Endocrine Exam 1 Review

Number to know: cutoffs for diabetes, how to correct serum ca level

 Cortisol def  measure early in the morning

 Cortisol excess  measure late at night
 **cortisol peaks in the morning and dec through the day**
 Primary hypo  low hormone (from affected organ), high stim hormone (from pit)
 Secondary hypo  low hormone AND stim hormone
 Free hormone is biologically active
o Abnormalities of binding globulins increases TOTAL hormone, but not FREE
hormone
 Underactive  try to stim
 Overactive  try to suppress
 Endocrine neoplasm:
o most small and benign (microadenoma)
o common, often incidental finding
o most non-functioning
o assess for hyperfxn, hypofxn rare (except in pituitary  mass effect)
o hard to det if malig, large size or rate of growth inc risk of malig
 FNA of thyroid neoplasms
 Pituitary:
o Anterior
 Chromophobes (50%)
 Chromophils (~50%)
 Basophils  purple
o “B-FLAT”  FSH, LH, ATCH, TSH made by basophils
 acidophils  PINK
o GH
o Prolactin
 Embryo: thyroid starts development at base of tongue and move down to anterior neck,
can be remnants of thyroid anywhere on its path down to the final location of the
thyroid
o Thyro-glossal cyst (usually in neck, lingual thyroid is possible)
 Parafollicular cells (C cells)  in thyroid, secrete calcitonin (dec Ca in blood)
o Affected in medullary carcinoma of thyroid
 Superior parathyroid  from 4th pouch
 Inferior para  3rd pouch
 Beta cells in pancreas make insulin
 Hormone transport:
o Peptide hormones: water soluble, circulate free and and on surface receptors
o Steroid hormones: lipid soluble, circulate bound to stuff, act on nuclear
receptors
 Types of signaling:
 o Endocrine  hormone to systemic circulation
o Paracrine  hormone to ECF, acts on adjacent cells
o Autocrine  hormone acts on cell that sec it by binding to cell surface receptor
o Intracrine  hormone acts inside cell that sec it
 Hypothalamic-pit relationships: (hypo  pit)
o GnRH  FSH, LH
o GHRH  GH
o SS  DEC GH and TSH
o TRH  TSH, PRL
o DA  DEC PRL (tonic inhibition)
o CRH  ACTH
 During ovulation, FSH and LH have temporary positive FB on estradiol production  LH
surge
 Central DI
o MCC are surgery and head trauma
o Due to dec ADH
 Pit adenoma
o Micro  <1cm
 Most common is prolactinoma (hypogonadism; low sex drive, erectile
dysfxn in men, amenorrhea and galactorrhea in F)
o Macro  >1cm
 Check for hormone excess (acromegaly, cushing)
o Local effect of large space occupying pit mass  bitemporal hemanopsia
(compression of optic chiasm)
 Pit infarction:
o Apoplexy  hemorrhage into pit, usually preexisting adenoma, destruction of pit
tissiue (rapid onset pit def)
 Rx w/ urgent surgery and HD glucocorticoids
o Sheehan syndrome  ischemic infarction after severe postpartum hemorrhage
(inadequate blood supple to enlarged pit gland)
 TSH def: DON’T give levothyroxine until pt has normal adrenal fxn or adrenal insuff has
been treated (normal ACTH reserve)
 GH def: abnorm body comp, dec bone density, inc risk of CVD, dec well being and
performance
o All of above improved w/ GH replacement, effect of GH replacement on mort
unknown
 Acromegaly: inc GH  due to pit tumor, inc IGF-1 used for dx, lack of GH suppression
during oral glucose tolerance test (glucose should dec GH levels), MRI of pit AFTER
biochem dx of GH excess made
 Negative feedback example: if you give a drug that blocks GH receptor, IGF-1 levels will
DEC and GH levels will INC  IGF1 normally has negative feedback on pit, when this is
gone the pit can make GH w/o opposition
 Causes of hyper-PRL: PREGNANCY, hypothyroidism
