adrenocortical disorders
TRANSCRIPT
Acquired Autoimmune AIDS Tuberculosis Bilateral injury
◦ Hemorrhage◦ Necrosis◦ Metastasis
Idiopathic Iatrogenic
Congenital Congenital
adrenal hypoplasia
Syndromes Autoimmune
polyglandular syndrome
1. APS12. APS2
Decrease function Increase function
Adrenal insufficiency CAH Low cortisol,
aldestrone Addison disease
Cushing syndrome High Cortisol Hyperaldosteronism
High aldestrone CAH Pheochromocytoma High catecholamine
.
Glucocorticoids are essential for life and have mutiple pysiological effects.
Metabolic actions include enhanced gluconeogenesis and inhibition of peripheral glucose utilization.
Glucocorticoids are required for vascular and bronchial smooth muscle to be responsive to catecholamines.
Glucocorticoids are structurly related to aldosterone, so they have aldosterone like action.
ACTH is the principal regulator of Glucocorticoids secretion.
Secretion of ACTH and glucocorticoids exhibit a diurnal rhythm, stimulated by stress and inhibited by circulating glucocorticoids.
Endogenous production of cortisol averages 20 mg \ day.
Mineralocorticoid excess
I- Primary hyperaldosteronism (Conn syndrome):
Conn syndrome is characterized by increased aldosterone secretion from the adrenal glands, it was first described in 1955 by J. W. Conn in a patient who had an aldosterone-producing adenoma.
Pathophysiology Primary hyperaldosteronism is caused by
increased aldosterone excretion from the adrenals, which results primarily from 2 major subtypes:
(1) unilateral aldosterone-producing adenoma , Conn syndrome, (50-60% of cases)
(2) idiopathic hyperaldosteronism (IHA) or bilateral adrenal hyperplasia (40-50% of cases).
(3) Rarely, aldosterone can be secreted by adrenocortical carcinomas and ovarian tumors.
Aldosterone, by inducing renal distal tubular reabsorption of sodium, enhances secretion of potassium and hydrogen ions, causing hypernatremia, hypokalemia.
Conn syndrome, is primarily related to; 1- Hypertension, especially if left untreated for
many years, can lead to many complications, including heart disease (eg, coronary artery disease, congestive heart failure), stroke, and intracerebral hemorrhage (with very high blood pressure).
2-Hypokalemia, especially if severe, causes cardiac arrhythmias, which can be fatal.
II- Secondary hyperaldosteronism:
There is increased renin-angiotensin with increased aldosteron secretion;
Causes: -CHF -Liver cirrhosis and ascitis -Nephrotic syndrome -Renal artery stenosis
Clinical manifestations -Hypertension;
-Hypokalemia; patients with severe hypokalemia report fatigue, muscle
weakness, cramping, headaches, and palpitations. They can also have polydypsia and polyuria from hypokalemia induced nephrogenic diabetes insipidus.
-Metabolic alkalosis; will lower ionized calcium levels and can cause tetany.
Investigations: Laboratory Studies Hypernatremia Hypokalemia; normokalemia does not exclude
primary hyperaldosteronism. Several studies have shown that 7-38% of patients with primary hyperaldosteronism have normal baseline serum levels of potassium
metabolic alkalosis Renin levels are suppressed to less than 1
ng/mL/h in patients with primary hyperaldosteronism.
A 24-hour aldosterone excretion rate of greater than 14 ug is diagnostic of primary hyperaldosteronism
Imaging Studies
-CT scanning -MRI
Treatment
Medical medical therapy is used preoperatively to prevent
the morbidity and mortality associated with hypertension and hypokalemia, thus decreasing surgical risk.
Sodium-restricted diet (<80 mEq or <2 g of sodium per day.
Potassium-sparing agent (first-step agent) such as spironolactone100 mg initially, increase to 400 mg/d for control of blood pressure.
Potassium supplementation should not be routinely administered with spironolactone because of the potential for the development of hyperkalemia.
Second-step agents include thiazides diuretics, ACE inhibitors, calcium channel antagonists, and angiotensin II blockers.
Mineralocorticoid deficiency
Hypo-aldosteronism Atrophy or destruction of both adrenal glands
results in a combined deficiency of Mineralocorticoid and glucocorticoid ( addison disease) .
Isolated Mineralocorticoid deficiency; Unilateral adrenalectomy Congenital
C\P
*Hypotension; due to hypovolemia *Metabolic acidosis *Hyperkalemia; any increase in Sr. potassium
without renal impairment, hypoaldosteronism should be considered.
