Pathology of Endocrine Disease

1. Pathology of Endocrine Disease Adrenal glands Dr. Arrigo Capitanio Department of Pathology 05-11

2. Adrenal glands • Anatomy and physiology • Cortical pathology • Hyper cortico-adrenalism • Hypo cortico-adrenalism • Medullary Pathology

3. 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

5. 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)

6. Zona glomerulosa Zona fasciculata Zona reticularis

7. VS

8. Adrenal cortex – normal steroid synthesis Normal adrenal steroid biosynthesis

9. Adrenal cortexHyperadrenalism • 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

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

11. 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.

13. Adrenal cortex • Secondary Hyperaldosteronism • Secondary hyperaldosteronism - adrenal response to increased levels of renin-angiotensin • Causes • Renal ischaemia • Chronic oedema (Nephrotic syndrome, ascites)

14. 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

15. Cushing’s syndrome - pathogenesis Slide 26.24

16. Cushing’s syndrome – adrenal adenoma and adrenal hyperplasia 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

17. 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

18. 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%)

19. 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

20. 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.

21. Adrenal cortex – hypoadrenalismPrimary acuteadrenal 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

22. Adrenal cortex – hypoadrenalismPrimary chronicadrenal 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

23. Massive adrenal haemorrhage, resulting in primary acute adrenal insufficiency Metastatic breast carcinoma affecting the adrenal gland and causing primary chronic adrenal insufficiency

24. Adrenal cortex – hypoadrenalismSecondary 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

25. Adrenal medulla • Most significant disorders are neoplasms • Phaeochromocytoma • Neuroblastoma • Ganglioneuroma

26. 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.

27. Adrenocortical adenoma

28. Adrenocortical adenoma

29. Adrenocortical carcinoma

30. Phaeochromocytoma

31. Phaeochromocytoma

32. Summarizing Adrenal glands • Anatomy and physiology • Cortical pathology • Hyper cortico-adrenalism • Hypo cortico-adrenalism • Medullary Pathology Tumours