Adrenal Gland Pathology Flashcards
Specific steroid and location of GC
Cortisol, adrenal cortex–>zona fasciculata
Specific steroid and location of MC
Aldosterone, adrenal coretx –> zona glomerulosa
Specific steroid and location of sex steroids
Estrogen, androgens - zona reticularis
Specific steroid and location of chromaffin cells
epinepherine, cats - adrenal medulla
Two types of endogenous, ACTH-dependent Cushing Syndrome
- Which is most common and W:M
- Cushing Disease - pituitary adenoma **70% of cases; 4:1 W:M
- Ectopic corticotropin syndrome (ACTH)
Four types of endogenous, ACTH-Independent Cushing Syndrome
- Adrenal adenoma or carcinoma
- Macronodular hyperplasia
- Primary pigmented nodular adrenal disease
- McCune-Albright Syndrome
Majority of ACTH-secreting pituitary adenomas are micro- or macroadenomas?
Microadenomas.
You see cortical cell hyperplasia, think what?
Think discrete adenoma.
- Primary OR
- Secondary (hypothalamic CRH producing tumor)
If you see a small cell carcinoma of the lung, be on the lookout for?
ACTH-dependent Cushing Syndrome - the nonpituitary tumor secreting ectopic ACTH
If there is a neuroendocrine neoplasm and resultant increased ACTH and hypercortisolism, what is it probably ectopically secreting?
CRH
Most common types of nonpituitary ectopic-ACTH secreting tumors (ACTH-dependent Cushing)
- SMALL CELL CARCINOMA
- carinoids, medularry thyroid carcinoma, islet cell tumors
- CRH-secreting neuroendocrine
Most common types of primary adrenal neoplasms (ACTH-independent Cushing Syndrome)
Adrenal adenoma (10%), carcinoma (5%)
Hallmark of ____?
↑ cortisol and ↓ ACTH
Primary Adrenal neoplasm (adenoma or carcinoma)
ACTH‐independent Cushing syndrome
If there is marked hypercortisolism, think what?
cortical carcinomas (not adenoma or hyperplasias)
Most hyperplastic adrenals are ACTH dependent or independent?
ACTH depenent
Early v. late characteristic features of Cushing Syndrome
Early - HTN, wt gain
Late - moon facies, buffalo hump, truncal obesity (central pattern of fat deposition)
List four major catabolic effects of Cushing Syndrome
– Skin is thin, fragile, and easily bruised
– Poor wound healing
– Cutaneous striae are particularly common in the abdominal area
– Osteoporosis
What affect does hypercortisolism (Cushing Syndrome) have on type 2 fast twitch myofibers?
ATROPHY - decreased muscle mass and proximal limb weakness
Presentation of SECONDARY DIABETES in Cushing Syndrome and why?
Presents with Hyperglycemia, glucosuria and polydipsia
– Glucorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells
Cushing Syndrome and the immune system
IMMUNE SUPPRESSION
Explain the (1) laboratory diagnosis of Cushing Syndrome and (2) its cause
(1)
• Increased 24‐hour urine free‐cortisol*
• Loss of normal diurnal pattern of cortisol secretion
(2)
• Determining the cause of Cushing syndrome:
– Serum ACTH
– Dexamethasone suppression test: Urinary excretion of 17‐hydroxycorticosteroids after administration of dexamethasone
A pt presents with HTN, think…
Primary hyperaldosteronism. Autonomous over production of aldosterone. Suppression of RAS
- Pts older with (less severe) hypertension
* Bilateral nodular hyperplasia of the adrenal glands
Bilateral Idiopathic Hyperaldosteronism
• Most common cause of primary hyperaldosteronism
Most likely type of adrenocortical neoplasm that causes primary hyperaldosteronism. Sex and age
Adenoma (conn Syndrome)
W>M (2:1), middle age
- Familial hyperaldosteronism
- Ch 8 rearrangement that places the gene for aldosterone synthase under the control of the ACTH responsive gene promoter
Glucocorticoid-Remediable Hyperaldosteronism
Labs for:
– ACTH stimulates the production of aldosterone
– Suppressible by dexamethasone
Glucocorticoid-Remediable Hyperaldosteronism
Aldosterone released in response to activation of the renin‐angiotensin system by ↑ plasma renin
Secondary hyperaldosteronism
In what three instances is secondary hyperaldosteronism typically seen?
- Decreased renal perfusion
- Arterial hypovolemia and edema
- Pregnancy
Long term effects of HTN on CV system (hyperaldosteronism)
LVH, decreased diastolic volumes, stroke, MI
A person presents with weakness, paresthesias, visual disturbances, and occasionally tetany. What notable electrolyte is abnormal and what is the cause?
Hypokalemia due to hyperaldosteronism.
