Pathology of Endocrine Disease

Adrenal glands

Dr. Arrigo Capitanio

Department of Pathology

05-11

Adrenal glands

• Anatomy and physiology

• Cortical pathology– Hyper cortico-adrenalism– Hypo cortico-adrenalism

• Medullary Pathology

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

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)

Zona glomerulosa

Zona fasciculata

Zona reticularis

VS

Normal adrenal steroid biosynthesis

Adrenal cortex – normal steroid synthesis

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

1. 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

Hyperadrenalisms

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.

1. 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

• 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

Hyperadrenalisms

Cushing’s syndrome - pathogenesis

Adrenal adenoma – encapsulated tumour composed of cortical cells with little variation in size and shape. The residual cortex is atrophic.

Cushing’s syndrome – adrenal adenoma and adrenal hyperplasia

Adrenal hyperplasia causing Cushing’s syndrome

VS

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

• 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%)

Hyperadrenalisms

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

Congenital adrenal hyperplasia – 21-hydroxylase deficiency

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• 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

Adrenal cortex – hypoadrenalismPrimary 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

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• 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

– Phaeochromocytoma– Neuroblastoma – Ganglioneuroma

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

Adrenocortical adenoma

Adrenocortical carcinoma

Phaeochromocytoma

Phaeochromocytoma

Summarizing Adrenal glands

• Anatomy and physiology

• Cortical pathologyHyper cortico-adrenalism

Hypo cortico-adrenalism

• Medullary Pathology

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