 o Hypothal and pit problems more common
 Rx of prolactinomas: MEDICAL not surgically treated, use dopamine agonists  dec PRL
secretion
o Cabergoline (1-2x/week)
o Bromocriptine (2-3x/day)
 Hashimoto’s dis
o COMMON (esp in women), painless, lymphocytic infiltrate
o Auto-immune destruction of thyroid follicles
 Graves dis
o AI  abs stim TSH receptor causing hyperthyroidism
o Ophthalmopathy is unique for graves (vs other causes of hyper thyroid) 
exophthalmos, proptosis
 Role of I-123/ I-131 uptake
o ONLY for hyperthyroid pts  measure % uptake (normal is 15-35%)
o Low suggests thyroiditis (low thyroid activity)  inc thyroid hormone due to
destruction of gland and release of hormones
o Normal or high uptake = high activity of gland (it is making lots of hormone) 
graves; “hot nodules”
 Tests for thyroid status:
o Circulating thyroid hormone  TSH level is better than T3/T4 (if you get
abnormal TSH, can confirm w/ T4)
 Subclinical thyrotoxicosis:
o low TSH, but normal T3/T4 (low TSH indicates that more T3/T4 is being made
than should be  subclinical HYPERthyroidism
o check heart, bones and metabolism to make sure that sx are being missed
 dx of thyroid modules:
o Check TSH (BEFORE FNA)  if normal or high  US guided FNA (1-1.5 cm or
larger, or suspicious on US) is gold standard for thyroid nodules
o If TSH low, do uptake test (hot nodules rarely cancer)
 Thyroid cancer:
o Papillary and follicular  papillary has better prognosis (~95% survival at 30
years), is more common (80% of thyroid cancer), spreads to LN of neck (follicular
spreads in bloodstream)
 Adrenal
o Underactive: adrenal insuff
o Overactive: cortisol  cushing, aldo  conn, catechol  pheo
o Mass lesions  most nonfxning adenomas (benign)
 Catecholeamine synthesis (occurs in adrenal medulla)
o Tyrosine hydroxylase is rate limiting enzyme (tyrosine  DOPA)
o Mech: tyrosine  DOPA  dopamine  NE  Epi
 Tyrosine to DOPA stim by sympathetic stimulation
 AA decarb cat DOPA  dopamine
  NE  Epi cat by PNMT (upregulated by cortisol; cortisol increases Epi
synthesis  main product of adrenal medulla)
 Primary Adrenal insuff (Addisons)
o MC due to Autoimmune destruction of gland  loss of all 3 layers (dec mineralo,
gluco and sex steroids)
o Labs  low cortisol and high ACTH
o Testing:
 Check AM cortisol, if high no further testing req (no dis), if very low pt has
adrenal insuff
 If indeterminate  do stimulation tests
 ACTH stimulation test to dx primary AI
 Meyrapone (blocks cortisol production) test to dx secondary AI
(should stim ACTH release, if ACTH levels are dec it means that pt
has low pit ACTH reserves)
o Blocks last step of cortisol synth  dec cortisol  inc
ACTH in resp to dec neg FB from cortisol
o 11-deoxycortisol accumulates in serum
o in NORMAL pts, ACTH and 11-DOC inc
o in hypo-pit pts, ACTH and 11-doc stay LOW (pt cant make
ACTH)
 Adrenal hyperfxn tests
o Cushing’s syn: 24 he urine cortisol, late night cortisol, dextamathasone sup test
o Conn syn: due to inc aldo  HTN+hypokalemia+met alkalosis
 Check aldo/renin ratio  aldo should be high, renin will be low
o Pheochromacytoma: HTN, tachy, headache, diaphoresis (all EPISODIC, OR
sustained HTN)
 Plasma or 24hr urine metanephrines
o Adrenal cortical adenoma: common, benign, small, usually don’t secrete
hormones (if they do, only secrete 1)
o Adrenal carc: very care, poor prog, large mass, sec multiple hormones
 Pharm: know site of action of steroid inhibitors used to treat corticosteroid excess
o Mifepristone: glucocorticoid receptor blocker, abortion drug
o Spironolactone: mineralocorticoid receptor blocker
