The Pathology of Adrenal Gland Flashcards
What is adrenal hyperfunction knwon as?
Hyperadrenalism
What are the three distinctive hyperadrenal clinical syndromes?
- Cushing syndrome
- Hyperadosetronism
- Adrenogenital or Virilzing syndromes
What characterizes Cushing syndrome?
Characterized by an excess in cortisol
What characterizes hyperaldosteronism?
Characterized by chronic excess aldosterone secretion
What causes adrenogenital or virilizing syndromes?
Excess of androgens
What causes hypercortisolism and Cushing syndrome?
Any condition that produces an elevation in glucocorticoid levels (exogenous or endogenous)
What could be the cause of exogenous hypercortisolism?
Result of administration of exogenous glucocorticoids (iatrogenic)
What does exogenous hypercortisolism lead to?
Leads to bilateral adrenal atrophy, steroid suppress ACTH secretion (negative feedback)
What are the causes of endogenous hypercortisolism? (3)
- Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH
- The secretion of ectopic ACTH by non-pituitary neoplasms
- Primary adrenocortical neoplasms (adenoma or carcinoma) and rarely primary cortical hyperplasia
What are primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH like? (3)
- Accounts for 70% of cases of Cushing syndrome
- 4x higher in women
- Age group: 20s to 30s
What causes primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH?
Corticotroph microadenoma or corticotroph cell hyperplasia
What are non-pituitary neoplasms that are associated with ACTH ectopic secretion like?
- Account for 10% of causes of Cushing syndrome
- Elevated ACTH –> Bilateral cortical hyperplasia
What causes non-pituitary neoplasms that are associated with ACTH ectopic secretion?
Lung cancer (small cell carcinoma)
Medullary carcinomas of the thyroid
What are the primary adenocortical neoplasms and primary cortical hyperplasia like? (2)
- Account for 15 to 20% of cases of endogenous Cushing syndrome
- Adrenals function autonomously (ACTH-independent Cushing syndrome, or adrenal Cushing syndrome)
What causes the primary adenocortical neoplasms and primary cortical hyperplasia?
1.A unilateral adrenocortical neoplasm: benign or malignant
2. Primary cortical hyperplasia: 2 variants –> macronodules of varying sizes or micronodules
What is considered a MACROnodule in primary cortical hyperplasia?
3mm or greater in diameter
What does the morphology of Cushing syndrome depend on?
It depends on the cause of hypercortisolism
What is the morphology of Cushing syndrome due to cortical atrophy? (2)
- suppression of endogenous ACTH
- Lack of stimulation of the zona fasciculata and zona reticularis by ACTH
What is the morphology of Cushing syndrome due to diffuse hyperplasia? (3)
- Patients with ACTH-dependent Cushing syndrome
- Both glands are enlarged (up to 30g)
- The yellow colour of diffusely hyperplasticity glands derives from the presence of lipid-rich cells, which appear vacuolated under the microscope
What is the morphology of Cushing syndrome due to macronodular or micronodular hyperplasia?
Cortex is replaced by darkly pigmented macronodules (> 3mm) or micronodules (1 to 3mm)
What is the morphology of Cushing syndrome due to Adenoma or carcinoma?
- Adrenocortical adenomas are yellow tumors surrounded by thin or well-developed capsules (weigh less than 30g)
- On microscopic examination, they are composed of cells similar to those encountered in the normal zona facsiculata
What are the cells upon microscopic examination in adenomas or carcinomas of Cushing syndrome?
Neoplastic cells vacuolated because of the presence of intracytoplasmic lipids
What is the progression of signs and symptoms of Cushing syndrome?
They represent an exaggeration of the known actions of glucocorticoids (they develop gradually)
What are the early manifestations of Cushing syndrome? (5)
- Hypertension
- Weight gain
- Muscle weakness
- Secondary diabetes
- Osteoporosis
What is the characteristic of weight gain in Cushing syndrome?
Characteristic centripetal distribution of adipose tissue becomes apparent, with resultant truncal obesity, fascial “moon face,” and accumulation of fat in the posterior neck and back “buffalo hump”
What is primary hyperaldosteronism? (2)
- Autonomous overproduction of aldosterone
- Suppression of the RAAS and decreased plasma renin activity
What are the potential causes of primary hyperaldosteronism? (3)
- Bilateral idiopathic hyperaldosteronism (60%)
- Adrenocortical neoplasm (35%)
- Familial hyperaldosteronism (rare)
What is bilateral idiopathic hyperaldosteronism?
