Endocrine Pathology Flashcards
What causes Cushing syndrome?
increased cortisol levels due to:
- exogenous corticosteroids that result in decreased ACTH and bilateral adrenal insufficiency (most common cause)
- primary adrenal adenoma, hyperplasia, or carcinoma resulting in decreased ACTH, and atrophy of the uninvolved adrenal gland
- ACTH secreting pituitary adenoma (aka Cushing disease) or paraneoplastic ACTH secretion from a cancer both resulting in increased ACTH and bilateral adrenal hyperplasia
What cancers most commonly cause paraneoplastic ACTH secretion?
small cell lung cancer
What are the symptoms of Cushing syndrome?
- HTH, weight gain
- moon facies
- truncal obesity and striae
- buffalo hump
- osteoporosis
- hyperglycemia
- amenorrhea
How should Cushing syndrome be diagnosed?
Measure ACTH. If decreased (less than 5pg/mL), suspect an adrenal tumor. If elevated over 20 pg/mL then it is an ACTH-dependent Cushing syndrome. From there, do a high-dose dexamethasome suppression test (HDDST) and a CRH stimulation test.
If the HDDST does not cause suppression it is an ectopic ACTH secretion, and if it does, it is Cushing disease
What is adrenal insufficiency?
the inability of the adrenal glands to generate enough glucocorticoids +/- mineralocorticoids resulting in symptoms including weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI disturbances, and sugar and/or salt cravings
What is a metyrapone stimulation test?
metyrapone blocks the conversion of 11-deoxycortisol to cortisol so the normal response is decreased cortisol and compensatory increase in ACTH. In adrenal insufficiency, ACTH remains depressed after the test
Describe primary adrenal insufficiency
this is a deficiency of aldosterone and cortisol production due to loss of gland function leading to hypotension, hyperkalemia, metabolic acidosis, and skin and mucosal hyperpigmentation due to MSH, a byproduct of increased ACTH production from POMC
the two main types are acute and chronic
What are the main causes of acute adrenal insufficiency?
hemorrhage
ketoconazole use
What are the main causes of chronic adrenal insufficiency (aka Addison disease)?
- autoimmunity
- TB
- metastasis
Acute primary adrenal insufficiency due to adrenal hemorrhage associated with Neisseria meningitidis is known as _______
Waterhouse-Friderichsen syndrome
Describe secondary adrenal insufficiency
What is the most common pediatric adrenal tumor?
a neuroblastoma, of the adrenal medulla
What causes neuroblastomas?
tumor of the sympathetic chain in the adrenal medulla in children usually under 4 yo
How does a neuroblastoma present clinically?
abdominal distension and a firm, irregular mass
may also have opsoclonus-myoclonus syndrome (aka ‘dancing eyes-dancing feet’)
What are these?
Homer-Wright bodies seen in neuroblastomas
How are neuroblastomas diagnosed?
elevated urine HVA (breakdown product of dopamine) and VMA (breakdown produt of nor)
bombesin and neuron-specific enolase +
What mutation is common in neuroblastomas?
N-myc
What is the most common adrenal medullar tumor in adults?
pheochromocytoma
Where do pheos come from?
chromaffin cells, derived from the neural crest
What is the ‘Rule of 10s’ with pheos?
10% are
- malignant
- bilateral
- extra-adrenal
- calcify
- are in kids
What are the symptoms of a pheo?
Episodic hyperadrenergic symptoms (5P’s):
Pressure (increased BP)
Pain (HA)
Perspiration
Palpitations
Pallor
What are some associations of pheos?
- neurofibromatosis type I
- VHL disease
- MEN 2A and 2B
How are pheos tx?
irreversible a-antagonists (e.g. phenoxybenazine) followed by B-blockers prior to tumor resection
How does hypothyroidism present clinically?
- cold intolerance (decreased heat production)
- facial/periorbial myxedema
- weight gain and decreased appetite (BMR decreased)
- fatigue, weakness, lethargy
- constipation
- areflexia
- bradycardia
How does hypothyroidism present in labs?
