Adrenal glands

Function of the cortex

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  • In adults the normal adrenal gland weighs 4g but with acute stress, lipid depletion may reduce the weight and with prolonged stress such as dying after a chronic illness, the glands may double in weight
  • Beneath the capsule is the narrow zona glomerulosa
  • An equally narrow zona reticularis lies next to the medulla
  • In between in the zona fasciculate which makes up about 75% of the cortex
  • The adrenal cortex synthesises 3 types of steroids;
    • Glucocorticoids, principally cortisol – produced by the zona fasciculata with a small contribution from the zona reticularis
    • Mineralocorticoids, the most important being aldosterone – produced by the zona glomerulosa
    • Sex steroids, oestrogen and androgens – produced by the zona reticularis
  • The adrenal medulla is composed of chromaffin cells which produce catecholamines, mostly adrenaline

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Adrenocortical hyperfunction (Hyperadrenalism)

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  • As there are 3 basic types of corticosteroids produced by the adrenal cortex, there are 3 distinctive hyperadrenal clinical syndromes;

·        Cushing syndrome – characterised by an excess of cortisol

·        Hyperaldosteronism

·        Adrenogenitial or virilising syndromes caused by an excess of androgens

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Cushing syndrome

  • This disorder is caused by any condition that produces an elevation in glucocorticoid levels
  • There are 4 possible sources of excess cortisol;
    • Pituitary Cushing syndrome – caused by a tumour in the anterior pituitary producing excess ACTH
    • Adrenal Cushing syndrome – caused by a tumour in the cortex of the adrenal gland
    • Paraneoplastic Cushing syndrome – caused by a nonendrocrine tumour producing ACTH
    • Iatrogenic Cushing syndrome – caused by the taking of exogenous glucocorticoids. This is the most common
  • The other three causes can be classified as endogenous Cushing syndrome

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  • Primary hyper secretion of ATCH accounts for 70-80% of endogenous hyperaldosteronism. This form of Cushing syndrome is called Cushing disease
    • F>M, occurs most frequently in the 20s and 30s
    • In majority of cases the pituitary contains an ACTH-producing microadenoma which doesn’t produce any mass effect
    • Disease may also be caused by a hypothalamic corticotrophin releasing hormone (CRH)-producing tumour
    • The adrenal glands of patients show varying degrees of cortical hyperplasia

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  • Primary adrenal neoplasms such as adrenal adenomas, carcinomas and primary cortical hyperplasia are responsible for 10-20% of endogenous Cushing syndrome
    • As the adrenals function autonomously it is ACTH independent. Therefore there are low levels of ACTH and high levels of cortisol
    • Carcinomas tend to produce more marked hypercortisolism then adenomas or hyperplastic processes.
    • If there is a single neoplasm, the uninvolved cortex of the other gland tends to atrophy because of suppression my ACTH
  • The vast majority of hyperplastic adrenals are due to secondary processes and primary cortical hyperplasia is rare
    • Two types of primary bilateral adrenocortical hyperplasia have been described in association with Cushing syndrome. These are;
      • Massive macronodular adrenocortical disease (MMAD) – nodules greater than 3cm. affects older people
      • Primary pigmental nodular adrenal disease (PPNAD) – seen more commonly in children. Diffuse bilateral micronodules that are darkly pigmented

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  • Secretion of ectopic ACTH accounts for the remaining cases (10%)
    • In most cases the tumour is small cell lung carcinoma
    • Other tumours associated with the syndrome are carcinoid tumours, medullary carcinomas of the thyroid, islet cell tumours of the pancreas
    • More common in men, usually in the 40s and 50s

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Morphology

  • The pituitary shows changes regardless of the cause. The most common alteration is Cooke hyaline change, when the granular basophilic cytoplasm of the ACTH producing cells become lighter and less basophilic
  • The adrenals can show one of the following abnormalities;
    • Cortical atrophy – seen in those whose syndrome is due to exogenous glucocorticoids. There is lack of stimulation of the zonae fasciculata and reticularis
    • Diffuse hyperplasia
    • Nodular hyperplasia
    • Adenoma or carcinoma – both are more common in women aged in their thirties and fifties. Microscopically adenomas are composed of cells similar to those of the zona fasciculate. With functioning tumours both benign and malignant, the adjacent cortex is atrophic owing to suppression of endogenous ACTH by high cortisol levels