Bilateral nodular hyperplasia of the adrenal glands
Germline mutation in the KCNJ5 gene
What is the function of the KCNJ5 gene?
Encodes a potassium channel protein that is expressed in the adrenal gland
What is adrenocortical neoplasm?
- Solitary aldosterone-secreting adenoma (Conn syndrome)
- Somatic mutations of KCNJ5
What is familial hyperaldosteronism?
The genetic defect that leads to overactivity of the aldosterone synthase gene, CYP11B2
What is secondary hyperaldosteronism?
Aldosterone release occurs in response to activation of the renin-angiotensin system (characterized by increased levels of plasma renin)
What is secondary hyperaldosteronism associated with?
- Decreased renal perfusion –> arteriolar nephrosclerosis, renal artery stenosis
- Arterial hypovolemia and edema –> CHF, cirrhosis, nephrotic syndrome
- Pregnancy –> caused by estrogen-induced increases in plasma renin substrate
What is the clinical hallmark of hyperaldosteronism?
Hypertension
Why is hypertension the hallmark of hyperaldosteronism?
Aldosterone increases sodium absorption and secretion of potassium and hydrogen ions (distal tubes and collecting duct)
Increased absorption of sodium expands plasma volume, leading to hypertension
What are the long-term effects of the hyperaldosteronism induced hypertension?
- Cardiovascular compromise
- Hypokalemia
- Variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and frank tetany
What is the cardiovascular compromise of hyperaldosteronism-induced hypertension?
LEft ventricular hypertrophy and reduced diastolic volumes
Increase in the prevalence of adverse events such as stroke and MI
What causes the hypokalemia of the hyperaldosteronism-induced hypertension?
Renal potassium wasting
What are adrenogenital syndromes?
Excess sex steroids with hyperplasia of nothing adrenal glands
What are the causes of congenital adrenal hyperplasia?
Inherited 21-hydroxylase deficiency (common cause 90%)
Impaired synthesis of cortisol and aldosterone
How does impaired synthesis of cortisol lead to CAH?
Deficiency of cortisol leads to increased (compensatory) ACTH secretion (due to the absence of feedback inhibition), which results in bilateral adrenal hyperplasia
How does impaired synthesis of aldosterone lead to CAH?
Deficiency of synthesis of aldosterone leads to salt wasting with hyponatremia, hyperkalemia, hypovolemia, and shock (neonatal adrenal crisis)
What are the clinical features of congenital adrenal hyperplasia (CAH)?
Signs of masculinization in females
Enlargement of the external genitalia and precocious puberty
What are the signs of masculinization seen in females (CAH)?
Clitoral hypertrophy and pseudohermaphroditism in infants to oligomenorrhea, hirsutism, and acne in postpubertal girls
What are the patterns of adrenal insufficiency?
- Primary hypoadrenalism
- Secondary hypoadrenalism
What are the subtypes of primary hypoadrenalism?
Acute (adrenal crisis)
Chronic (Addison disease)
What is secondary hypoadrenalism?
Decreased stimulation of the adrenals resulting from ACTH deficiency
What are the causes acute adrenocortical insufficiency?
- Waterhouse-Friderichse syndrome
- Stress in the pituitary with underlying chronic adrenal insufficiency
- Sudeen withdrawal from long-term corticosteroid therapy
What are the causes of Waterhouse-Friderichse syndrome?
- Neisseria meningitidis septicemia (common)
- Pneumococci, Haemophilus influenza (less common)
- Endotoxin-induced vascular injury with associated disseminated intravascular coagulation
What is Chronic adrenocortical insufficiency?
Addison disease, progressive destruction of the adrenal cortex
What is Addison’s disease caused by?
- Autoimmune adrenalitis
- Infections
- Metastatic cancers
What is autoimmune adrenalitis that could leadd to Addison disease?
Occurs in DEVELOPED countries
Autoimmune polyendocrine syndromes: APS1 caused by mutations in the AIRE gene or ASP2
Where is the AIRE gene found?
On chromosome 21
What are the infections that could cause Addison’s disease?
