Things I don't know: Path Flashcards
PAX8 genetic defect
HYPOTHYROID
FOXE1 genetic defect
HYPOTHYROID
TSH receptor mutation
HYPOTHYROID
THRB mutation
thyroid hormone resistance syndrome
HYPOTHYROID
Drugs that can cause hypothyroid
lithium, iodides, p-aminosalicylic acid
What causes the broad coarse facial features in hypothyroidism?
mucopolysaccharide-rich edematous fluid
subacute lymphocytic thyroiditis (painless thyroiditis)
variant of Hashimotos goiter or hyperthyroidism most recover some progress to hypothyroidism anti-thyroid peroxidase Ab excludes women: one year after deliver, abortion or miscarriage
thyroid stimulating immunoglobulin
Ab to TSH receptor
GRAVES
thyroid growth stimulating immunoglobulin
Ab to TSH receptor
GRAVES
Plummer syndrome
hyperthyroidism due to multinodular goiter
goitrogens
interfere with thyroid hormone synthesis
Brassicaceae (Cruciferae) family: cabbage, turnips, cauliflower, brussel sprouts
somatic mutations of TSH receptor signaling pathway
toxic adenomas
toxic multinodular goiter
somatic mutation of TSHR
toxic adenoma
toxic multinodular goiter
mutation of GNAS
alpha unit of Gs
- toxic adenoma
- toxic multinodular goiter
- anterior pituitary adenoma (40% of GH secreting, minority of ACTH secreting)
- macronodular ACTH independent adrenal hyperplasia
RAS mutation
minority of follicular adenomas
shared with follicular carcinomas
PIK3CA mutation
minority of follicular adenomas
shared with follicular carcinomas
In what population is follicular carcinoma more prevalent?
area with iodine deficiency
moans, groans, bones, stones
hyperparathyroidism
depression, muscle weakness, abdominal pain, kidney stones, osteitis fibrosa cystica, bone pain
Sx of gonadotroph adenoma
FSH, LH
hypogonadism, mass effect, hypopituitarism
when deficient: more likely LH secretion is impaired
FSH predominant secreted hormone
CDKN1B
gene associated with subset of MEN-like abnormalities
familial pituitary adenomas
PRKAR1A
gene
familial pituitary adenomas
AIP
gene associated with GH adenoma patients that are young
atypical adenoma
p53 mutation
more aggressive
GH excess Sx (besides acromegaly/ gigantism)
gonadal dysfunction, diabetes mellitus, generalized muscle weakness, HTN, arthritis, CHF, increased risk GI cancer
How does excess GH cause DM?
inhibits peripheral glucose uptake
increases hepatic glucose production
compensatory hyperinsulinism leads to insulin resistance
PAS stain
ACTH adenoma (may have hyper pigmentation) DM: thickening of BM; hyaline sclerosis, Kimmelstiel-Wilson nodules
plurihormonal adenoma
pituitary
multiple hormones
more aggressive
pituitary carcinoma
most are functioning: PRL and ACTH most common
recognized often by metastasis
empty sella syndrome: primary vs. secondary
any condition or treatment that destroys part or all of pituitary gland
Primary: anatomic defect: subarachnoid space herniates into the sella turcica and fills up with CSF; OBESE, HTN, MULTIPLE PREGNANCIES
Secondary: mass (ex: pituitary adenoma) enlarges the sella and is surgically removed or is infarcted
most common hypothalamic suprasellar tumors
gliomas
craniopharyngiomas
WNT signaling pathway abnormalities
craniopharyngioma
B-catenin mutation
activating
craniopharyngioma
wet keratin
craniopharyngioma
machine oil in cysts
looks like cholesterol cleft on histo
craniopharyngioma
Diabetes is the leading cause of what three things
- end stage renal disease
- adult onset blindness
- non-traumatic lower extremity amputation
what does excess glucose stick to in DM?
