Day 9.2 Endocrine Flashcards
Layers of the Adrenal Cortex
GFR:
Zona glomerulosa
Zona fasciculata
Zona reticularis
What controls the Zona Glomerulosa? What does it produce?
Renin-Ang –> ZG –> Aldosterone
“salt”
What controls the Zona Fasiculata? What does it produce?
ACTH, CRH –> ZF –> Cortisol and sex hormones
“sugar” (glucocorticoids)
What controls the Zona Reticularis? What does it produce?
ACTH, CRH –> ZR –> Sex hormones (e.g. androgens)
“sex”
What kind of cells are located in the adrenal medulla? From where are they embryologically derived?
Chromaffin cells
Come from neural crest.
What controls the adrenal medulla? What does it produce?
Preganglionic sympathetic fibers signal the adrenal medulla, it makes catecholamines (epi, NE)
Embryo: where does the cortex derive from? the medulla?
Cortex is from mesoderm
Medulla (chromaffin cells) is from neural crest
How do the adrenal hormones get into cells?
They diffuse in, where they act on intracellular receptors, which regulate DNA transcription.
What is the most common tumor of the adrenal medulla (medulla specifically!) in adults? in kids?
Adults: pheochromocytoma
Kids: adrenal neuroblastoma
Pheochromocytoma causes episodic HTN; neuroblastoma does not.
What adrenal tumor is most common in adults?
Benign adrenal adenoma.
For medulla specifically, pheochromocytoma is most common
Where and how do the adrenal glands drain?
Left adrenal —> L adrenal vein —> L renal vein —> IVC
Right adrenal —> R adrenal vein —> IVC
This is the same as L and R gonadal- R testes is higher than left bc R vein drains directly to IVC, so neg prs draws testicle upwards.
How is cholesterol converted to Aldosterone? Where does this take place?
Happens in ZG of cortex: Cholesterol (Desmolase) Pregnenolone (3B-hydroxysteriod dehydrogenase) Progesterone (21a hydroxylase) 11-Deoxycorticosterone (11B hydroxylase) Corticosterone (aldosterone synthase) Aldosterone
What converts cholesterol to pregnenolone? How is it stimulated? How is it suppressed?
Desmolase is the enz
ACTH stimulates desmolase
Ketoconazole (anti-fungal) inhibits it.
What is the precursor to cholesterol?
Acetate
How is Cortocosterone converted to Aldosterone? What stimulates this conversion?
Aldosterone synthase is the enz
Angiotension II stimulates aldo synthase.
How is cholesterol converted to Cortisol (glucocorticoids)? Where does this take place?
Happens in ZF of cortex Cholesterol (Desmolase) Pregnenolone (17a-hydroxylase) 17-hydroxypregnenolone (3B- hydroxysteroid dehydrogenase) 17-hydroxyprogesterone (21a hydroxylase) 11-Deoxycortisol (11B hydroxylase) Cortisol
How is cholesterol converted to androgens? where does this happen?
Happens in ZR of cortex Cholesterol (Desmolase) Pregnenolone (17a-hydroxylase) 17-hydroxypregnenolone (17, 20 lyase) Dehydroepiandrosterone DHEA (3B- hydroxysteroid dehydrogenase) Androstenedione (17B) Testosterone
In the periphery, Testosterone can be converted to DHT (more potent form by 5a-reductase)
How is cholesterol converted to estrogens? Where does this occur?
1st part of pathway is same is androgens, so occurs in the ZR.
But, actual conversion to estrogens rather than androgens occurs in the periphery.
Androstenedione (+Aromatase) –> Estrone
Testosterone (+Aromatase) –> Estradiol
Testosterone is also converted to DHT (more potent form) in the periphery- this is catalyzed by 5a-reductase.
Action of finasteride
Drug that inhibits 5a-reductase, therefore it doesn’t allow conversion of testosterone to DHT.
What are the 3 things that cause congenital bilateral adrenal hyperplasia? Why are the adrenals hyperplastic?
17a-hydroxylase deficiency
21-hydroxylase deficiency
11B-hydroxylase deficiency
All congenital adrenal enz defects cause enlgmt of the adrenals since cortisol is decreased. Decreased cortisol causes increased ACTH, and the increased ACTH is what causes the enlgmt.