Occur in the DEVELOPING countries
Tuberculosis, AIDS (opportunistic pathogens)
Fungi
What fungal infection could lead to Addison’s disease?
Histoplasma capsulatum
What types of .metastic cancers could lead to Addison’s disease?
Carcinomas of the lung and breast
What is secondary adrenocortical insufficiency?
Any disorder of the hypothalamus and pituitary that reduces the output of ACTH (metastatic cancers, infections, infractions or irradiation)
Can ACTH develop alone ?
Most of the time, it develops alone, but in some instances, it is one of the panhypopituitarisms associated with multiple pituitary hormone deficiencies
What is tertiary adrenal insufficiency?
Any disorder that interferes with the secretion of ACTH-releasing hormone (CRH) by the hypothalamus can lead to inadequate ACTH secretion and, thus, adrenal insufficiency
What are the clinical features of adrenal insufficiency? (5)
- Patients typically present with fatigue, weakness, and GIT disturbances
- Hypotension, hyponatremia, hypovolemia, hyperkalemia –> decreased aldosterone activity
- Hypoglycemia due to glucocorticoid deficiency and impaired gluconeogenesis
- Weakness
- Hyperpigmentation -> due to increased ACTH –> increased melanocytic production
WHat is the adrenal medulla?
- Composed of NCC-derived chromaffin cells
- Main physiologic source of catecjolamines
WHat is pheochromocytoma?
Neoplasm composed of chromaffin cells (synthesize and release catecholamines)
What are the clinical features of the pheochromocytoma due to?
Increased serum catecholamines
What are the clinical features of pheochromocytoma?
Episodic hypertension, headache, palpitations, tachycardia, and sweating
What is the rule of 10s when it comes to pheochromocytoma?
10% of pheochromocytomas are extra-adrenal, organ of Zuckerkandl, and the carotid body (paragangliomas)
10% of adrenal pheochromocytomas are bilateral
10% of adrenal pheochromocytomas are malignant
10% of adrenal pheochromocytomas are familial (recently modified to 25%)
What are the mutations which lead to familial pheochromocytomas?
Germline mutations of the RET (type 2 MEN syndromes), NF1, VHL
What are the gross features of pheochromocytomas?
Small, circumscribed lesions confined to the adrenal
Large hemorrhagic masses weighing several kilograms
What is the cut-surface of small pheochromocytomas?
Yellow-tan, well-defined lesion that compress the adjacent adrenal
What is the cut surface of larger lesions?
Hemorrhagic, necrotic, and cystic typically affect the adrenal gland
Incubation of the fresh tissue with potassium dichromate solutions turns the tumor dark brown
Wha are the microscopic features of pheochromocytomas cells?
Polygonal to spindle-shaped chromaffin cells, compartmentalized into small nests (Zellballen) by a rich vascular network
What are the microscopic features of the cytoplasm of pheochromocytoma?
Finely granular appearance
What are the microscopic features of the nuclei of pheochromocytomas?
Often pleomorphic
What are the clinical features of pheochromocytomas?
Hypertension
Associated with tachycardia, palpitations, headache, sweating, tremor
Cardiac complications
What are the cardiac complications associated with pheochromocytomas?
- Catecholamine cardiomyopathy
- Catecholamine-induced myocardial instability
- Ventricular arrhythmias
What is the lab diagnosis of pheochromocytomas based on?
Demonstration of increased urinary excretion of free catecholamines and their metabolites
What are examples of the catecholamine metabolites?
Vanillylmandelic acid anemia metanephrines
What is neuroblastoma?
The second most common solid malignancy of childhood after brain tumors, accounting for 7 to 10% of all pediatric neoplasms
Where do neuroblastomas aruse from?
Neural crest-derived cells in the sumpathetic ganglia and adrenal medulla
What do neuroblastomas secrete?
Secrete catecholamines, whose metabolites can be used for screening patients
What is the pathogenesis of neuroblastomas?
Germline mutations in the ALK gene –> familial predisposition to neuroblastoma
Somatic gain-of-function ALK mutations are also observed in 8 to 10% of sporadic neuroblastomas
What are important diagnostic features of neuroblastomas?
Elevated blood levels of catecholamines
Elevated urine levels of catecholamine metabolites (VMA and HVA)