Screening and confirmation lab test for hyperaldosteronism
- Screening test: Elevated ratio of plasma aldosterone concentration to plasma renin activity
- Confirmation test: Aldosterone suppression test
Treatment of hyperaldosteronism due to:
- adenoma
- bilateral hyperplasia
- Secondary hyperaldosteronism
- adenoma - resection
- bilateral hyperplasia - pharm (aldosterone antagonist like spironolactone)
- Secondary hyperaldosteronism - tx underlying cause
Deficiency or total lack of an enzyme involved in the biosynthesis of cortical steroids, esp. cortisol. Presents with androgen excess, with or without aldosterone and glucocorticoid deficiency.
Congenital Adrenal Hyperplasia
Increased androgens in CAH = ?
Impaired aldosterone secretion = ?
virilization
Salt wasting
Three distinct syndromes in 21-hydroxylase deficiency
– Salt‐wasting syndrome
– Simple virilizing adrenogenital syndrome without salt wasting
– Nonclassic or late‐onset adrenal virilism
Genetics of 21-hydroxylase deficiency
CYP21A2 mutation
Inability to convert progesterone into deoxycorticosterone. What is this called and what are the clinical effects?
Salt-wasting syndrome - salt wasting (hyponatremia and hyperkalemia) → acidosis, hypotension, cardiovascular collapse, and possibly death
When is Salt Wasting Syndrome recognized?
– Virilization recognized in the female at birth or in utero
– Males come to clinical attention 5‐15 days later because of some salt‐losing crisis
What presents with:
• Presents as genital ambiguity
• ~1/3 of 21‐hydroxylase deficiency
• Progressive virilization
Simple Virilizing Andrenogenital Syndrome Without Salt Wasting
• Most common form of CAH
• Only a partial deficiency in 21‐hydroxylase
function
• Asymptomatic
• Hirsutism, acne, and menstrual irregularities
Nonclassic or Late-onset Adrenal Virilism
Neonate is born with ambiguous genetalia. What should be suspected immediately?
CAH
What enzyme deficiency does this female have?
• Clitoral hypertrophy and pseudohermaphroditism in infants
• Oligomenorrhea, hirsutism, and acne in postpubertal
21‐hydroxylase deficiency
What enzyme deficiency does this male have?
• Enlargement of the external genitalia and other evidence of precocious puberty in prepubertal patients
• Oligospermia in older males
21‐hydroxylase deficiency
Why does severe 21‐hydroxylase deficiency have such a strong effect on the adrenal medulla? What results?
ADRENOMEDULLARY DYSPLASIA
GC required to make cats (Epi/NE).
Low cortisol levels → adrenomedullary dysplasia (↓ catecholamine secretion) → hypotension and circulatory collapse
Treatment for CAH (two)
- exogenous GC
2. MC supplementation in salt-wasting variants of CAH
What occurs in this setting? Exogenous corticosteroids, in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
Primary Acute Adrenocortical Insufficiency
Massive adrenal hemorrhage damages the adrenal cortex and causes Primary Acute Adrenocortical Insufficiency - what settings can this damage occur in?
–Newborns after traumatic delivery and hypoxia
– Anticoagulant therapy
– Postsurgical patients who develop DIC
– Disseminated bacterial infection (Waterhouse‐Friderichsen syndrome)
What is this?
• Rapidly progressive hypotension leading to shock
• DIC associated
with widespread purpura
• Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
• Fatal, unless promptly recognition and treated
Waterhouse-Friderichsen Syndrome
Bug associated with Waterhouse-Friderichsen Syndrome.
Neisseria meningitidis septicemia
What is this - progressive destruction of adrenal cortex. If caused by autoimmune adrenal insufficiency, then seen more common in whites and women. Sx when 90% of cortex is lost.
Primary Chronic Adrenocortical Insufficiency (Addison Disease)
- Autoimmune destruction of steroidogenic cells
* Autoantibodies to 21‐hydroxylase and 17‐ hydroxylase have been detected
Autoimmune Adrenalitis, 60-70% of Addison Disease
Occur in either APS1 and APS2
• Candidiasis
• Abnormalities of skin, dental enamel, and nails (ectodermal
dystrophy)
• Autoimmune dz/polyendocrine disorders (i.e. Autoimmune Adrenalitis)
APS1
Genetics of APS1
Mutation in AIRE gene on ch21
– autoimmunity
Autoantibodies against what two IL’s to eliminate defense against fungal infections?
IL‐17 and IL‐22
- Usually starts in early adulthood
* Presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
APS2
- Early manifestations: progressive weakness and easy fatigability
- GI disturbances – Anorexia, N/V/D, weight loss
- Primary adrenal disease: get hyperpigmentation of the skin
- Hypoglycemia can occur – impaired gluconeogenesis
Addison Disease
Where on the body is hyperpigmentation form Addison Diseaemost prominent?
Sun‐exposed areas and pressure points (e.g. neck, elbows, knees, and knuckles)
Why does this hyperpigmentation occur in Addison Disease?