What does 17a-hydroxylase do?
Converts pregenolone (ZG) to 17-hydroxypregnenolone (ZF) Converts Progesterone (ZG) to 17-hydroxyprogesterone (ZF)
Once converted, the ZF hormones follow the pathway to make glucocorticoids (cholesterol)
17a-hydroxylase deficiency
Decreased sex hormones and decreased cholesterol, bc can’t get from the ZG to the ZF and ZR. Mineralocortocoids (aldosterone) are increased, bc everything stays in the ZG.
Sx: HYPERtension, hypokalemia
The HTN is bc there is excess mineralocorticoids, so increased Na+ and fluid retention.
XY: decreased DHT causes pseudohermaphroditism (externally phenotypic female, no internal reproductive structures)
XX: Externally phenotypic female w normal sex organs, but lacking secondary sex char (sexual infantilism)
What does 21-hydroxylase do?
Converts Progesterone (ZG) to 11-deoxycortisone (ZG) --> > > mineralocorticoids Converts 17-hydroxyprogesterone (ZF) to 11-deoxycortisol (ZF) --> > > Glucocorticoids
21-hydroxylase deficiency
Most common adrenal hormone deficiency.
Bc ZG and ZF pathways are blocked, there is decreased cortisol (and therefore increased ACTH) and also decreased mineralocorticoids (aldo)
Everything is shunted to the ZR, so there are increased sex hormones. (more testosterone is made)
Sx: HYPOtension, hyperkalemia, increased plasma renin acitivity and vol depletion. Salt wasting can lead to hypo-vol shock in a newborn
Masculinization and female pseudohermaphroditism
The hypotension is bc you can’t make mineralocorticoids
What does 11B-hydroxylase do?
Converts 11-deoxycorticosterone (ZG) to Corticosterone (ZG) –> > mineralocorticoids
Converts 11-deoxycortisol (ZF) to Cortisol (ZF) -so makes glucocorticoids
11B-hydroxylase deficiency
Decreased corticosterone and aldosterone (from ZG), decreased cortisol ZF), and eveything is shunted to the ZR, so increased sex hormones.
11B- hydroxylase converts 11-dexoxycorticosterone to corticosterone (and that goes to aldo), so when there is no enz, the 11-deoxycorticosterone builds up in the ZG- and since it’s part of the mineralocorticoid pathway, it’s also a mineralocorticoid (altho a weaker one).
So: deficiency causes HYPERtension (due to the excess 11-deoxycorticosterone which acts as a mineralocorticoid)
Other Sx include masculinization from the increased sex hormones.
Which adrenal hormone deficiencies cause masculinization?
11B-hydroxylase
21a-hydroxylase
(masculinization has a 1 in the 2nd digit)
Which adrenal hormone deficiencies cause HTN?
11B-hydroxylase
17a-hydroxylase
(HTN has a 1 in the 1st digit)
3B-hydroxylase deficiency
Can’t make anything! No mineralocorticoids, glucocorticoids, androgens or estrogens.
Results in excess salt in urine
Early death.
Where is cortisol made?
Adrenal zona fasiculata
Function of cortisol
- Maintains BP by up-regulating alpha-1 receptors in arterioles (doesn’t stimulate them, just puts them there. Has a “permissive effect” on Epi. Alpha-1 is responsible for vasoconstriction- in septic shock can give cortisol to incrse BP)
- Decreases bone formation (will get osteoporosis if you take steroids too long)
- Anti-inflammatory
- Decreases immune fn
- Increases gluconeogenesis, lipolysis, proteolysis (counter-reg hormone. more likely to get diabetes if you take it.)
How is cortisol regulated?
By ACTH.
CRH from hypothal stim’s ant pit to rls ACTH, which stim’s ZF to make cortisol.
What effect does excess cortisol have on the hormones that regulate cortisol?
Neg fdbk:
Decreased CRH, decreased ACTH, and decreased cortisol secretion.
What are the ways to have primary, secondary, and tertiary cortisol deficiency?
Primary: no adrenals
Secondary: no ACTH from ant pit
Tertiary: no CRH from hypothal
What hormone is affected in Cushing’s syndrome?
Cortisol (increased)
What is the #1 cause of Cushing’s syndrome?