-increased TSH (in primary)
decreased free T3/T4
hypercholesterolemia due to decreased LDL receptor expression
How does hyperthyroidism present clinically?
heat intolerance
weight loss and increased appetite
hyperactivity
diarrhea
increased reflexes
pretibial myxedema
warm, moist skin
What are some main causes of hypothyroidism?
- Hashimoto thyroidits
- Congenital hypothyroidism (cretinism)
- Subacute thyroiditis (de Quervain)
- Riedel thyroiditis
Describe Hashimoto thyroiditis
this is the most common cause of hypothyroidism in iodine-sufficient regions and is an autoimmune disorder marked by Abs against thyroid peroxidase that may present as hyperthyroidism early in its course due to thyrotoxicosis following follicular rupture
and typically has an enlarged, nontender thyroid
associated with HLA-DR5 and increased risk of non-Hodgkin lymphoma
What are the histo findings of Hashimoto thyroiditis?
-Hurthle cells, lymphoid aggregates with germinal centers
How does cretinism present?
-pot-bellied, pale,
umbilical hernia
protuberant tongue
poor brain development
What is Subacute thyroiditis?
a self-limited disease following flu that may be hyperthyroidism early in its course but transitions to hypothyroidism and is associated with a tender thyroid and jaw pain
What is Riedel thyroiditis?
this occurs when the thyroid is replaced by fibrous tissue (hypothyroid), and fibrosis may extend to local strucures mimicking anaplastic carcinoma. Considered a manifestation of IgG4-related systemic disease
the thyroid is hard, rock like, and painless
What are the main causes of hyperthyroidism?
- Graves disease
- toxic multinodular goiter
- thyroid storm
- Jod-Basedow phenomenon
Describe Graves disease
This is the most common cause of hyperthyroidism caused by autoantibodies that stimulate TSH receptors on the thyroid and manifesting as protuberant eyes and pretibial myxedema
Toxic multinodular goiter is when focal patches of hyperfunctioning thyroid cells arise independent of TSH due to mutations in the TSH receptor (hot nodules are rarely malignant)
What causes a thyroid storm?
stress-induced catecholamine surge seen in chronic disease, presenting as agitation, confusion, fever, diarrhea, coma, and tachyarrhythmias
How is thyroid storm tx?
BBs (e.g. Propranolol), Propylthiouracial, and corticosteroids (eg. Prednisolone)
What is Jod-Basedow phenomenon?
thyrotoxicosis when a pt with iodine deficiency goiter is made iodine replete
What are some complications of thyroid removal?
hoarseness (recurrent laryngeal n. damage)
hypocalcemia (if the parathyroids are damaged)
What are the main types of thyroid cancer?
- Papillary carcinoma
- Follicular carcinoma
- Medullary carcinoma
- Anaplastic carcinoma
- Lymphoma
Describe papillary carcinomas
these are the most common and have the best prognosis that spread via lymph and are marked histologically by:
- empty appearing nuceli with central clearing (aka Orphan Annie eyes) (below)
- psamomma bodies
- nuclear grooves
What mutations are common in papillary carcinomas of the thyroid?
RET and BRAF
Describe medullary carcinomas
these arise from C cells and produce calcitonin, and sheets of cells in an amyloid stroma (below). These spread via heme
Medullary carcinoma of the thyroid is seen in _______
MEN 2A and 2B
Thyroid lymphoma is a common sequelae of ______
Hashimoto thyroiditis
What are the most common causes of hypoPTHism?
- accidental removal surgical excisions,
- autoimmune destruction
- DiGeorge syndrome
What is Chvostek sign?
tapping of the facial nerve (cheek) causes contraction of facial muscles in hypoPTHism
What is Trousseau sign?
occlusion of the brachial a. with a BP causes carpal spasm
Unresponsiveness of the kidney to PTN resulting in hypocalcemia, shorteneded 4th/5th digits, and shoft stature is known as ______
pseudo-hypoPTHism
What causes familial hypocalciuric hypercalcemia?
a defective Ca2+ sensing receptor of parathyroid cells leading to elevated PTH even in the face of elevated calcium
What are the main causes of primary hyperPTHism?