everything, esp basement membranes
what happens to excess intracellular glucose in DM
sorbitol pathway to fructose (more potent glycosylator than glucose)
A1C, fasting glucose, oGTT
- diabetic
- prediabetic
- A1C: 6.5 or above; fasting: 126 or above; oGTT: 200 or above
- A1C: 5.7 to 6.4; fasting 100 to 125; oGTT: 140 to 199
Pitfalls in DM testing
hemoglobin variant (sickle cell) anemia hemolysis heavy bleeding recent blood transfusion
HLA-DR3
Hashimotos
Graves
T1DM
HLA-DR5
Hashimotos
HLA-B8
Graves
HLA-DR4
T1DM
anti-insulin
Ab against islets
T1DM
anti-GAD
Ab against islets
T1DM
anti-ICA512
Ab against islets
T1DM
CTLA4 polymorphisms
inhibit T cell response
T1DM
PTPN22 polymorphisms
inhibit T cell response
T1DM
insulin gene VNTRs
T1DM
formation of advanced glycation end products
complication of DM
formed from glucose precursors and proteins
induce inflammatory cells on ENDOTHELIUM and SMOOTH MUSCLE
ROS, procoagulant, crosslinks and traps proteins in vessel walls (LDL, albumin)
complications of DM: activation of PKC
VEGF: neovascularization seen in retinopathy
disturbances in polyol pathways
complications of DM
in tissues that do NOT use insulin: so have HIGH intracellular glucose
glucose to sorbitol and eventually fructose: ALDOSE REDUCTASE
uses: NADPH (needed for glutathione reductase to generate GSH (an antioxidant)
sorbitol in lens: cataract formation
Most common cause of death in DM
- MI
2. renal failure
types of diabetic nephropathy
- glomerular lesions
- renal vascular lesions (arteriolosclerosis)
- pyelonephritis (inc. necrotizing papillitis)
glomerular lesions in diabetic nephropathy
- BM thickens
- diffuse mesangial sclerosis
- nodular glomerulosclerosis (Kimmelstiel-Wilson disease)
Kimmelstiel-Wilson disease
nodules of hyaline in glomerular capillary loops in glomerulus due to non-enzymatic glycosylation of proteins
associated with RENAL FAILURE in DM
charcot joint (neuropathic arthropathy)
DM
progressive, destructive: dead bone, subluxation, extreme deformity, fibrosis, reactive new bone
luxol fast blue
stains myelin blue
if see pink: segmental demyelation
what is the first sign of diabetic neuropathy
segmental demyelination
autonomic (ex: bladder) and peripheral
Why and where do diabetics get infection?
impaired innate immune system: (NEUTROPHILS) due to too much glucose
skin, feet, lungs, urinary tract
How does hyperglycemia impair neutrophils?
neutrophils: upregulate CD11b
endothelial cells: upregulate ICAM-1, VCAM-1, E-selectin
ADHESIVE phenotype impairs neutrophil exit from blood vessels to infection
pancreatic NETs (neuroendocrine tumors)
rare
most: middle age, sporadic, non-functioning
MALIGNANT
metastases: LIVER
CHROMOGRANIN A (not specific)
associations: MEN-1, von Hippel Lindau syndrome, neurofibromatosis-1, tuberous sclerosis
SALT and PEPPER; NESTs or CORDs
graded on: MITOTIC FIGURES, Ki-67
stains not helpful: stain does not correlate with secretion
What is the exception to a pancreatic NET being malignant?
micro adenoma or insulinoma
von Hippel Lindau syndrome
PANCREATIC NETs
PHEOCHROMOCYTOMA
cysts of kidney, liver, epididymis
renal cell carcinoma (clear cell type), angiomas, cerebellar hemangioblastoma
neurofibromatosis-1
pancreatic NETs
tuberous sclerosis
pancreatic NETs
How are carcinomas diagnosed?
based on LOCAL INVASION and DISTANT METASTASIS
glucagonoma (alpha cell tumor)
perimenopausal, postmenopausal women
anemia, DM, NECROLYTIC MIGRATORY ERYTHEMA
somatostatinoma (delta cell tumor)
achlorhydria
CHOLELITHIASIS (inhibits CHOLECYSTOKININ release and therefore gallbladder emptying)
DM (inhibits insulin)
STEATORRHEA (inhibits pancreatic secretion and lipid absorption)
most don’t have symptoms
insulinoma
MOST COMMON functioning pancreatic NET
EPISODIC HYPOGLYCEMIA, confusion, blurred vision, muscle weakness, sweating, palpitations
may have AMYLOID
VIPoma
vasoactive intestinal peptide
HYPOKALEMIA, acidosis, hypovolemia, ACHLORHYDRIA
SEVERE WATERY DIARRHEA
associations: neural crest tumors: neuroblastomas, ganglioneuroblastoma, ganglioneuromas, pheochromocytomas
gastrinoma
SECOND most common pancreatic NET
parietal cell hyperplasia (increase acid): PEPTIC ULCERS, DIARRHEA
Zollinger-Ellison syndrome
gastrinoma
islet hyperplasia
hyperinsulinism
can happen in adults
most: CONGENITAL with hypoglycemia in neonates/infants
scenarios that may result in islet hyperplasia
- maternal DM
- Beckwith-Wiedemann syndrome
- rare mutations in the B cell K channel protein or sulfonylurea receptor
How can maternal DM effect fetus/neonate?
maternal hyperglycemia results in increase in number and size of fetal islets
after birth: hyperactive islets cause serious episodes of hypoglycemia in neonate (transient phenomenon)
What pancreatic NET is associated with neural crest tumors?
What are these neural crest tumors?
VIPoma
includes: neuroblastoma, ganglioneuroblastoma, ganglioneuromas, pheochromocytomas
MEN1
- What is the most common manifestation?
- What is most likely to kill them?
- What is the most frequent pituitary manifestation?