Exogenous (iatrogenic) steroids.
Causes decreased CRH and ACTH d/t neg fdbk.
What are the 3 endogenous causes of Cushing’s syndrome?
- Cushing’s dz (70%)
- Ectopic ACTH
- Adrenal
What is Cushing’s Dz?
Pituitary adenoma that produces ACTH. (and therefore increases cortisol levels)
(So ACTH is elevated- but only mildly)
What’s the difference b/t Cushing’s Syndrome and Cushing’s Dz?
Cushing’s Syndrome = increased cortisol, can be for any reason (eg taking steroids)
Cushing’s Dz is one of the possible reasons for Cushing’s Syndrome. The Dz is a Pit Tumor that secretes ACTH (thereby increasing cortisol).
When is Cushing’s d/t ACTH that’s produced ectopically?
Non-pituitary tsu makes ACTH:
Sml cell lung cancer, bronchial carcinoids
ACTH is majorly increased ^^^, and so cortisol is increased (Cushing’s Syndr)
When is Cushing’s d/t an adrenal cause?
Adrenal adenoma, Adrenal carcinoma, or Nodular adrenal hyperplasia.
This causes the adrenals to secrete cortisol on their own, w/o any signal.
ACTH is decreased/undetectable, since all of the cortisol is causing neg fdbk. The cortisol doesn’t need ACTH to be produced- the adrenals are just producing it on their own.
Findings in Cushing’s Syndrome (increased cortisol)
HTN Weight gain Buffalo hump, Truncal obesity, Moon facies Hyperglycemia (insulin resistance) Skin chgs (thinning, purple striae) Osteoporosis Amennorhea Immune suppression
How to Dx Cushing’s Syndrome
Dexamethasone suppression test
Dex is a synthestic glucocorticoid. So basically, it’s like giving cortisol.
How will a dose of dexamethasone affect a healthy pt?
Dex is like cortisol.
So, after a dose of dex, cortisol will decrease. This is bc there will be neg fdbk from the dex on ACTH. Decreased ACTH means decreased cortisol.
How will a dose of dexamethasone affect an ACTH-producing tumor?
Dex is like giving cortisol.
After a low dose of Dex, nothing will happen- the tumor is producing ACTH, so cortisol will remain high (increased ACTH means increased cortisol)
However
After a high dose of dex, the ACTH secretion from the tumor will be suppressed (neg fdbk, on the tumor)- so there will be less cortisol, since there is less ACTH.
How will a dose of dexamethasone affect an Ectopic ACTH-producing tumor
The ACTH from a non-pituitary source will not be suppressed, no matter what kind of dose you give.
Since ACTH is high, cortisol will remain high.
The dex has no effect.
How will a dose of dexamethasone affect a cortisol-producing tumor?
There is no effect.
Cortisol stays high no matter what the dose.
The ACTH will be suppressed (regardless of the dex or not) bc the cortisol is high.
Dex has no effect.
Which is the only tumor that is suppressible with Dexamethasone
An ACTH-producing tumor of the pituitary (must be in the pit). Only suppressed by high doses tho.
List the glucocorticoids (drugs)
Hydrocortisone Prednisone Triamcinolone Dexamethasone Beclomethasone
How do glucocorticoid drugs work?
Inhibit Phospholipase A2- so no arachnidonic acid, and therefore no leukotrienes and no prostaglandins.
They also inhibit expression of COX-2 (so no prostaglandins)
So overall, they inhibit inflam.
Clinical use for glucocortiocoid drugs
Inflammation (they reduce it)- arthritis Immune suppression Asthma Addison's dz Keloids (they decrease collagen synthesis, so decrease excess scarring)
Toxicity of glucocorticoid drugs
Iatrogenic Cushing's Syndrome (increased cortisol) and all Cushing's Sx. Adrenocortical atrophy Peptic ulcers Diabetes (if chronic use) Psychosis Insomnia Glaucoma Acne
Where is aldosterone made?
Zona Glomerulosa of adrenal corex
When is aldosterone secreted, and what does it do?
Aldo is secreted when there is low blood volume (via AT II) and when there is increased K+.
Keeps Na+, dumps K+ and H+
Aldo increases Na+ channel insertion and Na+/K+ ATPase insertion in principle cells.
