low aldosterone high renin ACTH stimulation test :primary vs secondary adrenal insufficiency CRH stimulation test: hypothalamic vs pituitary plasma ACTH Metyrapone test
- 19. Adrenal crisis management Assuming normal cardiovascular function One litre of 0.9% saline should be given over 30-60 minutes with 100 mg of intravenous bolus hydrocortisone.Subsequent requirements are several litres of saline within 24 hours plus hydrocortisone, 100 mg i.m., 6-hourly, until the patient is clinically stable. Oral replacement medication is then started, unless unable to take oral medication, initially hydrocortisone 20 mg, 8- hourly, reducing to 20-30 mg in divided doses over a few days. Glucose if hypoglycaemic
- 20. Congenital adrenal hyperplasia (CAH) Pathophysiology This condition results from an autosomal recessive deficiency of an enzyme in the cortisol synthetic pathways. 6 types,most common is 21-hydroxylase deficiency which occurs in about 1/15 000 births Due to defects on Xsom 6 near the HLA-region affecting one of the cytochrome p450 enzymes Cortisol secretion is ↓and feedback leads to ↑ACTH secretion to maintain adequate cortisol →to adrenal hyperplasia.
- 21. Diversion of the steroid precursors into the androgenic steroid pathways→ increased 17-hydroxyprogesterone, androstenedione and testosterone levels →virilization. Aldosterone synthesis may be impaired with resultant salt wasting. Other enzymes affected are:llfi-hydroxylase, 17a- hydroxylase, 3fS-hydroxysteroid dehydrogenase and a cholesterol side-chain cleavage enzyme (p450scc)
- 22. Clinical features symptoms due 2 ↓ cortisol , & depending upon the site of block, ↓ or ↑mineralocorticoids & androgen. If severe, presents at birth with sexual ambiguity or adrenal failure (collapse, hypotension, hypoglycaemia), S’times with salt-losing state (hypotension, hyponatremia). In female- clitoral hypertrophy, urogenital abnormalities and labioscrotal fusion are common Precocious puberty with hirsutism is a later presentation Milder cases only present in adult life, usually accompanied by primary amenorrhoea.
- 23. Investigations Expert advice is essential in the confirmation and differential diagnosis of 21-hydroxylase deficiency 17-Hydroxyprogesterone levels are increased. Urinary pregnanetriol excretion is increased. Basal ACTH levels are raised. RX : Replacement of glucocorticoid activity, and mineralo- corticoid activity if deficient
- 24. ADRENAL HYPERFUNCTION Cushing syndrome High Cortisol Hyperaldosteronism High aldestrone Pheochromocytoma High catecholamine
- 25. Hyperaldosteronism Rare Can be: 1. Primary – hyporeninemic hyperaldosteronism. Causes : adrenal adenoma (Conn’s syndrome)60%, bilateral hypertrophy of zona glomerulosa 30%, adrenal ca Hypertension, renal K wasting, hypokalemic alkalosis 1. Secondary – Hyperreninemic hyperaldosteronism Causes : CCF, Liver cirrhosis with ascites, nephrotic syndrome, renal artery stenosis, Na losing nephritis, renin secreting tumours HTN, muscle weakness, paralysis, tetany, paraesthesia, polydipsia, polyuria, nocturia
- 26. Investigations Electrolyte & BGAs Hypernatremia, hypokalemia, alkalosis Plasma aldosterone:renin ratio in pmol/liter per µg/(liter·h). Is a screening test
- 27. Saline infusion test 1.25l of 0.9% saline over 2 hrs. If aldosterone remains >240pmol/l Conn’s syndrome Plasma aldosterone morning sample pt recumbent since waking and after 4 hrs of ambulation Urinary potassium loss > 30 mmol/day in hypokalemia. CT - adenoma vs hyperplasia MRI RX Surgical excision for adenoma Spironolactone PO 100-400mg/day OD/BD S.E nausea, rash, gynecomastia
- 28. Secondary hyperaldosteronism Arises when there is excess renin (and hence angiotensin II) stimulation of the zona glomerulosa. Common causes asso. with hypertension • accelerated hypertension • renal artery stenosis Causes associated with normotension • congestive cardiac failure • cirrhosis Excess aldosterone production contributes to sodium retention.