 Anti-aldosterone
o Ketoconazole: blocks synthesis at multiple levels
o Metyrapone: blocks final step of cortisol synthesis
o Phenoxybenzamine: irrev alpha ad antag, use to treat pheo
 Can also treat pheo w/ phentolamine or prazosin (alpha 1), reversible
antagonists
 Addition of beta antag may be necessary
 21-HO def
o MCC of congential adrenal hyperplasia
 o Cant make cortisol or aldo  inc ACTH levels  inc production of sex steroids
(since nothing else can be made)
o Common sx: salt wasting
 Poor feeding, poor weight gain, dehydration
 Hyperkalemia and hyponatremia
 Hypovolemic shock and met acidosis in severe cases
 Adrenal crisis (peak at 10-14 days after birth)
 Genital sx: XX  ambig genitalia due to andro excess; XY  no abnorm
o Dx: 17-hydroxyprogesterone levels increased
 MEN syndromes:
o MEN1: 3 Ps  pituitary, pancreatic and parathyroid tumors
o MEN2A: 2Ps  parathyroid, pheo, medullary thyroid carcinoma
o MEN2B: 1P  pheo, medullary thyroid carcinoma, oral/intestinal
ganglioneuroma
o 2A/2B  RET protooncogene mutations
o all MEN are AD inheritance
 regulation of serum Ca
o Ca in serum has negative FB on PTH  low Ca = inc PTH secretion
o PTH: inc Ca and phos resorption from bone, inc renal ca resorption, inc renal
phos excretion, activates Vit D (inc intestinal ca and phos absorption)
 Direct effects on bone and kidney, indirect effect on intestine
o Vit D: activated in kidney by 1 alpha hydroxylase, increases intestinal phos and
Ca absorption
 D3 from skin (sun) and diet
 D2 form diet only
 D2 and D3 25-hydroxylated in liver  25 (OH) Vit D
 25 (OH) Vit D 1 alpha hydroxylated in kidney  1,25 (OH) Vit D **this is
the ACTIVE form of Vit D**
o Know how to correct serum Ca level:
 Each g/dl albumin binds .8mg/dl Ca
 Corrected Ca = Ca (meas) + 0.8 x [normal Alb – Alb (meas)]
 Normal Alb is 4 g/dl
 Example: meas Ca = 7.0 mg/dl, meas Alb = 2.0 g/dl  Ca (corr) = 7.0 + 0.8
x [4-2]  Ca (corr) = 8.6 mg/dl
 Bone turnover
o RANKL binds to RANK on osteoclast and activates it  inc bone resorption
o OPG blocks RANKL  prevents activation of osteoclasts  inc bone production
(dec bone loss)
 Biochem markers of bone met:
o Alk Phos is MC used marker of bone formation (inc Alk Phos also in kidney and
liver dis)
 Diagnostic categories of bone mass
 o ANY hx of fragility fracture meets definition of osteoporosis regardless of
measured bone density (T-score)
o T score is comparison to young, healthy controls
o Normal is within 1 SD of young adult mean
o Osteoporosis: 2.5 SD or more below young adult mean
o Osteopenia: 1-2.5 SD below young adult mean
 Osteoporosis pharm: 2 classes of meds
o Antiresorptive  inhibit osteoclast bone resorption
 Estrogen
 Calcitonin
 Raloxifene
 Bisphosphonates (-dronates)
 Denosumab (binds RANKL and inhibits it from binding RANK)
o Anabolic  stim osteoblast formation
 Teriparatide: strongest drug to increase bone density, it is part of PTH
molecule
 Mech: PTH actually increase bone formation if given in PULSES (vs
continuous secretion in hyperpara  bone resorption)
 Ddx of hypercalcemia
o PTH mediated (high PTH)
 Primary hyperpara
 Familial hypocalciuric hypercalcemia: must r/o before dx of primary
hyperpara made
 AD, inactivating mutation of Ca sensing receptor
 Lifelong, moderate, asymptomatic hypercalciuria
 Benign course (no stones, not being excreted in urine, not being
taken out of bone)  no treatment
 Check urine Ca levels to diff from primary hyperpara
 Li-induced hypercalcemia
o NOT PTH mediated (low PTH)  everything else (cancer, eating too much Ca, Vit
D tox, etc.)