Therefore
Aldo causes increased Na+ reabs (and therefore more water reabs to raise blood vol).
It also increases indirect K+ secretion and increases H+ secretion. And by secretion, it means secretion into the urine (excretion)- bc it also upreg’s principle cells K+ chnls and intercalated cell H+ chnls.
Aldo keeps Na+ and gets rid of K+ and H+.
What is primary hyperaldosteronism?
Aka Conn’s. High aldo d/t an aldo-secreting tumor.
Aldo normally keeps Na+ and gets rid of K+ and H+, so this effect is amplified:
HTN, hypokalemia, metabolic alkalosis.
All of this happens w LOW renin tho, bc the aldo is coming from the tumor. High renin feeds back to suppress renin
What is secondary hyperaldosteronism?
Hyperaldo is d/t overactive renin-ang system.
Kidney thinks there is low blood volume, and so induces the renin-ang system to fix it.
Reasons kidney thinks there is low vol:
Renal artery stenosis
Chronic renal failure
CHF (low LV ejection fraction –> poor renal perfusion)
Cirrhosis (low protein state, so lose fluid from blood vessels)
Nephrotic syndrome (also low protein state)
In secondary, the renin level is high (that’s what causing the aldo!)
Rx for Hyperaldosteronism
If primary- remove the tumor!
Also:
Spironolactone (K+ sparing diuretic)- acts as an aldo antagonist
Aldo keeps Na+ and dumps K+ and H+.
Spironolactone gets rid of the water that Aldo brought in, but also keeps the K+ that aldo is trying to dump.
Primary adrenal insufficiency
Addison’s dz.
D/t adrenal atrophy, or destruction of adrenals by dz (autoimm, TB, mets)
Have deficiency of both Aldo (mineralocorticoid) and Cortisol (glucocorticoid).
Causes hypotension (d/t hyponatremic volume contraction- no aldo means no Na+ and water retention) Causes hyperpigmentation. (d/t MSH. Increased ACTH production (trying to increase cortisol) also means increased MSH, since they both come from the POMC.)
Addison’s = Adrenal Atrophy in Absence of hormone production; involves All 3 cortical divisions.
Secondary adrenal insufficiency
Secondary is at level of pituitary.
Decreased pit ACTH production, so decreased cortisol. But, adrenals still make aldo, so don’t have hyperkalemia, bc aldo is dumping the K+.
Also, don’t see skin hyperpigmentation as in primary, since the ACTH is decreased (so MSH is not overproduced)
Tertiary adrenal insufficiency
Tertiary is from hypothalamus (CRH)
Usu d/t the abrupt withdrawal of corticosteroids.
If a pt is on long-term corticosteroids, they are neg’ly feeding back on CRH. No CRH -> no ACTH -> no endogenous cortisol is being made. (But, there is still aldo, so K+ is normal)
If you take pt off of corticosteroids abruptly, there will be no CRH right away.
Waterhouse-Friedrichsen syndrome
Acute primary adrenocortical insufficiency d/t adrenal hemorrhage.
The adrenal hemorrhage can be from N. meningitidis septicemia, from DIC (CV collapse causes hemorrhage, see petechial rash), and from endotoxic shock (gram neg)
Multiple Endocrine Neoplasias- what are the types?
MEN 1 - Wermer’s Syndrome (PPP)
MEN 2A - Sipple’s Syndrome (MPP)
MEN 2B (MOP)
2A and 2B are a/w Ret gene
MEN 1 (Werner’s syndrome)
MEN 1 = PPP Parathyroid tumors Pituitary tumors (prolactin or GH) Pancreatic endocrine tumors (Zol-Ellison, insulinomas, VIPomas, glucagonomas-rare)
MEN 1 commonly presents w kidney stones and stomach ulcers.
MEN 2A (Sipple’s Syndrome)
MEN 2A = MPP
Medullary thyroid carcinoma (secretes calcitonin- get amyloidosis)
Pheochromocytoma
Parathyroid tumors
MEN 2B
MOP
Medullary thyroid carcinoma (secretes calcitonin- get amyloidosis)
Oral/Intestinal ganglioneuromas (a/w marfanoid habitus) aka mucosal neuroma
Pheochromocytoma
Which MENs have pheochromocytoma?
