Pathology of Endocrine Disease Department of Pathology 12/01/10 Pathology of Endocrine Disease Adrenal glands Dr. Arrigo Capitanio Department of Pathology 05-11

Adrenal glands Anatomy and physiology Cortical pathology 12/01/10 Adrenal glands Anatomy and physiology Cortical pathology Hyper cortico-adrenalism Hypo cortico-adrenalism Medullary Pathology

12/01/10 Adrenal glands Adrenal glands are retroperitoneal structures located on the upper poles of the kidneys Combine two distinct endocrine systems Adrenal cortex – derived from the mesoderm synthesises and secretes corticosteroid hormones produced from cholesterol Adrenal medulla – derived from the neuroectoderm neuroendocrine component - synthesises and secretes the catecholamines adrenaline, noradrenaline and dopamine

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Adrenal cortex Composed of three zones: Zona glomerulosa 12/01/10 Adrenal cortex Composed of three zones: Zona glomerulosa Outermost zone comprising 10% of the cortex and synthesising the mineralocorticoid aldosterone (regulated by plasma K+ and renin-angiotensin) Zona fasciculata Middle zone comprising 80% of the cortex and containing large amounts of relatively inactive cholesterol, on stimulation forms cells resembling the reticularis Zona reticularis Innermost zone which, with the zona fasciculata, synthesises glucocoticoids including cortisol and corticosterone, and androgens (under ACTH control)

12/01/10 Zona glomerulosa Zona fasciculata Zona reticularis

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Adrenal cortex – normal steroid synthesis 12/01/10 Adrenal cortex – normal steroid synthesis Normal adrenal steroid biosynthesis

Adrenal cortex Hyperadrenalism 12/01/10 Adrenal cortex Hyperadrenalism Excessive secretion of any one of the three basic types of corticosteroids gives rise to a distinct clinical syndrome: 1. Aldosterone – hyperaldosteronism (Conn’s syndrome) 2. Cortisol – Cushing’s syndrome 3. Androgens – adrenogenital syndromes

Primary Hyperaldosteronism 12/01/10 Hyperadrenalisms Adrenal cortex Primary Hyperaldosteronism Primary hyperaldosteronism – excess aldosterone secretion which is independent of the renin-angiotensin system (Conn’s syndrome) Causes: Aldosterone secreting adenoma Bilateral hyperplasia of the cortex Rarely carcinoma Clinical features: Hypertension, hypokalaemia, sodium retention, muscle weakness, paraesthesia, ECG changes, cardiac decompensation renin-angiotensin system: renin, secreted by the juxtaglomerular apparatus, activates the precursor angiotensinogen. This liberates angiotensin I, then angiotensin II, a vasoconstrictor and stimulant to the secretion of aldosterone. 10

12/01/10 Renin-Angiotensin System: renin, secreted by the juxtaglomerular apparatus, activates the precursor angiotensinogen. This liberates angiotensin I, then angiotensin II, a vasoconstrictor and stimulant to the secretion of aldosterone.

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Secondary Hyperaldosteronism 12/01/10 Adrenal cortex Secondary Hyperaldosteronism Secondary hyperaldosteronism - adrenal response to increased levels of renin- angiotensin Causes Renal ischaemia Chronic oedema (Nephrotic syndrome, ascites)

2. Adrenal cortex Cushing’s syndrome 12/01/10 Hyperadrenalisms 2. Adrenal cortex Cushing’s syndrome A chronic excess of cortisol Pathogenesis: Prolonged treatment with glucocorticoids such as prednisolone Pituitary hypersecretion of ACTH (e.g. by adenoma) = Cushing’s disease Ectopic secretion of ACTH by a non-pituitary tumour – small cell carcinoma of lung, medullary carcinoma of thyroid, carcinoid of bronchus/pancreas etc. Glucocorticoid hypersecretion by adrenal adenoma, hyperplasia or carcinoma

Cushing’s syndrome - pathogenesis 12/01/10 Cushing’s syndrome - pathogenesis Slide 26.24

Cushing’s syndrome – adrenal adenoma and adrenal hyperplasia 12/01/10 Adrenal hyperplasia causing Cushing’s syndrome Adrenal adenoma – encapsulated tumour composed of cortical cells with little variation in size and shape. The residual cortex is atrophic. VS

Adrenal cortex Cushing’s syndrome – clinical features 12/01/10 Adrenal cortex Cushing’s syndrome – clinical features Obesity Moon facies Weakness and fatigability Hirsutism Hypertension Polycythaemia Glucose intolerance/diabetes Osteoporosis Abdominal striae Menstrual abnormalities Neuropsychiatric abnormalities