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Clinical features

  • Central obesity – accumulation of fat in the posterior neck and back is called a buffalo hump
  • Moon facies
  • Weakness and fatigability – due to selective atrophy of fast twitch type 2 myofibres
  • Hirtuism
  • Hypertension
  • Plethora
  • Glucose intolerance/diabetes
  • Osteoporosis
  • Neuropsychiatric abnormalities
  • Menstrual abnormalities
  • Skin striae
  • Infection risk

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  • Cushing syndrome is diagnosed by;
    • 24hr urine free cortisol level which is increased
    • Loss of normal diurnal pattern of cortisol secretion

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  • Determining the cause of Cushing syndrome depends on the level of ACTH and measurement of urinary steroid excretion after administration of dexamethasone;
  • In pituitary form, ACTH levels are not suppressed by low dose dexamethasone (therefore the uninary steroid excretion is not reduced) but is suppressed by high dose dexamethasone
  • Ectopic ACTH is completely insensitive to high or low dexamethasone
  • When caused by an adrenal tumour the ACTH is low due to feedback inhibition. Levels are insensitive to high and low dose dexamethasone

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Primary Hyperaldosteronism

  • Caused by chronic excess aldosterone secretion
  • Excessive aldosterone causes sodium retention and potassium excretion causing hypertension and hypokalaemia
  • May be primary or secondary

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  • Primary hyperaldosteronism indicates autonomous overproduction of aldosterone with resultant suppression of the renin-angiotensin system.
  • It is caused by one of the 3 mechanisms;
    • An aldosterone producing neoplasm (adenoma or carcinoma) – in approximately 80% of cases primary hyperaldosteronism is caused by a solitary aldosterone secreting adenoma – this is known as Conn syndrome. Occur more commonly in middle aged women
    • Primary adrenocortical hyperplasia – characterised by bilateral nodular hyperplasia. Genetic basis is unclear but may be due to over activity of the aldosterone synthase gene CYP11B2
    • Glucocorticoid-remediable hyperaldosteronism – uncommon familial cause of primary hyperaldosteronism caused by chimeric fusion of the 11b-hydroxylase gene with the aldosterone synthase gene

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  • In secondary hyperaldosteronism, aldosterone release occurs in response to activation of the renin-angiotensin system. It is characterised by increased levels of plasma renin and is encountered in the following conditions;
    • Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
    • Arterial hypovolaemia and oedema (congestive heart failure, cirrhosis, nephrotic syndrome)
    • Pregnancy (due to oestrogen-induced increases in plasma renin substrate)

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Morphology

  • Aldosterone-producing adenomas are almost always solitary, small, more commonly on the left than the right. They are bright yellow on cut section and strangely resemble fasciculata cells more than glomerulosa cells.
  • A characteristic feature of aldosterone producing adenomas is the presence of eosinophilic laminated cytoplasmic inclusions, known as spironolactone bodies
  • In contrast to cortical adenomas associated with Cushing syndrome those associated with hyperaldosteronism do not usually suppress ACTH secretion, therefore the adjacent cortex and that of the contralateral gland are not atrophic
  • Bilateral idiopathic hyperplasia – hyperplasia of cells resembles those of the normal zona glomerulosa. Hyperplasia is often wedge shaped, extending from the periphery towards the centre of the gland

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Clinical course

  • Manifestations are hypertension and hypokalaemia
  • Serum renin is low
  • Hypokalaemia results in;
    • Weakness
    • Paresthesia
    • Visual disturbances
    • Frank tetany
  • Sodium retention;
    • Hypertension
  • The expanded extracellular fluid volume and the hypokalaemia put extra stain on the heart causing ECG changes and cardiac decompensation
  • Diagnosis is made based on high levels of aldosterone and low levels of renin

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Adrenogenital syndromes

  • The adrenal cortex secretes two compounds, dehydroepiandrosterone and androstenedione which require conversion to testosterone in the periphery
  • ACTH regulates adrenal androgen formation
  • The adrenal causes of androgen excess include;
    • Adrenocortical neoplasms
    • A group of disorders that have been designated congenital adrenal hyperplasia

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  • Functioning adrenocortical neoplasms are more likely to be carcinomas and are more likely to produce a mixed syndrome with virilisation is combination with hypercortisolism