- 29. Treatment Treatment for heart failure: Spironolactone is of value 25 mg/day has been shown to improve survival in heart failure
- 30. Cushing syndrome Group of symptoms occurring due to high cortisol. Cushing disease is due to incr. ACTH production by pituitary Causes: Exogenous/iatrogenic – intake of glucorticoids (most common) Endogenous – pituitary tumour - cushing disease 70% nodular pituitary hyperplasia adrenal tumour 15% ectopic ACTH tumours 15% bronchus, thymus, pancreas, ovary Pseudocushings is caused by alcoholism, anorexia nervosa, obesity, PCOS, severe depression thought to be due to HPA axis stimulation
- 31. Clinical features Symptoms Signs 1. Weight gain (central) 2. Change of appearance 3. Depression, Insomnia,Psychosis 4. Amenorrhoea/oligomenorrhoea 5. Poor libido 6. easy bruising 7. Hair growth/acne 8. Muscular weakness 9. Growth arrest in children 10. Back pain 11. Polyuria/polydipsia 1. Moon face, Central obesity , Kyphosis 'Buffalo hump’(dorsal fat pad), exophthalmos (retroorbital fat) 2. Plethora 3. Depression/psychosis 4. Hirsuitism, Frontal balding (female) 5. Thin skin,Bruising, Poor wound healing 6. Pigmentation, Acne 7. Striae (purple or red) 8. Skin infections- tinea versicolor 9. Hypertension 10. Osteoporosis, Pathological # (vertebrae and ribs) 11. Oedema 12. Proximal myopathy 13. Glycosuria
- 33. Ix 24 hr urinary free cortisol Circadian rhythm 8am and 11pm (50% less) serum cortisol. Rhythm lost in cushing’s syndrome normal in pseudo cushing
- 34. Low dose Dexamethasone suppression test 0.5 mg Dexamethasone (oral) given 6 hourly for 2 days, blood for plasma cortisol collected 6 hour after last dose urine for UFC is collected before & on the 2nd day of Dexa Result: UFC suppress by 50% ( < 70nmol/24h) normal plasma cortisol suppress < 140 nmol/L pseudo- Cushing no suppression of UFC & Pl. cortisol Cushing's synd UECs hypokalemia, hypernatremia
- 35. Investigating cause CRH test Plasma ACTH Imaging : CT adrenal, MRI sella turcica, CT or MRI thorax & abdomen for ectopic ACTH tumour, radiolabeled octreotide RX Depends on cause Adrenal adenoma, Adrenal Carcinoma – resection, radiation Cushing’s disease - transphenoidal hypophysectomy Drug ( block cortisol synthesis ) – metyrapone PO 750mg/day Q 6-8hrly Ketoconazole PO 200mg TDS
- 36. Phaeochromocytoma Def: tumours of the sympathetic nervous system very rare <1/1000 cases of hypertension Rule of 10s 10% extradrenal 10% familial 10% malignant 10% childhood onset 10% bilateral Some asso. with MEN 2 syndromes & the von Hippel-Lindau syndrome Most tumours release both NE& adrenaline but large tumours & extra-adrenal tumours produce almost entirely NE.
- 37. Pathology Oval groups of cells occur in clusters and stain for chromogranin A. Of neural crest origin Clinical features are those of catecholamine excess and are frequently intermittent. Anxiety or panic attacks, Palpitations, Tremor, Sweating, Headache, Flushing, Nausea and/or vomiting, Weight loss, Constipation or diarrhea, Raynaud's phenomenon, Chest or abd pain, Polyuria/nocturia. Signs : Arrhythmias, Bradycardia, Orthostatic hypotension, Pallor or flushing, Glycosuria, Fever (Signs of hypertensive damage)
- 38. Diagnosis: Measurement of urinary catecholamines and metabolites. Normal levels on three 24-hour collections of metanephrines virtually exclude the diagnosis. Resting plasma catecholamines are raised. Plasma chromogranin A (a storage vesicle protein) is raised. Clonidine suppression and glucagon stimulation tests may be appropriate Imaging : CT abdomen, MRI,Scanning with [131I]metaiodobenzylguanidine (mlBG) which gives specific uptake in sites of sympathetic activity with about 90% success.
