Adrenal

Adrenal Glands

Adrenal Glands Anatomy

Adrenal Cortex

Three zones

Zona glomerulosa Aldosterone ( regulated by Renin angiotensin system)

Zona fasciculata Cortisol (regulated by - ACTH )

Zona reticularis Adrenal androgens ( DHEA and small amount of testosterone ) regulated by ACTH

Adrenal Medulla

HPA Axis?

Variations in serum Cortisol levels

Simple obesity

Cortisol is bound to Cortisol binding globulin -normal serum cortisol levels depend on level of CBG

Low CBG is seen in critical illness and nephrotic syndrome.

herefore low values obtained for serum cortisol assays

High CBG concentrations- oral estrogen administration

Simple obesity

Hypersecretion of cortisol

antianabolic effects of cortisol. — osteopenia, thin skin, and ecchymoses — not present in patients with simple obesity but are present in patients with Cushing’s syndrome.

Serum cortisol levels are elevated

24 urinary free cortisol excretion is increased

Disorders of the Adrenals

Hypersecretion

Cortisol - Cushing's Disease

Cushing's Syndrome

Aldosterone - Conn’s Syndrome

Catecholamines - Phaechromocytoma

Hyposecretion

All hormones of adrenal – Addison's disease

Multiple and other causes

CUSHING's SYNDROME

Symptoms & Signs

Causes

corticotropin-secreting pituitary microadenoma

ectopic corticotropin secretion is

evaluated with CT followed by MRI

Of abdomen and pelvis.

If no source can be identified

Bilateral adrenalectomy or blockade of synthesis

Corticotropin-independent Cushing’s syndrome is usually caused by an adrenal neoplasm

Adrenal tumors secreting more than one hormone (i.e., cortisol and androgen or estrogen) are almost always malignant

Investigations

urinary free cortisol

plasma corticotropin ( ACTH )

plasma cortisol

Dexamethasone Suppression Test

Low dose Dexamethasone suppression test

Differentiate between Obesity and Cushing’s Disease

High dose Dexamethasone Suppression Test

Suppression is present in patients with Cushing disease.

Suppression is absent in patients with Cushing syndrome due to ectopic ACTH secretion or adrenal disease.

Management

Mainly surgical- Tumor resection

Ketoconazole - inhibits the first step in cortisol biosynthesis and to a lesser extent conversion of 11-deoxycortisol to cortisol

Metyrapone — an 11-beta-hydroxylase an inhibitor that blocks the final step in cortisol biosynthesis

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Conn's Syndrome

What is it?

Hypersecretion of Mineralocorticoid

Aldosterone

Physiological function exaggerated

Hypertension

High Na

Low K

Metabolic alkalosis on ABG

The Axes of volume regulatiion (2)

Causes

Adenoma 40%

Hyperplasia 60%

Carcinoma ( very rare )

When to suspect? (4)

Hypertension: severe / moderate

Resistant hypertension, which is defined as failure to achieve goal blood pressure (BP) despite adherence to an appropriate three-drug regimen including a diuretic.

with low K and a metabolic alkalosis

Muscle weakness due to hypokalemia

Correlate- Absence of hypertension with low K, Metabolic alkalosis- Salt loosing nephropathy

When to investigate for 2 secondary cause for hypertension? (5)

Hypokalemia ( spontaneous or low dose diuretic-induced)

Severe or resistant hypertension, which is suggestive of some form of secondary hypertension

Hypertension with adrenal incidentaloma

Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years)

All hypertensive first-degree relatives of patients with primary aldosteronism

Diagnostic investigation, Primary aldosteronism Aldosterone Renin ratio

Aldosterone Renin ratio

In general, Plasma renin activity (PRA) is undetectable

Plasma Aldosterone Concentration (PAC) is >15 ng/dL (416 pmol/L)

PAC/PRA ratio is greater than 20 while some use a cutoff ratio of 30

Management

Control hypertension

Correct electrolyte abnormalities

Surgical resection if adenoma can be identified (After adrenal vein sampling for aldosterone concentration )

Adrenal Failure

Three categories? Six causes of primary adrenal insufficiency?

Primary adrenal failure : A primary adrenal disorder resulting in deficiency of cortisol

Infections :Tuberculosis HIV Fungal

Infiltrative disease Malignancies

Granulomatous diseases : eg. Sarcoidosis

Hemorrhagic infarction

Autoimmune adrenalitis

Clustering with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune syndromes types I and II

Secondary adrenal failure :A pituitary disorder resulting in deficiency of corticotropin (ACTH) secretion

u-Tertiary adrenal failure: A hypothalamic disorder resulting in deficiency of corticotropin-releasing hormone (CRH) and secondarily of ACTH

Dynamic tests of Adrenal Function?

ACTH ( Cosyntropin / Synacthan) stimulation test

Standard high dose test (250 mcg) —

Normal response

a rise in serum cortisol concentration after either at 30 or 60 minutes to a peak of ≥18 to 20 mcg/dL (500 to 550 nmol/L)

-A normal response to the high-dose (250 mcg) ACTH stimulation test excludes primary adrenal insufficiency

CRH stimulation test

The CRH test has been proposed for the distinction between secondary or tertiary adrenal insufficiency.