- manifestation: primary hyperparathyroidism (hyperplasia or adenoma)
- kill: pancreatic NET
- pituitary: prolactin secreting
familial medullary thyroid cancer
variant of 2A medullary cancer without clinical manifestations
Wermer syndrome
MEN1
Sipple syndrome
MEN2A
Features of ACTH independent macro nodular adrenal hyperplasia (primary cortical hyperplasia)
greater than 3mm sporadic association: GNAS, McCune-Albright prominent nodules of various sizes mix of lipid poor and lipid rich cells between nodules have microscopic nodularity
Features of ACTH independent micro nodular adrenal hyperplasia (primary cortical hyperplasia)
1-3 mm
darkly pigemented: LIPOFUSCION
nodules with intervening atrophy
lipofusion
micronodular primary adrenal hyperplasia
primary adrenocortical neoplasia
malignant or benign
more likely malignant in children: Li-Fraumeni, BeckwithWiedemann
Li-Fraumeni
primary adrenocortical neoplasia
Beckwith-Wiedemann
primary adrenocortical neoplasia
Are adrenal cortex carcinomas or adenomas more likely to be functional and virilizing?
carcinomas
Histo: adrenal cortical adenomas
LIPID rich
Histo: adrenal carcinoma adenoma
anaplastic (can’t tell it’s carcinoma without this until it metastasizes)
poor prognosis
larger than adenoma
Causes of hypercortisolism in order from most common to least
- exogenous
- pituitary adenoma
- primary adrenal neoplasm
- paraneoplastic ACTH tumor
Conn’s syndrome
SECOND most common hyperaldosteronism adrenal adenoma producing aldosterone Tx: Sx Sx: HTN, hypokalemia, low renin SPIRONOLACTONE BODIES after spironolactone Tx
bilateral adrenal hyperplasia
MOST COMMON primary hyperaldosteronism
idiopathic
Tx: spironolactone (K sparing)
Sx: HTN, hypokalemia, low renin
secondary hyper-aldosteronism
due to activation of renin-aldosterone system (decreased renal perfusion, arterial hypovolemia, pregnancy)
21-hydroxylase deficiency
MOST common adrenogenital syndrome
low cortisol: more production of precursors leading to excess androgens
wastes Na
11-B-hydroxylase deficiency
second most common adrenogenital syndrome
low cortisol: more production of precursors leading to excess androgens
DOC maintains Na levels
congenital adrenal hyperplasia
suspect in neonate with AMBIGUOUS GENITALS
huge adrenals with cerebriform appearance
BROWN on cut surface rather than yellow (lipid depleted)
may have hyperplasia of corticotrophs in the pituitary
may have tumors in TESTES HILUS (due to increased ACTH)
causes of primary adrenocortical insufficiency
acute?
chronic?
acute: adrenal crisis, acute hemorrhagic necrosis
chronic/Addison’s: autoimmune, infection (TB, fungal, HIV), amyloid, sarcoid, metastatic carcinoma
APS1/APS2
Ab to steroidogenic enzymes AUTOIMMUNE ADRENALITIS (one form of chronic adrenalitis)
Addison’s labs
low Na, glucose
high K
all due to lack of cortisol
HYPERPIGENTATION: ACTH increased
Tumors that metastasize to adrenal
lung breast kidney suspect if: bilateral and multifocal metastases: MOST COMMON adrenal malignancy
Zellballen
cluster of cells
PHEOCHROMOCYTOMA
Familial causes of pheochromocytoma
MEN2A/B
Sturge-Weber
von Hippel Lindau
von Recklinghausen
Sturge-Weber
hemangioma of trigeminal nerve
PHEOCHROMOCYTOMA
von Recklinghausen
aka: neurofibormatosis type 1
neurofibromatosis, schwannoma, meningioma; composite tumors with neuroblastoma, ganglioneuroma, ganglioneuroblastoma
PHEOCHROMOCYTOMA
paragangliomas
extra-adrenal pheochromocytomas
sites: branchiomeric, intravagal, aortico-sympathetic
neuroblastoma
neoplasm of POSTGANGLIONIC SYMPATHETIC neurons
ADRENAL MEDULLA (other sites: sympathetic chain, neck, thorax, retroperitoneum, pelvis)
N-MYC, DNA ploidy
metastasize to (lymphatics or blood): SKIN, BONES (SKULL or ORBIT), liver
Sx: PALPABLE ABDOMINAL MASS, diastolic HTN
Dx: increased urine VMA and HVA; bone scan, 131I-MIBG
HOMER-WRIGHT ROSETTES
N-MYC amplification
poor prognosis in neuroblastoma
good prognosis for neuroblastoma
metastasize to skin, liver, bone
stage 4S
VMA in urine
neuroblastoma (very sensitive)
HVA
neuroblastoma (very sensitive)
BRAF point mutations
part of MAP kinase signaling
poor prognosis factors: metastasis and invasion
papillary cancer
RET/PTC rearrangements
part of MAP kinase signaling
papillary carcinoma
medullary carcinoma
manifestations of pheochromocytoma
palpitations, headache, episodic sweating (PHE)
HTN
cardiac arrhythmias, myocarditis, MI, dilated cardiomyopathy, pulmonary edema
hypertensive crisis: leading to encephalopathy (confusion, neuro probs, seizure, stroke)
chromogranin stain
pancreatic NET
Neuroblastoma
synaptophysin
neuroblastoma
Hutchinson’s syndrome
neuroblastoma metastasis to SKELETAL system (skull and orbit common)
Pepper’s syndrome
neuroblastoma metastasis to LIVER