 Important one to know is sarcoidosis and granulomatous disease
 1 alpha hydroxylase is found in lymphoid tissue and pulmonary
macrophages  increased levels of active Vit D
 Etiology of hypercalc depends on where you are:
o Inpatient setting  malignancy  NON PTH mediated
o Outpatient setting  primary hyperpara  PTH mediated
 ALWAYS do biochem test first, THEN imaging
 Management of hypercalcemia
o IV rehydration w/ normal saline  pts are very dehydrated (due to polyuria),
and this will cause them to pee out lots of the Ca
 Can add loop diuretic (furosemide) later
 Labs in Vit D def
 o In pt w/ normal or low Ca and elevated PTH, ALWAYS consider Vit D def
o Best test to dx vit D def is 25 (OH) vit D  dec levels in vit D def
 When 25 levels drop, PTH will be inc and will in turn inc levels of active
(1,25) Vit D  can still have normal levels of active vit D and Ca in pts w/
mild vit D def, ONLY way to detect the def is to check 25 Vit D levels
o Severe/classic: dec ca, inc PTH, dec phos, dec 25 vit D, dec active Vit D, inc Alk
Phos
o Milk: NORMAL Ca, inc PTH, normal phos, normal or dec 25 vit D, inc active vit D,
inc or normal Alk phos
 Diabetes
o Insulin secretion from beta cells:
 Fasting state  ATP sensitive K channel open, cell polarized, Ca channel
closed
 Active/stimulated state  glucose moves into beta cells through Glut-2
 glucose metabolized (glucokinase is 1st enzyme) and forms ATP  ATP
binds to K channel and closes it  cell depolarizes  Ca channel open 
Ca influx  secretion of insulin
o Insulin signaling: insulin binds to insulin receptor (IR) on muscle cells and
adipocytes, many effects
 Glut-4 insertion on membranes  allows glucose to move into these cells
for metabolism
 Pi3 pathway (metabolic)  protein and lipid synthesis, glucose transport,
glycogen synthesis
 MAP kinase pathway (growth)  gene transcription, cell growth, gene
expression
 Insulin resistance can be due to mutation in the insulin receptor, Glut-4,
or any of the other pathways  high insulin w/o low glucose
 Type 2 DM and obesity more commonly associated w/ mutation
at the post-receptor level (somewhere in the signaling cascade)
 Inherited mutations are rare
 Acquired causes of resistance: obesity, aging, medications, other
 Insulin and IGF-1 are similar in structure, can bind each other’s receptors
w/ low affinity
 When insulin is very high, it can have effects that are due to
binding of the IGF-1 receptor  acanthosis nigricans (keratinocyte
and melanocyte proliferation)
o It is a sign of insulin resistance, pts likely to go on to
develop DM
o Incretin hormones: peptides released from GI cells in response to nutrient
stimulus that enhances glucose-dependent insulin release
 Include GLP-1 and GIP  used to treat patients
 Beta cells shown to secrete more insulin in response to oral glucose than
to IV glucose  has something to do w/ incretins?
o Effects of stress (biological  infection, etc.) of blood glucose:
 Inc catecholeamines (main)  muscles less insulin sensitive, dec insulin
sec and inc glucagon sec from beta cell  net effect is to put out more
glucose into the bloodstream (inc blood glucose), stress hormones
(cortisol, GH, epi) inhibit glucose uptake into muscle so it is shunted to
non-insulin dependent tissues (ex- WBCs)
o Criteria for dx of DM **know these**
 Fasting plas gluc: >/= 126 mg/dl (pre-DM: 100-125)
 2 hr oral gluc tolerance test: >/= 200 (pre-DM: 140-199)
 random plas gluc: >/= 200; must have Sx
 A1C: 6.5% (pre-DM: 5.7-6.4%)
o Pathogenesis:
 Type 1: insulin def due to AI destruction on beta cells
 Type 2: dual defect
 Impaired insulin action  insulin resistance
 Impaired beta cell fxn  insulin secretion
o Treatment of advanced insulin def (type 2 or type 1)
 Want to replicate physiologic secretion of insulin  basal amount of
insulin made to keep glucose levels consistent, even when not eating,
burst of insulin after eating (take short acting dose of insulin right before
meal)
 Activity profiles of insulin preparations:
 Lispro, aspart, glulisine: very short acting, highest peak
o <15 min onset
o 4-6 hr duration
 Regular: short acting, 2nd highest peak
o .5-1 hr onset
o 6-8 hr duration
 NPH: intermediate acting, 3rd highest peak
o 1-2 hr onset
o 12+ hr duration
 Detemir, glargine: long acting, lowest peaks
o 1-1.5 hr onset
o 12-24 hr duration
 strategy of basal/bolus insulin replacement pattern: 1 long acting