-parathyroid adenoma or hyperplasia
What are the lab findings of primary hyperPTHism?
hypercalcemia, hypercalciuria (renal stones), hypophosphatemia, elevated PTH
elevated ALP, and cAMP in urine
How does hyperPTHism present?
most often asymptomatic but can present with:
bones (bone pain), stones (kidney stones), groans (constipation), and moans (depression)
What is osteitis fibrosa cystica?
the formation of cystic bone sapces filled with brown fibrous tissue that causes bone pain
What are the main causes of secondary hyperPTHism?
decreased calcium or vitD, or elevated phosphate, most often occurring in chronic kidney disease
What is the most common pituitary adenoma?
prolactinoma (benign)
How can pituitary adenomas present?
they may be fucntional (hormone producing) or nonfunctional (silent). Nonfunctional tumors present with mass effect including bitemporal hemianopia, hypopituitarism, and HA
a functional prolactinoma would present with amenorrhea, galactorrhea, low libido, inferility
What is the tx of a prolactinoma?
-dopamine agonists like bromocriptine or cabergoline
Acromegaly increases the risk of what?
colorectal polyps and cancer
What is the most common cause of death with gigantism?
HF
How is acromegaly diagnosed?
increased IGF-1
failure to suppress serum GH following an oral glucose tolerance test
What is diabetes insipidus?
failure to concentrate urine due to failure of secretion (central) or binding of ADH (nephrogenic)
What are the main causes of central DI?
-pituitary tumor, trauma, surgery, idiopathic
What are the lab findings of central DI?
- decreased ADH
- urine SG less than 1.006
serum osmolarity over 290 mOsm/kg
What are the main causes of nephrogenic DI?
-hereditary (ADH receptor mutation)
secondary to hypercalcemia, lithium, demeclocycline (ADH antagonist)
How can central and nephrogenic DI be differentiated?
central will show a 50+% increase urine osmolarity after administration of an ADH analog (desmopressin acetate) while nephrogenic will not
How is central DI tx?
intranasal desmopressin acetate (ADH analog)
Hydration
How is nephrogenic DI tx?
HCTZ, indomethacin, amiloride
Hydration
Describe SIADH
syndrome of:
- excessive free water retention
- Euvolemic hyponatremia with continued urinary na+ excretion
- urine osmolarity > serum osmolarity
What are the complications of SIADH?
the body responds to water retention by decreasing aldosterone from the adrenal glands. Thre resultant hyponatremia can lead to cerebral edema and seizures
Must correct slowly to prevent osmotic demyelination syndrome
What are the main causes of SIADH?
- Ectopic ADH (e.g. small cell lung cancer)
- CNS disorders/head trauma
- pulmonary disease
- drugs (cyclophosphamide)
How is SIADH tx?
-demeclocycline
-vaptans
- fluid restriction
- IV hypertonic saline
What are the main causes of hypopituitarism?
- nonsecreting pituitary adenoma, craniopharyngioma
- Sheehan syndrome
- Empty sella syndrome
- Pituitary apoplexy
- brain radiation, injury
What is Sheehan syndrome?
ischemic infract of the pituitary following postpartum bleeding presenting with the classic triad of:
-failure to lactate
-absent menstruation
-loss of pubic hair
and cold intolerance
What is a major cause of empty sella syndrome?
obesity compressing the pituitary
What is pituitary apoplexy?
sudden hemorrhage, often in the presence of an existing adenoma
What is a craniopharyngioma?
a type of brain tumor derived from pituitary gland embryonic tissue, that occurs most commonly in children but also in men and women in their 50s and 60s. People may present with bitemporal inferior quadrantanopia leading to bitemporal hemianopsia, as the tumor may compress the optic chiasm.
Describe the pathophysi of diabetes mellitus
insulin deficiency or resistance (and/or glucagon excess) leads to decreased glucose uptake and increased proteolysis and lipolysis all promoting hyperglycemia leading to dehyration and acidosis
What are the symptoms of DM?
-polydipsia, polyuria, polyphagia
DNA (type I)
hyperosmolar coma (type II)
What are some chronic complications of diabetes?
nonezymatic glycation leading to:
- small vessel diffuse thickening of BM leading to retinopathy (hemorrhage, exudates, microaneurysms)
- nephropathy (Kimmelstiel-WIlson nodules)
- large vesse; atherosclerosis, CAD, gangrene, occlusive disease
What is the most common cause of death in DM?