MEN 2A and 2B
Which MENs have parathyroid tumors?
MEN 1 and MEN 2A
How are MEN syndromes inherited?
Auto-dom
Types 2A and 2B are assoc w Ret gene
What do the MEN 2’s have in common?
Both MEN 2A and 2B have:
Medullary thyroid carcinoma
Pheochromocytoma
(2A has parathyroid tumors; 2B has oral/intestinal ganglioneuromatosis)
Rx to control the BP in Pheochromocytoma
Phenoxybenzamine (a-blocker)
+IV saline to correct vol depletion
Endocrine pancreas cell types
Islets of Langerhans have alpha, beta, delta endocrine cells. Islets are most numerous in the tail of the pancreas.
Islets arise from the pancreatic buds.
alpha cells make glucagon (peripheral)
beta cells make insulin (central- INsulin is INside)
delta cells make somatostatin (interspersed throughout islet.
capillaries are also found running thru the islets.
Where and why and how is insulin made?
Made in B-cells of the pancreas
Made and released when Glucose enters the Bcell thru GLUT-2 and undergoes aerobic respiration there- this makes a lot of ATP.
The increased ATP causes K+ channels to close, which means the cell depolarizes, and opens Ca2+ channels.
All of the Ca2+ comes rushing into the cell, and the increase in Ca2+ causes (as usu) exocytosis of vesicles. The vesicles contain insulin. And that’s how insulin gets into the blood steam.
Insulin is made because it’s required by adipose and skel musc cells, in order for them to be able to take up glucose.
Serum C-peptide
A marker of endogenous insulin.
Proinsulin is cleaved to insulin + C-peptide
But, if the insulin is coming from an exogenous source (injection), then there will be no C-peptide.
If a pt’s high insulin level is d/t an insulinoma, there will be high C-peptide, since it’s endogenous.
What cells DON’T need insulin for glucose uptake?
BRICK-L Brain RBCs Intestine Cornea Kidney Liver
What cells use GLUT-1 receptors?
RBCs and Brain (they don’t need insulin to take up glucose)
What cells use GLUT-2 receptors?
B islet cells, liver, kidney (they don’t need insulin to take up glucose)
What cells use GLUT-4 receptors?
GLUT-4 receptors are insulin responsive (they need insulin in order to be activated)
Adipose tsu
Skeletal musc
What are the 6 anabolic effects of insulin?
- Increased glucose txport
- Increased glycogen synth and storage
- Increased TG synth and storage
- Increased Na+ retention (kidneys)
- Increased protein synth (musc)
- Increased cellular uptake of K+
What does the brain use for fuel?
Glucose for normal metabolism; ketone bodies in starvation
What do RBCs use for fuel?
Glucose.
RBCs are always dependent on glucose. But, they don’t need insulin in order to use it.
T/F RBCs and the brain take up glucose independent of insulin levels.
True.
They both use GLUT-1 to do it.
Insulin deficiency and glucagon excess in diabetes mellitus leads to what 3 main problems?
- Decreased glucose uptake
This causes hyperglycemia, glycosuria, osmotic diuresis, and electrolyte depletion, all of which cause dehydration and acidosis. They can lead to coma/death. - Increased protein catabolism (breakdown).
This results in increased plasma AAs and nitrogen loss in urine, which lead to hyperglycemia, glycosuria, osmotic diuresis, and electrolyte depletion, all of which cause dehydration and acidosis. They can lead to coma/death. - Increased lypolysis (B-oxid)
This leads to increased plasma FFAs, ketogenesis, ketonuria, ketonemia, which all cause dehydration and acidosis. This can lead to coma/death.
Acanthosis nigricans can be indicative of DM and what else?
Visceral malignancy
What are the acute manifestations of DM?
polydipsia, polyuria, polyphagia (thirsty, peeing, hungry)
weight loss
DKA (in DM-I)
HHS- hyperosmolar hyperglycemic state (in DM-II)
unopposed secretion of GH and epinephrine (which exacerbate the hyperglycemia)
What are the 2 (general) chronic manifestations of DM?
- Non-enzymatic glycosylation (glucose is added to things- like vessels- but w/o the help of an enz.