(detemir/glargine) for basal insulin throughout day, short acting/prandial
(lispro, aspart, glulisine) right before meal
 calculate total daily dose of insulin:
 insulin naïve = weight in kg x 0.5
 on insulin = current daily insulin amount
 50% basal, 50% prandial
o divide prandial by 3 meals
 Example: 100 kg pt  TDD = 100 x .5 = 50 units
 o 25 units basal
o 25 units prandial
 3 meals/day = 8 units before each meal
o Pharm for type 2 DM: **metformin and sulfonylureas are the most commonly
used**
 Pt who has tried diet and lifestyle change whose A1C levels are still higher
than target (>6.5)
 1st line is Metformin
o Insulin sensitizer, biguanide, dec gluconeogenesis
 Pt on multiple oral agents but still failing (A1C 9-10)
 Basal insulin (glargine, detemir)  titrate to keep morning
(fasting) sugar normal
 Can add prandial insulin (aspart, lispro, glulisine) once pt gets
used to basal
 SE profiles:
 Drugs that stimulate secretion of insulin have HIGH RISK OF
HYPOGLYCEMIA + weight gain
o Sulfonylureas, meglitinides
 Insulin sensitizers: don’t gain weight, lower risk of hypoglycemia
o Metformin, thiazolidinediones
o Chronic complications of DM
 Elevated glucose enters cells through insulin independent pathways that
cause cell damage through multiple mechanisms, all these pathways
result in increased oxidative stress
 Polyol pathway: sorbitol causes cell damage
o Inc sorbitol
 Hexosamine pathway: glucosamine inhibits insulin secretion and
insulin signaling
o Inc glucosamine 6-P
 Protein kinase C pathway: altered endothelial permeability,
vasoconstriction, ECM synthesis, turnover, cell growth,
angiogenesis, cytokine activation, leukocyte adhesion
 AGE pathway: glucose irrev binds proteins and nuc acids (NON-
enzymatic glycosylation) altering structure and fxn, later
modifications produce proinflammatory AGE (advanced
glycosylation end products) molecules
 Pathogenesis of diabetic nephropathy: Know the order of progression
 Hyperglycemia leads to hyperfiltration  endothelial injury w/
GBM thickening, podocyte loss, mesangial and ECM expansion 
microalbuminuria  glomerulosclerosis (Kimmelsteil Wilson
nodules)  dec perfusion, filtration, HTN, nephron loss  Renal
Failure (inc Cr)
 Diabetic ketoacidosis (usually occurs in Type 1)
  High glucose and high ketones contribute to it
 Due to inc insulin requirements from inc stress (stress  epi sec
 inc glucagon sec  excess fat breakdown, ketogenesis and FFA
due to unopposed action of glucagon  production of ketone
bodies)
 Occurs due to combination of insulin secretion and increased
glucagon, epi, GH, cortisol (all counter-regulatory to insulin)
 Pathogenesis:
o Inc glucose production by liver combined w/ dec glucose
uptake in periph tissues  hyperglycemia  osmotic
diuresis  volume depletion
o Inc release of FFA from adipose tissue combined w/ inc
ketogenesis by liver  ketoacidosis  dec alkali reserve
 metabolic acidosis
 Electrolyte replacement: potassium YES, bicarb NO
o Serum K level may be high, normal, or low at presentation
o K levels will invariably fall during treatment  important
to avoid hypokalemia
 b/c insulin will cause inc uptake into cells
 Can cause arrhythmias, muscle flaccidity, paralysis,
etc
o Add IV fluids
o Continue oral replacement for 5-7 days
o **even though the serum K levels may be high, the pts
total body K levels are actually low b/c the dec insulin
causes dec K uptake into cells and the buffering
mechanism for the acidosis is to pull protons (H+) into the
cells and pusk K out**
o Bicarb therapy should NOT be given to DKA pts UNLESS
arterial pH < 7.0, or other indications exist (severe
hyperkalemia, shock, etc.)  last measure
 Evaluation of hypoglycemic episode: low blood sugar w/ whipples triad
 Low blood sugar: <45-55 mg/dl
 Whipples triad:
o Sx after fasting or heavy exercise
o Low plasma glucose measured same time as glucose
o Relief of sx when glucose raised to normal
 Also check: serum insulin, C peptide, pro-insulin, screen for
sulfonylureas or meglitinides, insulin auto-ab (rare)
o C pep and proinsulin help determine whether the insulin is
endogenous or exogenous
 Labs: be able to diff b/w exog insul, sulfonylurea use/abuse,
insulinoma
 o Diff insulinoma and SU abuse by imaging, possible
association w/ MEN1

Cause Insulin Pro-ins C-pep

Exog insul Inc dec dec
SU inc Inc inc
insulinoma inc inc inc