*hyponatremia
Glucocorticoid excess
Cushing syndrome
Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids
Causes:
Exogenous steroid administration Symptoms of glucocorticoid excess generally
occur with the administration of oral steroids; however, occasionally injections of steroids into joints and the use of steroid inhalers can cause Cushing syndrome.
Patients at risk to develop cushing syndrome includes:
rheumatological, pulmonary, neurological, and nephrologic diseases that respond to steroid therapy.
Patients who have undergone organ transplants due to exogenous steroids required as part of graft antirejection medication regimens.
Endogenous glucocorticoid administration
ACTH-producing pituitary adenoma ( Cushing disease).
Primary adrenal lesions; Overproduction of glucocorticoids may be due to an adrenal adenoma, adrenal carcinoma, or macronodular or micronodular adrenal hyperplasia.
Ectopic ACTH is sometimes secreted by oat cell or small-cell lung tumors or by carcinoid tumors.
Amino acid catabolism (muscle wasting)… gluconeogenesis in the liver.. Hyperglycemia… increased insulin output… eventual beta cell failure… fat deposition… diabetes
Ca resorption, impairment of Ca absorbtion, increased renal Ca excretion…. osteoporosis
Increased gastric acidity… ulcer formation or aggravation
K loss and Na retention… edema and hypertension Initially increased antibody release.. Eventually
decreased antibody production, lymphocytopenia, eosinopenia, neutrophelia, polycythemia… susceptibility to infections
Maintenance of arteriolar tone and blood pressure
Obesity -moon facies-buffalo hump-Central obesity, increased waist-to-hip ratio
greater than 1 in men and 0.8 in women
Skin Facial plethoraabdominal striae facial hairHirsutism and Steroid acne
Cardiovascular and renal Hypertension and possibly edema may be present
due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention
Gastroenterologic Peptic ulceration may occur with or without
symptoms.
endocrine Galactorrhea and menstrual disturbancesdecreased libido and impotence in men.
Skeletal/muscular Proximal muscle weaknessOsteoporosis and osteopeniaAvascular necrosis of the hip
Neuropsychological emotional liability, fatigue, and depression
Investigations
Laboratory StudiesHyperglycemiaHypokalemic metabolic alkalosis
Biochemical evaluation of Cushing syndrome:1-Urinary free cortisol excretion over 150 ug\ day.
2- dexamethasone suppression test; glucocorticoids inhibit secretion of hypothalamic CRH and pituitary ACTH but do not directly affect adrenal cortisol production.
The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 PM with subsequent measurement of cortisol level at 8 am.
In healthy individuals, the serum cortisol level should be less than 2-3 ug/dL.
3-loss of circadian rhythm of cortisol secretion Normal values, 10-25 ug\ml in the morning, 2-10
ug\ml in the evening, elevated serum cortisol at 11 PM can be an early finding.
Recently, measuring salivary cortisol level has gained interest, as it is a simple and convenient way of obtaining a night time sample. Levels less than 1.3-1.5 ng/mL exclude Cushing syndrome.
4- A plasma ACTH of less than 5 pg/mL is suggestive of a primary adrenal tumor. An ACTH level greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome.
Imaging studies CT or MRI brain and abdomen
Pathophysiology Addison disease is adrenocortical insufficiency
due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.
Causes 1- idiopathic
2- Chronic granulomatous diseases; TB, histoplasmosis.
3- Hematologic malignancies; Hodgkin and non-Hodgkin lymphoma and leukemia.
4- Metastatic malignant disease; as metastatic cancer of the lung, breast, colon or renal cell carcinoma.
5-Infiltrative metabolic disorders; Amyloidosis and hemochromatosis.
6- AIDS.
Secondary adrenal insufficiency is a result of inadequate ACTH secretion by the pituitary, the most common cause of secondary adrenal insufficiency is iatrogenic, the result of the administration of exogenous glucocorticoids.
C\P Patients usually present with features of both
glucocorticoid and mineralocorticoid deficiency. The predominant symptoms vary depending on the duration of disease.
-Hyperpigmentation of the skin and mucous membranes due to high ACTH.
- vitiligo, which most often is seen in idiopathic autoimmune Addison disease.
-clinical manifestations due to cortisol deficiency; weakness, fatigue, hypoglycemia, hypotension, and weight loss.
-Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea.
- Patients with secondary insufficiency have a history of taking cortisol.
clinical manifestations due to aldosterone deficiency; hyponatremia, hypovolemia, hypotension, hyperkalemia.
Investigations
Laboratory Studies -ACTH stimulation test; In patients with Addison
disease, both cortisol and aldosterone show minimal or no change in response to ACTH.
Hyponatremia Hyperkalemia
elevated (BUN) and creatinine due to the hypovolemia with decreased glomerular filtration rate.