- 39. Treatment Tumours should be removed if this is possible; 5-year survival is about 95% when not malignant Medical pre-op and peri-op Tx is vital Complete α & ß blockade with phenoxybenzamine (20-80 mg daily initially in divided doses) then propranolol (120-240 mg daily), plus transfusion of whole blood to re-expand the contracted plasma volume. When operation is not possible, α & ß blockade can be used long term. Radionucleotide treatment with mlBG has been attempted with limited success over 10% recur or develop a further tumour- Catecholamine excretion measurements at least annually.
- 40. REFERENCES Davidsons Principles and practice of medicine Current medical diagnosis and treatment Upto date http://www.endocrinology.org UK Society of Endocrinology http://www.endo-society.org Endocrine Society http://www.pituitary.org.uk The Pituitary Foundation (UK charity) Medscape
Editor's Notes
- Minerallocorticoids EC balance Na & K in distal tubule. Corticosterone & cortisol in excess have some mineralocorticoid activity but kidney converts cortisol to inactive cortisone Weak androgens until converted to testosterone or dihydrotestosterone in testes
- Metabolic failure in hormone production Congenital adrenal hyperplasia e.g. 21-hydroxylase deficiency, 3-β hydroxysteroid dehydrogenase deficiency Enzyme inhibition e.g. ketoconazole Accelerated hepatic metabolism of cortisol e.g. phenytoin, barbiturates, rifampicin Other causes ACTH blocking antibodies Mutation in ACTH receptor gene Adrenal hypoplasia congenital Familial adrenal insufficiency
- association of Addison disease with hypoparathyroidism and mucocutaneous candidiasis is described as polyglandular autoimmune type 1 association of Addison disease and Hashimoto thyroiditis is known as Schmidt syndrome association of Addison disease with type 1 diabetes mellitus and Hashimoto thyroiditis or Graves disease is described as polyglandular autoimmune syndrome type 2
- Orthostasis due to volume depletion, loss of the mineralocorticoid effect of aldosterone loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.
- Treat TB
- No stress and salt restriction 24 hrs prior. Take baseline samples in purple top if renin put on ice.
- Muscle weakness & paralysis from hypokalaemia Polydipsia, polyuria and nocturia due to hypokalaemic nephropathy
- Standardize for posture and time. > primary hyperaldosteronism Standing = renal blood flow stimulate renin secretion incr. aldosterone level
- Spironolactone, aldosterone antagonist
- Minerallocorticoids and androgens may also be in excess Excess cortisol binding globulin Estrogen therapy : Osteoporosis, OCP Pregnancy ACTH-dependent disease Pituitary-dependent (Cushing's disease) Ectopic ACTH-producing tumours ACTH administration Non-ACTH-dependent causes Adrenal adenomas Adrenal carcinomas Glucocorticoid administration
- Hirsuitism, menstrual irregularities – androgens Hyperpigmentation - ACTH ↑ HTN – Minerallocorticoid Back pain – osteoporosis ↓ intestinal calcium absorption, ↓ bone formation, ↑bone resorption, and ↓ renal calcium reabsorption Psychiatric disturbances – mania, euphoria, depression Skin atrophy - stratum corneum is thinned,loss of subcutaneous fat ,skin eventually becomes fragile Easy bruisability - Loss of subcutaneous connective tissue due to the catabolic effects of glucocorticoid. Striae — Purple striae occur as the fragile skin stretches due to the enlarging trunk, breasts, and abdomen
- Two phases : confirm presence of cushings find cause
- The 5 Ps of Pheochromocytoma Pressure Palpitation Pallor Perspiration Pain