- Osmotic dmg (generally by sorbitol)
Chronic DM: Non-enzymatic glycosylation
In small vessel dz, adding glucose results in diffuse thickening of the basement mbr. This can lead to:
Retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation)
Glaucoma
Nephropathy (nodular sclerosis, progressive protenuria, chronic renal failure, arterioscelrosis leading to HTN, Kimmelsteil-Wilson nodules)
In larger vessels, adding glucose leads to: Lg vessel atherosclerosis CAD Periph vasc occlusive dz and gangrene Cerebrovascular dz
Small vessel dz in chronic DM can cause nephropathy, including progressive proteinuria. What is used to reduce the prog proteinuria?
ACE-inhibitors or ARBs
Chronic DM: Osmotic damage
Caused by sorbitol.
Leads to:
Neuropathy (motor, sensory, autonomic degeneration)
Cataracts (d/t sorbitol accumulation in lens)
How is sorbitol made?
Glucose is converted to sorbitol by the enz aldose reductase (along with NADPH).
How is sorbitol converted to fructose? Where does this occur?
Sorbital dehydrogenase and NAD+ (this is an oxidation rxn)
Only some tsu’s have this enz: liver, ovaries, and seminal vesicles.
In tsu’s that do not have it, there is risk for sorbitol accumulation
What tsu’s have aldose reductase, but don’t have sorbitol dehydrogenase? What are they at risk for?
Schwann cells, lens, retina, kidneys have only aldose reductase- so they can make sorbitol- but then they can’t convert it to anything else.
At risk for sorbitol accumulation, which causes ostomotic dmg to these tsus- cataracts, retinopathy, peripheral neuropathy (all seen in chronic diabetics)
Why is sorbitol osmotically active? What does this mean?
Osmotically active bc can’t freely cross the cell mbr like glucose can.
Accumulation of sorbitol causes osmotic prs that makes water enter the cell- this is what produces the osmotic dmg.
Sorbitol is made using aldose reductase. What other things are converted with aldose reductase?
High blood levels of fructose and galactose are converted to their respective alcohol forms via aldose reductase
Like sorbitol, they are also osmotically active.
How is neuropathic pain in DM treated?
Gabapentin or Pregabilin
Note: Pregabilin is also used as Rx for fibromyalgia
Tests for DM
Fasting serum glucose
Glucose tolerance test
HbA1c for long-term control
What is the primary defect in DM-I vs DM-II
DM-I: no insulin d/t viral or auto-immune destruction of the B cells of the pancreas. (Have anti-islet cell Ab)
Must replace the insulin.
DM-II: insulin resistance. No problem in making insulin, but the peripheral cells don’t respond to it.
Insulin sensitivity in DM-I vs DM-II
DM-I is highly sensitive to insulin. No insulin is made, so cells really need it, and are super responsive when they do get it.
DM-II has low sensitivity- the problem in DM-II is that there is insulin resistance.
Genetic predisposition
Assoc w HLA system
Usual age
in DM-I vs DM-II
DM-I: weak genetic predisposition. it’s polygenic.
despite the genetic connection not being very strong, DM-I is assoc w HLA-DR3 and HLA-DR4.
Usu happens in pts 40yo
DKA: when does it occur, what happens biochemically?
Common complication of DM-I
Usu d/t increased insulin demand from increased stress (eg infection)
There is excess fat breakdown (insulin deficiency results in increased lipolysis), so increased FFAs. Ketogenesis makes ketone bodies from the FFAs.
(B-hydroxybutarate more so than acetoacetate)
Signs/Sx of DKA
Kussmaul respirations (rapid, deep breathing, trying to blow off the acidic CO2)
Naus/vom
Abd pain
Psychosis/delirium
Dehydration
Fruity breath odor d/t the ketones- exhaling acetone.
Labs in DKA
Hyperglycemia (glucose >300)
Increased H+ and decreased HCO3- this is anion-gap metabolic acidosis.
Increased ketones in blood and urine
Leukocytosis
Hyperkalemia, but depleted intracellular K+
Acidosis means increased H+, which drives H+/K+ countertransporter to take in the H+ and dump K+ out. The kidneys then work really hard to try to pee out the K+. The total K+ is actually low, but have hyperK+ in blood.