Hypoglycemia
adrenal autoantibodies may be present
Imaging study
Chest x-ray TB
CT abdomen
.
Congenital adrenal hyperplasia (CAH) is a general term used to describe a group of inherited disorders in which a defect in cortisol biosynthesis is present with consequent overproduction of (ACTH) and secondary adrenal hyperplasia as a consequence.
Patients with 11-beta-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children.
Approximately two thirds of patients also have hypertension, which may or may not be associated with mineralocorticoid excess, hypokalemia, hypernatremia and metabolic alkalosis.
The hypertension is initially responsive to glucocorticoid replacement, but it may become a chronic condition subsequently requiring standard antihypertensive therapy.
Ambiguous genitalia in girls Hyperpigmentation Dehydration Salt-loss presentations with electrolytes
imbalance◦ Hyponatremia ◦ Hyperkalaemia
Hypoglycemia Shock
Are unrecognized at birth because their genitalia are normal.
Present early with salt wasting crisis resulting in dehydration, hypotension,
hyponatremia and hyperkalemia
Or present later in childhood with early pubic hair, precocious puberty and accelerated growth
Neural Crest
Sympathoadrenal Progenitor Cell(Neuroblasts)
Chromaffin Cell Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenalPheochromocytoma
Ganglioneuroma
Neuroblastoma
Pheochromocytoma Paraganglioma (extra-adrenal pheo)
Originate in extra-adrenal sympathetic chain/chromaffin tissue
Ganglioneuroma Behave like paraganglioma biochemically
Neuroblastoma Common malignancy in children, adrenal or
sympathetic chain. Rapid growth & widespread metastasis Some differentiate and spontaneously regress Rx complex (surgery, RT, chemotherapy)
Cheodectoma Carotid body, behave like paraganglioma
biochemically Glomus jugulare tumor
Intracranial branch of CN IX and X Behave like paragangliomoa biochemically
Neuroendocrine tumour of the medulla of the adrenal glands
Originates from the chromaffin cells along the paravertebral sympathetic chain extending from pelvis to base of skull
>95% are abdominal >90% in adrenal medulla Secretes excessive amounts of adrenaline
and noradrenaline 80% occur unilateral
10% extra-adrenal (closer to 15%) 10% occur in children 10% familial (closer to 20%) 10% bilateral or multiple (more if familial) 10% recur (more if extra-adrenal) 10% malignant 10% discovered incidentally
Tyrosine L-Dopa Dopamine
Norepinephrine
Epinephrine
Catecholamines
Normetanephrine
Metaneprine
PNMT
DBH
COMT
COMT
Metabolites
Homovanillic acid(HVA)
MAO, COMT
Vanillymandelic Acid(VMA)
MAO
MAO
TH
Alpha-Adrenergic Receptors 1: vasoconstriction, intestinal relaxation, uterine
contraction, pupillary dilation 2: presynaptic NE (clonidine), platelet aggregation,
vasoconstriction, insulin secretion
Beta-Adrenergic Receptors 1: HR/contractility, lipolysis, renin secretion
2: vasodilation, bronchodilation, glycogenolysis
3: lipolysis, brown fat thermogenesis
0.01-0.1% of HTN population Found in 10% of those screened
M = F 3rd to 10th decades of life Rare, investigate only if clinically suspicion:
Signs or Symptoms Severe HTN, HTN crisis Refractory HTN (> 4drugs) Adrenal lesion found on imaging (ex. Incidentaloma)
The five P’s: Pressure (HTN) 9% Pain (Headache) 80% Perspiration 71% Palpitation 64% Pallor 42%
Paroxysms (the sixth P) The Classical Triad:
Pain (Headache), Perspiration, Palpitations Lack of all 3 virtually excluded diagnosis of pheo
in a series of > 21,0000 patients
Diagnosis1. Biochemical2. Localization
Positive results (> 2-3 fold elevation): 24h Ucatechols > 2-fold elevation
ULN for total catechols 591-890 nmol/d 24h Utotal metanephrines > 1.2 ug/d (6.5 umol/d) 24h UVMA > 3-fold elevation
ULN 35 umol/d for most assays Detected by high performance liquid
chromatography
Test Characteristics: 24h urinary catechol Sen 83% Spec
88% 24h U total metanephrines Sen 76% Spec 94% 24h Ucatechols + Utotal metanephrines Sen 90% Spec 98% 24h UVMA Sen 63% Spec 94%
Sensitivity increased if 24h urine collection begun at onset of a paroxysm
Serum creatinine measured for all collections of urine to determine adequacy of collection
Plasma free metanephrines sen 99% spec 89%
Plasma catecholamines sen 84% spec 81%