ADRENAL DISEASE Dr. Kareithi Adrenal anatomy and function £ Wt 8-10 g £ Outer - cortex with 3 zones producing steroids § Zona reticularis § Zona fasciculata § Zona glomerulosa , £ Inner - medulla that synthesizes, stores and secretes catecholamines £ adrenal steroids grouped into 3 classes based on their predominant physiological effects. § Glucocorticoids § Mineralocorticoids § Androgens Corticosteroids -Effects Increased or stimulated £ Decreased or inhibited £ Gluconeogenesis £ Protein synthesis £ Glycogen deposition £ Host response to £ Protein catabolism infection £ Fat deposition £ Lymphocyte transformation £ Sodium retention £ Delayed hypersensitivity £ Potassium loss £ Circulating lymphocytes £ Free water clearance £ Circulating eosinophils £ Uric acid production £ Circulating neutrophils Mineralocorticoids £ Their predominant effect is on the EC balance of Na ⁺⁺⁺ and K⁺⁺⁺ in the distal tubule of the kidney. £ Aldosterone , § solely from zona glomerulosa , § is the predominant mineralocorticoid in humans £ corticosterone makes a small contribution £ mineralocorticoid activity of cortisol is weak but it is present in considerable excess Androgens £ Have only relatively weak intrinsic androgenic activity until metabolized peripherally to testosterone or dihydrotestosterone. Biochemistry Physiology £ Glucocorticoid production by the adrenal is under hypothalamic-pituitary control. £ Corticotropin-releasing hormone (CRH): § secreted in the hypothalamus in response to circadian rhythm &stress. § It travels down the portal system to stimulate ACTH release from the anterior pituitary § is derived from the prohormone pro-opiomelanocortin, which also produce a number of other peptides including beta-lipotrophin and beta-endorphin. £ Many of these peptides, including ACTH , contain melanocyte-stimulating hormone (MSH )-like sequences which cause pigmentation when levels of ACTH are markedly raised. £ ACTH stimulates cortisol production in the adrenal gland £ Cortisol causes negative feedback on the hypothalamus and pituitary to inhibit further CRH/ACTH release. £ This system varies through the day according to the circadian rhythm £ Mineralocorticoid secretion is mainly controlled by the renin- angiotensin system Classification £ Adrenal gland Hyperfunction V Cushings syndrome V Hyperaldosteronism £ Adrenal gland Hypofunction V 1˚ hypoadrenalism- Addissons disease V 2˚ hypoadrenalism V Adrenaleukodystrophy £ Adrenal hyperplasia £ Adrenal cortex disease- neoplasm: adenoma & ca Cushings syndrome £ Def : § term used to describe the clinical state of increased free circulating glucocorticoids £ Occurs most often following the therapeutic administration of synthetic steroids or ACTH £ Spontaneous forms of the syndrome are rare. Causes £ Spontaneous Cushing's syndrome is rare, with an incidence of < 5/million/year. £ ACTH-dependent disease § Pituitary-dependent (Cushing's disease) § Ectopic ACTH -producing tumours § ACTH administration £ Non-ACTH-dependent causes § Adrenal adenomas § Adrenal carcinomas § Glucocorticoid administration £ Others § Alcohol-induced pseudo-Cushing's syndrome Pathophysiology £ Two things happen: V increased circulating ACTH from V the pituitary (65% of cases)- Cushing's disease , or V from an 'ectopic' non -pituitary, ACTH -producing tumour elsewhere in the body (10%) with consequential glucocorticoid excess V a primary excess of endogenous cortisol secretion (25% of spontaneous cases) by an adrenal tumour or nodular hyperplasia, with subsequent (physiological) suppression of ACTH Clinical features Symptoms £ Weight gain (central) £ Change of appearance £ Depression /Insomnia £ Amenorrhoea/oligomenorrhoea £ Poor libido £ Thin skin/easy bruising £ Hair growth/acne £ Muscular weakness £ Growth arrest in children £ Back pain £ Polyuria/polydipsia £ Psychosis Signs £ Moon face £ Plethora £ Depression/psychosis £ Acne £ Hirsutism £ Frontal balding (female) £ Thin skin,Bruising £ Poor wound healing £ Pigmentation £ Skin infections £ Hypertension £ Osteoporosis £ Pathological fractures(especially vertebrae and ribs) £ Kyphosis 'Buffalo hump’(dorsal fat pad) £ Central obesity £ Striae (purple or red) £ Oedema £ Proximal myopathy £ Proximal muscle wasting £ Glycosuria Progressive obesity –centripetal obesity usually involving the face, neck, trunk, abdomen and, internally, spinal canal and mediastinum £ Fat accumulation in the cheeks results in a "moon" face £ A "buffalo hump" or dorsocervical fat pad £ Bulging supraclavicular fat pads make the neck appear thick and shortened £ Retroorbital fat deposition may result in exophthalmos Skin