Complications of DKA
life-threatening mucormycosis or Rhizopus infections (invade sinuses and cause brain abscess)
Cerebral edema
Cardiac arrhythmias d/t K+ and Mg2+ depletion
Heart failure
Rx for DKA
IV fluids
Insulin (corrects the hypoglycemia, but also is really imp bc it closes the anion gap)
K+ and Mg2+ to replete intracellular stores
Glucose if nec to correct hypoglycemia
What is the eqn for anion gap?
Anion gap = Na+ - (Cl- + HCO3-)
What things cause increased anion gap in metabolic acidosis w compensation (hypervent)
Increased anion gap = MUD PILES
Methanol (formic acid)
Uremia
DKA
Paraldehyde or Phenformin Iron tablets or INH Lactic acidosis Ethylene glycol (oxalic acid) Salicylates (aspirin)
How can you tell if an acidosis is respiratory or metabolic w compensation?
Respiratory acidosis has PCO2 > 40mmHg
Compensated metabolic acidosis has PCO2 <40mmHg. Check the anion gap.
What is HHS? Hyperosmolar hyperglycemic state?
Occurs in Type 2 DM Glucose >800 No Kussmaul's bc no acidosis High osmolarity (>340) No ketones (bc insulin is present, which inhibits lipolysis- which how ketones are made)
Histology of the islet cell in DM-I vs DM-II
DM-I: islet cell infiltrates; number of B cells decreased
DM-II islet amyloid deposits; number of B cells is variable
DM treatment strategy for DM-I vs DM-II
DM-I: low sugar diet, must replace insulin bc not producing it.
DM-II: diet and exercise for weight loss; oral hypoglycemics and insulin replacement
What are the main classes of drugs used to treat DM?
Insulin Sulfonylureas Biguandes Thiazolidinedions (Gitazones) a-glucosidase inhibitors Mimetics GLP-1 mimetics
List the insulins used to treat DM
Lispro, Aspart, Regular (all short acting)
NPH (intermediate)
Glargine, Detemir (both long acting)
How does exogenous insulin work to treat DM?
It binds to the insulin receptor (which has tyrosine kinase activity)
In liver: the increased glucose is stored as glycogen
In muscle: there is increased glycogen and protein synthesis and K+ uptake
In fat: it aids TG storage
Clinical use for exog insulin
Type I DM
also some Type II DM
and life-threatening hyperkalemia, stress-induced hyperglycemia
Toxicity from exog insulin
Hypoglycemia (get low blood sugar if you give too much)
V rare: HPS rxn
Also, weight gain.
List the Sulfonylureas
1st gen:
tolbutamide
chlorpropamide
1st gen are not really used much.
2nd gen:
glyburide
glimepiride
glipizide
Mech of action of sulfonylureas
Close K+ chnl in the Beta-cell mbr, so that cell depolarizes- therefore Ca2+ comes in and insulin rls is triggered.
Increases insulin secretion.
Clinical use: sulfonylureas
Stimulate rls of endog insulin in DM II. (Must be used in early DM II, when pancr is still working)
Requires some islet fn, so doesn’t work in DM I.
Toxicities of sulfonylureas
1st gen: disulfiram-like effects. 1st gen are not really used.
2nd gen- hypoglycemia
What diabetes medicine is a biguanide?
Metformin. The important one.
Mechanism of biguanides (metformin)
Unknown. Decreases GNG in the liver Increases serum glycolysis Decreases serum glucose levels Overall acts as an insulin sensitizer
Clinical use for biguanides/metformin
Oral hypoglycemic for diabetics.
Can be used in pts w/o iselt fn. (so works in DM I and late II)
Can be used in pregnancy
Also used in PCOS.
Toxicity of metformin (a biguanide)
Most grave: lactic acidosis.
Therefore, it is contraindicated in renal failure/insufficiency (Cr >1.5), liver dz, CHF.
Also avoid if pt is getting IV contrast.
What are the thiazolidinediones (TZDs, aka glitazones)?
Pioglitazone
Rosiglitazone
Mech of action of glitazones
Increase insulin sensitivity (and decrs resistance) in peripheral tsu.
They bind to the PPAR-gamma receptors in adipose, skel musc, liver.