MI
Seen in DM nephropathy
Omsotic damage in DM can also cause neuropahty and/or cataracts. How does this occur?
sorbitol accumulation in organs with aldose reductase and decreased or absent sorbitol dehydrogenase
Describe type I Diabetes
cause: autoimmune destruction of B cells
insulin is always needed for tx
severe glucose intolerance
insulin resistance less common
What are the HLA associations of type I DM?
HLA-DR3/4 (less genetic predispostion than type II)
Islet leukocytic infiltrate (below) of IOL is a characteristic finding of what _____
Type I DM
What are the HLA associations of Type II DM?
None but more genetic disposition than type I
What is the classic histo finding in the IOL in Type II diabetes?
amyloid deposits
What causes DKA?
Commonly seen only in Type I DM due to excessive fat breakbown (lipolysis) and ketogenesis from increased circulating free fatty acids (B-hydroxybutyrate > acetoacetate)
NOTE: Only seen in type I becuase insulin prevents lipolysis
What are the signs and symptoms of DKA?
- Kussmaul respirations (rapid/deep breathing)
- fruity breath
N/V
abdominal pain
dehydration
delirium
What are the lab findings of DKA?
hyperglycemia
acidosis and decreased HCO3- (increased anion gap metabolic acidosis)
leukocytosis
-kyperkalemia, but depleted total body K+ (due to extracellular shift)
What are the major complications of DKA?
- Rhizopus mucormycosis
- cerebral edema
- cardiac arryhthmia or HF
How does a glucagonoma present?
Tumor of pancreatic a cells causing overproduction of glucagon presenting as the four D’s:
dermatitis, diabetes, DVT, and depression
Describe insulinomas
tumor of B cells causing overproduction of insulin leading to hypoglycemia
How might insulinomas present?
Whipple triad:
hypoglycemia
lethary, syncope, diplopia (symptoms of hypoglycemia)
resolution of symptoms after normalization of BG
What is carcinoid syndrome?
syndrome seen in metastatic carcinoid tumors caused by secretion of serotonin that results in bouts of diarrhea, cutaneous flushing, wheezing, HTN, and right-sided valvular disease
What are the lab findings of Carcinoid syndrome?
increased urine 5-HIAA
niacin deficiency (pellagra)
What is Pellagra?
A vitamin deficiency disease most frequently caused by a chronic lack of niacin (vitamin B3 or vitamin PP, from pellagra-preventing factor) in the diet. It can be caused by decreased intake of niacin or tryptophan, and possibly by excessive intake of leucine. It may also result from alterations in protein metabolism in disorders such as carcinoid syndrome or Hartnup disease. A deficiency of the amino acid lysine can lead to a deficiency of niacin, as well
What is the Rule of 1/3rds in Carcinoid syndrome?
1/3:
metastastize
present with a 2nd malignancy
are multiple
What is Zollinger-Ellison Syndrome?
Gastrinoma of the pancreas or duodenum causing acid hypersecretion leading to recurrent ulcers, abdominal pain, and diarrhea
How is ZES diagnosed?
paradoxical increase in gastrin levels following adminstration of secretin, which normally inhibits gastrin
All MEN syndromes have _____ MOI
AD (All MEN are dominant)
What are the components of MEN1?
- Parathyroid tumor
- Pituitary tumors (proalctin or GH)
- Pancreatic endocrine tumor (ZES, insulinomas, VIPomas, glucagonomas)
What is the cause of MEN 1?
mutation of MEN1 gene (menin, a tumor suppressor)
What causes MEN2A AND MEN2B?
RET gene
What are the components of MEN2A?
- Parathyroid hyperplasia
- Pheochromocytoma
Medullary thyroid carcinoma (Secretes calcitonin)
What are the components of MEN 2B?
- Pheochromocytoma
- Medullary thyroid carcinoma (secretes calcitonin)
- Oral/intestinal ganglioneuromatosis (mucosal neuromas) (below)
MEN 2A and 2B are associated with _______
marfanoid habitus