manifestations £ 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 £ Fungal infections — Cutaneous fungal infections, especially tinea versicolor £ Hyperpigmentation — Hyperpigmentation is induced by increased ACTH £ Hypokalaemia - due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion £ Menstrual irregularities - due to suppression of secretion of gonadotropin-releasing hormone by hypercortisolemia. £ Signs of adrenal androgen excess — The major source of androgens in women is the adrenal glands Signs of adrenal androgens excess in females £ Hirsutism, £ Acneiform rash, £ Oily facial skin, £ Increased libido, £ Virilization- temporal balding, £ Deepening voice, £ Clitoris hypertrophy £ Proximal muscle wasting and weakness — induced by the catabolic effects of excess glucocorticoid on skeletal muscle £ Bone loss — Osteoporosis caused by ↓ intestinal calcium absorption, ↓ bone formation, ↑bone resorption, and ↓ renal calcium reabsorption £ Glucose intolerance - due to stimulation of gluconeogenesis by cortisol and peripheral insulin resistance caused by obesity £ Hypertension and cardiovascular risk- Increased peripheral vascular sensitivity to adrenergic agonists Increased hepatic production of renin substrate (angiotensinogen). Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol £ Thromboembolic events - due to increased plasma concentrations of clotting factors, especially Factor VIII and von Willebrand factor complex, and decreased fibrinolytic activity £ Neuropsychological changes and cognition - Emotional lability, Agitation, depression, Irritability, Anxiety, Panic attacks, Mild paranoia Diagnosis - Laboratory £ There are two phases to the investigation: confirmation of the presence or absence of Cushing's syndrome differential diagnosis of its cause (e.g. pituitary, adrenal or ectopic). £ Dexamethasone suppression tests § Administration of a synthetic glucocorticoid to a normal subject produces prompt feedback suppression of CRH and ACTH levels and thus of endogenous cortisol secretion § Normal individuals suppress plasma cortisol to < 50 nmol/L. § Patients with Cushing's syndrome fail to show complete suppression of plasma cortisol levels . § This test is highly sensitive (> 97%). £ Circadian rhythm. § After 48 hours in hospital, cortisol samples are taken at 0900h and 2400h (without warning the patient). § Normal subjects show a pronounced circadian variation ; those with Cushing's syndrome have high midnight cortisol levels (> 100 nmol/L), though the 0900h value may be normal. £ Plasma potassium levels. § Hypokalaemia is common with ectopic ACTH secretion. £ Plasma ACTH levels. § Low or undetectable ACTH levels (< 10 ng/L) on two or more occasions are a reliable indicator of non-ACTH- dependent disease £ CRH test. § An exaggerated ACTH and cortisol response to exogenous CRH suggests pituitary-dependent Cushing's disease Imaging £ Adrenal CT or MRI scan. § Adrenal adenomas and carcinomas causing Cushing's syndrome are relatively large and always detectable by CT scan £ Pituitary MRI. § A pituitary adenoma £ Chest X-ray § is mandatory to look for a carcinoma of the bronchus or a bronchial carcinoid/ CT m £ Radiolabelled octreotide ( In octreotide) is occasionally helpful in locating ectopic ACTH sites Treatment £ If untreated death from § hypertension, myocardial infarction, infection and heart failure £ Metyrapone , § an 11(3-hydroxylase blocker, which is given in doses of 750 mg to 4 g daily in three to four divided doses. £ Ketoconazole (200 mg three times daily) § aim 2 reduce the mean level of Plasma cortisol during the day to 150-300 nmol/L, equivalent to normal production rate. £ Aminoglutethimide and trilostane (which reversibly inhibits 3(3-hydroxysteroid dehydrogenase/8-5 £ Other specific tx depends on cause V Cushing's disease (pituitary-dependent hyperadrenalism) § Trans-sphenoidal removal of pituitary tumour effective in 75- 80% of cases § External pituitary irradiation alone is slow acting, only effective in 50-60% £ Medical therapy to reduce ACTH (e.g. bromocriptine,cyproheptadine) is rarely effective £ Bilateral adrenalectomy is an effective last resort V Adrenal adenomas V should be resected after achievement of clinical remission with metyrapone or ketoconazole V Adrenal carcinomas V are highly aggressive and the prognosis is poor. V Debulking and use of adrenolytic drug op'DDD (Mitotane ) may inhibit growth of the tumour and prolong survival V Tumours secreting ACTH ectopically V should be removed if possible. V Irradiation and chemo. V If the source of ACTH is not clear , cortisol hypersecretion should be controlld till dx