 

Congenital adrenal hyperplasia

  • Represents a group of autosomal recessive, inherited metabolic errors, each characterised by a deficiency or lack of a particular enzyme involved in the biosynthesis of cortical steroids, particularly cortisol. Steroidogenesis is channelled into other pathways , leading to increased production of androgens and the deficiency in cortisol results in increased ACTH which induces adrenal hyperplasia
  • There is a spectrum of disorders from a lack of a particular enzyme or a mutuation that onky slightly impairs enzyme function
  • The most common of these disorders are;
    • 21-Hydroxylase deficiency
      • Accounts for 90% of congenital adrenal hyperplasia
      • Due to defect in the conversion of progesterone to 11-deoxycorticosterone by 21-hydroxylase
      • Deficiency may range from a total lack of enzyme to a mild loss depending on the mutation
      • Three distinctive clinical syndromes have been described;
        • Salt-wasting (classic) adrenogenitalism
        • Simple virilising adrenogenitalism
        • Nonclassic adrenogenitalism (mild disease, that may be completely asymptomatic or only associated with symptoms of androgen excess during childhood/puberty)

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·        The carrier frequency of the classical from is 1 in 60 whilst the carrier frequency of the nonclassical form is 1 in 50 or 1 in 5, depending on the ethnic group (Hispanic and Ashkenazi Jews have the highest frequencies)

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·        The salt wasting syndrome is due to an inability to produce mineralocorticoids or glucocorticoids

    • Usually presents after birth with hyponatraemia, hypokalaemia, acidosis, hypotension and cardiovascular collapse. The excessive androgens also produces virilisation which is particularly noticeable in the female

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·        Simple virilising adrenogenital syndrome may occur in individuals with a less than total 21-hydroxylase deficiency. Therefore the levels of mineralocorticoid , although reduced, are generally sufficient to stop salt wasting but are not sufficient to cause feedback inhibition of ACTH secretion. Thus the levels of aldosterone is reduced, the level of testosterone increased and ACTH elevated resulting in adrenal hyperplasia

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·        Nonclassic or late onset adrenal virilism is much more common. Patients may be asymptomatic of only have mild symptoms such as hirsutism

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Morphology

  • In all cases the adrenals are bilaterally hyperplastic
  • The adrenal cortex is thickened and nodular and on cut surface appears brown owing to depletion of all the lipid
  • Hyperplasia of corticotroph (ACTH-producing) cells is present in the anterior pituitary of most CAH patients

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Clinical course

  • Depends on the degree and specific enzyme deficiency
  • As high levels of intra-adrenal glucocorticoids are required for the production of medullary catecholamines, patients severe salt-wasting 21-hydroxylase deficiency have medullary defects predisposing to further hypotension and circulatory collapse
  • CAH should be suspected in any neonate with ambiguous genitialia
  • Patients are treated with exogenous glucocorticoids and mineralocorticoids in the case of patients with severe salt-wasting disease

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Adrenal Insufficiency

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  • May be primary due to adrenal disease or secondary due to decreased ACTH
  • There are three patterns of adrenal insufficiency;
    • Primary acute adrenocortical insufficiency (adrenal crisis)
    • Primary chronic adrenocortical insufficiency (Addison disease)
    • Secondary adrenocortical insufficiency

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Primary acute adrenocortical insufficiency

  • Can occur in a variety of clinical settings;
    • A crisis in patients with chronic adrenocortical insufficiency precipitated by stress which requires an immediate steroid output form the glands
    • In patients on exogenous corticosteroids which has been withdrawn abruptly or have not been increased in response to a stress may precipitate a crisis
    • As a result of massive adrenal haemorrhage which destroys the adrenal cortex. This may occur in newborns following a prolonged and traumatic delivery, in patients on anticoagulant therapy, post surgical DIC, or following a bacteraemic infection – Waterhouse Friderichsen syndrome
  • Waterhouse Friderichsen syndrome is characterised by the following;
    • An overwhelming bacterial infection classically associated with Neisseria meningitides but also associated with pseudomonas, pneumococci, haemophilus influenzae and staph
    • Shock
    • DIC leading to widespread purpura, particularly of the skin
    • Rapidly developing andrenocortical insufficiency associated with massive bilateral adrenal haemorrhage

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