3. Adrenal cortex Adrenogenital syndromes 12/01/10 Hyperadrenalisms 3. Adrenal cortex Adrenogenital syndromes Congenital adrenal hyperplasia – a small group of congenital metabolic errors, each characterized by a deficiency or lack of a particular enzyme involved in the synthesis of cortical steroids Steroidogenesis is then channeled into other pathways, leading to increased production of androgens resulting in virilisation The deficiency of cortisol leads to increased ACTH secretion and thus adrenal hyperplasia Certain enzyme defects impair aldosterone secretion resulting in salt-wasting The most common defects are 21-hydroxylase deficiency (95%) and 11 hydroxylase deficiency (3%)

Congenital adrenal hyperplasia – 21-hydroxylase deficiency 12/01/10 Congenital adrenal hyperplasia – 21-hydroxylase deficiency 21-hydroxylase deficiency may be mild or total and three syndromes are possible: Salt-wasting adrenogenitalism – total deficiency => salt wasting, Na, K, acidosis, cardiovascular collapse, virilisation of female, precocious puberty in male. Simple virilizing adrenogenital syndrome – subtotal deficiency => reduced level of aldosterone but still sufficient for salt resorption; levels of glucocorticoid insufficient to inhibit ACTH, therefore ACTH (and adrenal hyperplasia). Nonclassic adrenal virilism – mild deficiency => may be asymptomatic and only be diagnosed by genetic studies and demonstration of defects of steroidogenesis

12/01/10 In newborn girls with this disorder, the clitoris is enlarged with the urethral opening at the base (ambiguous genitalia, often appearing more male-like than female). The internal structures of the reproductive tract (ovaries, uterus, and fallopian tubes) are normal. As they grow older, masculinization takes place: deepening of the voice, presence of facial hair, and failure to menstruate. In a newborn boy no obvious abnormality is present, but after a few years, the child becomes muscular, the penis enlarges, pubic hair appears, and the voice deepens. He may appear to enter puberty at 2-3 years of age. At puberty, the testes are small.

Adrenal cortex – hypoadrenalism Primary acute adrenal insufficiency 12/01/10 Adrenal cortex – hypoadrenalism Primary acute adrenal insufficiency Clinical features Hypotension, hyponatraemia, collapse Causes Rapid withdrawal of long term steroid therapy Sepsis/stress in patients with chronic adrenal dysfunction Massive destruction of the adrenals Perinatal haemorrhagic necrosis Adrenal haemorrhage – heparin/warfarin, DIC Post partum infarction Adrenal haemorrhage complicating bacteraemia (eg meningococcal) = Waterhouse-Friderichson syndrome trauma

12/01/10 Adrenal cortex – hypoadrenalism Primary chronic adrenal insufficiency: Addison’s disease Clinical features Lethargy, depression, anorexia, weight loss Hypotension – caused by salt and water loss Hyperpigmentation – melanocytes stimulated by excess ACTH − Na, K, urea, glucose Causes Autoimmune Tuberculosis, metastases, amyloid, haemochromatosis, lymphoma

12/01/10 Massive adrenal haemorrhage, resulting in primary acute adrenal insufficiency Metastatic breast carcinoma affecting the adrenal gland and causing primary chronic adrenal insufficiency

Adrenal cortex – hypoadrenalism Secondary adrenocortical insufficiency 12/01/10 Adrenal cortex – hypoadrenalism Secondary adrenocortical insufficiency Causes Any disorder of the hypothalamus or pituitary which results in a reduction in ACTH secretion Metastases, infection, infarction, irradiation Clinical features Similar to Addison’s disease, but without hyperpigmentation (melanocytes not stimulated as no excess ACTH) Deficient cortisol and androgen output, but normal aldosterone (not ACTH dependent) and so no marked hyponatraemia or hyperkalaemia

Adrenal medulla Most significant disorders are neoplasms 12/01/10 Adrenal medulla Most significant disorders are neoplasms Phaeochromocytoma Neuroblastoma Ganglioneuroma

12/01/10 Phaeochromocytoma – shown enclosed within an attenuated cortex with residual adrenal below. Originates from chromaffin cells of the adrenal medulla (85%) or other, extra-adrenal, locations. 90% occur sporadiacally, 10% occur in relation to other syndromes (MEN, von-Hippel lindau, von Recklinghausen, Sturge-Weber). Clinically, causes a catecholamine-induced hypertension which can be cured by excision. Residual adrenal Electron micrograph of phaechromocytoma. The tumour cells contain membrane-bound secretory granules in which catecholamines are stored.

Adrenocortical adenoma 12/01/10 Adrenocortical adenoma

Adrenocortical adenoma 12/01/10 Adrenocortical adenoma

Adrenocortical carcinoma 12/01/10 Adrenocortical carcinoma

12/01/10 Phaeochromocytoma

12/01/10 Phaeochromocytoma

Summarizing Adrenal glands 12/01/10 Summarizing Adrenal glands Anatomy and physiology Cortical pathology Hyper cortico-adrenalism Hypo cortico-adrenalism Medullary Pathology Tumours