– Results from elevated levels of pro‐opiomelanocortin (POMC)
• Originates in ant-pit and is precursor of ACTH and melanocyte stimulating hormone (MSH)
A person with Addison has previously undergone some sort of stress ( infection, trauma, surgical procedure). Presents with intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse. What do they have and what therapy must begin immediately to avoid death?
acute adrenal crisis. begin Corticosteroid therapy
Electrolyte/labs in Addison, due to decreased MC activity
hyperkalemia, hyponatremia
volume depletion, hypotension
Define secondary adrenocortical insufficiency
Any disorder of the hypothalamus and pituitary (met cancer, infection, infarction, radiation) that REDUCES the output of ACTH.
Main differences between Addison Disease and secondary adrenocortical insufficiency.
No hyperpigmentation, no hyperklaemia/hyponatremia.
Lab dx for secondary adrenocortical insufficiency
**Labs - low cortisol and androgen output, but normal or near normal aldosterone.
(give exogenous ACTH –> prompt rise in cortisol)
Major bacteria possibly implicated in Waterhouse
Neisseria meningitidis septicemia
– Also see with Pseudomonasspecies, pneumococci, Haemophilus influenzae, or even staphylococci
Adrenocortical neoplasms: type and age
Adenomas = carcinomas in adults
Carcinomas > adenomas in kids
Familal or sporadic - adrenocortical carcinomas
both.
Familial = Li‐Fraumeni syndrome and Beckwith‐Wiedemann syndrome
Mutation in Li-Fraumeni Syndrome
Germline TP53 mutation
More likely adenoma or carcinoma:
• Hyperaldosteronism and Cushing syndrome
• Virilizing neoplasm
- More likely from a functional adenoma
2. More likely carcinoma
Benign lesions composed of mature fat and marrow in adrenal gland.
Adrenal myelolipomas
– Frequent abdominal imaging led to discovery many incidental adrenal masses
– Asymptomatic
– ~4% of the population
– Majority are small, nonsecreting cortical adenomas
“adrenal incidentaloma”
Rare cause of surgically correctable hypertension
– ~2/3 have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations (can be fatal)
Pheochromocytoma
What type of neoplasm is a pheochromocytoma?
composed of chromaffin cells in the adrenal medulla
“Rule of 10s” for pheochromocytomas
– 10% are extra‐adrenal – 10% bilateral – 10% malignant – 10% don’t have hypertension (10% calcify, kids, bilateral)
What can precipitate paroxysmal episodes in pts with pheochromocytoma?
– Emotional stress – Exercise – Changes in posture – Palpation in the region of the tumor – Patients with urinary bladder paragangliomas = paroxysm during micturition
Bilateral, younger onset, occurs in 1/2 of people with pheos and paragangliomas - are they familial or sporadic?
familial
RET gene - syndrome and lesion
MEN-2A/2B; pheochromocytoma
SDHD/SDHB gene - syndrome and lesion
Familial paraganglioma 1 and 4; pheochromocytoma and paraganglioma
Dx of a pheo
Increased urinary excretion of free catecholamines and metabolites:
• Vanillylmandelic acid and metanephrines
Tx of a pheo
Surgical excision, tx HTN
Parathyroid, Pancreas, Pituitary (PRL-oma), and possible:
• Duodenum is the most common site of gastrinomas
• Carcinoid tumors
• Thyroid adenomas
• Adrenocortical adenomas
• Lipomas
MEN-1 “wermer Syndrome”
MEN1 genetics
Mutation in MEN1 tumor suppressor gene - encodes menin.
What do these three characterize?
• Pheochromocytoma (40‐50%)
• Medullary carcinoma of the thyroid (~100%)
• Parathyroid hyperplasia (10‐20%)
Sipple Syndrome, MEN-2A
MEN-2A genetics
germline mutation in RET proto-oncogene; ch10
• Medullary carcinoma of the thyroid (~100%), most aggressive
• Pheochromocytomas
• Neuromas or ganglioneuromas of the skin, oral mucosa,
eyes, respiratory tract, and gastrointestinal tract
• Marfanoid habitus
MEN-2B
Genetics of MEN-2B - offer at risk family members prophylactic what?
germline mutation in single aa in RET - prophylactic thyroidectomy
- Variant of MEN‐2A
- Only medullary thyroid cancer
- Pts older
- More indolent course
Familial medullary thyroid cancer
– Photosensory and neuroendocrine functions
– Secretes melatonin
Tumors are rare
Pineal Gland
If tumor present (rare), what type in the pineal gland?
– Most commonly germ cell tumors - Germinomas, embryonal carcinomas; choriocarcinomas, teratomas
– Pinealomas - Pineoblastomas and pineocytomas
do adrenal adenomas suppress ACTH?
no
Four syndromes in which paragangliomas form.
VHL, Familial paraglanglioma 1,3,4