For this purpose the test is primarily used in patients without the expected elevation in basal plasma ACTH levels in the presence of adrenal insufficiency

Autoimmune adrenalitis

Stage 1: High plasma renin activity and normal or low serum aldosterone

Stage 2: Impaired serum cortisol response to ACTH stimulation

Stage 3: Increased morning plasma ACTH with normal serum cortisol

Stage 4: Low morning serum cortisol and overt clinical adrenal insufficiency

APS1

APS2

Clinical Presentation of primary adrenal insufficiency

Fatigue Weight loss

Nausea and vomiting and abdominal pain – more likely in acute adrenal crisis

Craving for salt

Diffuse myalgia and arthralgia

Psychiatric symptoms

Hypotension / postural hypotension

Hyperpigmentation of skin creases and buccal mucosa

Areas of vitiligo ( due to autoimmune destruction of melanocytes )

Loss of libido

Labaratory Investigations

Hyponatraemia

Hyperkalaemia ( due to mineralocorticoid deficiency)

Hypoglycaemia

ABG- metabolic acidosis ( due to mineralocorticoid deficiency)

Diagnosis of adrenal insufficiency

Morning serum cortisol concentration — In normal subjects, serum cortisol concentrations are higher in the early morning (about 6 AM), ranging from 10 to 20 mcg/dL (275 to 555 nmol/L), than at other times of the day.

An early morning low serum cortisol concentration (less than 3 mcg/dL [80 nmol/L]) is strongly suggestive of adrenal insufficiency

A serum cortisol concentration greater than 11 mcg/dL (300 nmol/L) makes it unlikely that the patient has clinically important hypothalamic-pituitary-adrenal insufficiency

Hormone profile in primary adrenal failure

ACTH –

high

Plasma Cortisol -low

Plasma - renin high

Aldosterone - low

Hormone profile in secondary adrenal failure

ACTH low

Plasma cortisol low

Plasma renin normal

Aldosterone normal

Management of adrenal failure

hydrocortisone 15-20 mg PO every morning and

Hydrocortisone 5-10 mg PO between 4:00-6:00 PM every afternoon.

9 alpha- Fluorocortisol Maintenance mineralocorticoid levels may be achieved by administering 0.05-0.1 mg every morning. (This treatment is necessary only for primary adrenocortical insufficiency.)

Patients should be advised on the need for life long therapy.

Continued therapy even during concurrent illness

To inform their health care provider that they are on replacement therapy

=Carry a card with them at all times stating the diagnosis and dose of steroids

Management of ADRENAL CRISIS

Use aggressive volume replacement therapy - 0.9% saline solution or( 5% dextrose with 0.9% saline- if hypoglycaemia is present )

orrect electrolyte abnormalities as follows:

Hypoglycemia (67%)

Hyponatremia (88%)

Hyperkalemia (64%, may be offset by concurrent vomiting/diarrhea resulting in potassium loss)

Hypercalcemia (6-33%)

Administer hydrocortisone 100 mg intravenously (IV) every 6 hours.

Administer fludrocortisone acetate (mineralocorticoid) 0.1 mg every day as needed.

CONGENITAL ADRENAL HYPERPLASIA

Pathophysiology?

Clinical presentation

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in one of two clinical syndromes:

a salt-losing form or a

non-salt-losing (simple virilizing) form.

Girls with either form present as neonates with ambiguous genitalia.

Boys

salt-losing form : neonates (with a hyponatremia, hyperkalemia, and failure to thrive)

non-salt-losing form : toddlers with signs of precocious puberty

Diagnosis

A very high serum concentration of 17-hydroxyprogesterone in a randomly timed blood sample is diagnostic of classic 21-hydroxylase deficiency.

Therapy

The goal of treating 21-hydroxylase deficiency in women is to lower serum concentrations of adrenal precursors and androgens

Normalize steroid hormone levels

In males

Salt loosing form may require mineralocorticoid replacement

Dexamethasone 0.25- 0.75 mg / day

Prednisolone 4- 10 mg /day

Hydrocortisone 15- 40 mg /day

Any one of the above can be used. Such patients are best managed in specialized centers

Reconstructive surgery

Minerolocorticoid replacement?

Rarely necessary

usually given as fludrocortisone , in a dose sufficient to restore normal serum sodium and potassium concentrations and plasma renin activity

PHAECHROMOCYTOMA

Two types?

Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla- pheochromocytoma 85 %

Catecholamine-secreting tumors that arise sympathetic ganglia - catecholamine-secreting paragangliomas“ 15 % ("extra-adrenal pheochromocytomas")

Clinical Features

Diagnosis

The 24-hour urine collection for fractionated metanephrines and catecholamines

24 urinary excretion of VMA

CT and MRI of Abdomen

When to clinially suspect?

has an incidental adrenal mass,

has a family history of adrenal tumor

has symptoms of episodic headache, sweating, or tachycardia

has sustained severe hypertension or paroxysmal hypertension

is of young age (eg, <20 years)

has a idiopathic dilated cardiomyopathy

Differential diagnosis

Autonomic dysfunction

A stress response

Multiple endocrine neoplasia MEN

Hereditary forms

Management

Preoperative medical therapy is aimed at:

Controlling hypertension (including preventing a hypertensive crisis during surgery)

Volume expansion

Phenoxybenzamine is the preferred drug for preoperative preparation to control blood pressure and arrhythmia

irreversible, long-acting, nonspecific alpha-adrenergic blocking agent. Allows for volume expansion preventing cardiovascular collapse after removal of tumor

Followed by Beta blockers to prevent adrenergic symptoms tumor handling

Metyrosine — Another approach involves the administration of metyrosine (alpha-methyl-para-tyrosine), which inhibits catecholamine synthesis.

Operative complications

Acute hypertensive crisis

Cardiac arrhythmia

Postoperative hypotension