Clinical use for glitazones
Typer II DM- can be used as monotherapy or in combo w other drugs
Toxicity of glitazones
Weight gain, edema, CHF exacerbation
Hepatotoxicity.
CV toxicity- esp MI w rosiglitazone.
List the a-glucosidase inhibitors
Acarbose
Miglitol
(these are not commonly used)
Mech of action of a-glucosidase inhibitors
Inhibit intestinal brush-border a-glucosidases
Therefore cause delayed sugar hydrolysis and glucose abs, so there is decreased post-prandial hyperglycemia
Clinical use for a-glucosidase inhibitors
DM II
monotherapy or combo w other drugs
Toxicity of a-glucosidase inhibitors
GI- upset stomach, pain, naus, cramping
What is the mech of action of mimetics like pramlintide? When is it used?
Decrease glucagon
Used in DM II
Toxicity of pramlintide
Hypoglycemia
Nausea, diarrha
What is the use of the GLP-1 mimetics (Exenatide)? When are they used?
Increase insulin, decrease glucagon rls
Used in DM-II
Toxicities of Exenatide
Naus/vom
Pancreatitis
How is Hb glycosylated in DM to form HbA1c?
Non-enzymatic glycosylation
Metabolic syndrome
Any 3 of these: Abd obesity (>40in M, >35in F) TG >150 HDL 130/85 (pre-HTN) Fasting serum glucose >100 or 2hr post-prandial >140
What is Orlistat? Mech, use, tox
Weight loss drug.
Alters fat metabolism by inhibiting pancreatic lipases.
Used for long-term obesity mgmt (w diet)
Tox: steatorrhea, GI discomfort, reduce abs of fat-soluble vitamins (esp Vit D), headache
What is Sibutramine? Mech, use, tox
Weight loss drug
Sympathomimetic: inhibits serotonin and NE reuptake (works peripherally, not in CNS)
Used for both short-term and long-term obesity mgmt
Toxicity: HTN and tachycardia
Avoid SSRIs d.t risk of serotonin syndrome
Contraindicated in coronary dz, CHF, TIA/stroke, hx of arrhythmia.
Function of ADH
Aka vasopressin, secreted from Post Pit.
Inserts H20 channels in principle cells of kidney tubule, increasing water reabs (anti-diuretic)
Primarily regulates osmolarity, but also responds to low blood volume, which is even more urgent than osmolarity.
What is SIADH?
Syndrome of Inappropriate (high) ADH secretion.
- Excessive water retention
- Hyponatremia
- Urine osmolarity > serum osmolarity.
V low serum sodium levels can lead to seizures- correct slowly.
Rx for SIADH
Demeclocycline (ADH antagonist) or H20 restriction
Causes of SIADH
- Ectopic ADH secretion (by sml cell lung cancer)
- CNS disorder/head trauma
- Pulmonary dz
- Drugs (cyclophosphamide)
What is Diabetes Insipidus?
Thirsty + polyuria, with an inability to concentrate urine.
Central DI- can’t concentrate urine bc there is no ADH (pit tumor, trauma, surgery, histiocytosis X)
Nephrogenic DI- can’t concentrate urine bc of lack of renal response to ADH- ADH is there, kidney just doesn’t see it. Can be hereditary or secondary to hypercalcemia, lithium, or demeclocycline(ADH antagonist)
(Demeclocycline is the Rx for SIADH)
How is Diabetes Insipidus Dx’d?
Water deprivation test- urine osmolarity does not increase even tho it should since there is less water.
To know if it's central or nephrogenic, give desmopressin (ADH analog): If central (no ADH made), desmopressin will help If nephrogenic (ADH is there, kidneys just don't respond), desmopression will not help.
Lab findings in Diabetes Insipidus
Urine sp grav 290 mOsm/L
Rx for Diabetes Insipidus
Adequate fluid intake
For central DI (no ADH made)- give intranasal desmopressin, and ADH analog
For nephorgenic DI (ADH made but kidneys not responsive)- give hydrochlorothiazide (diuretic- helps conc urine), indomethacin (decreased renal blood flow. anti-inflam also used in arthritis), or amiloride (K+ sparing diruetic, closes Na+ chnls in CT)
What paraneoplastic syndromes can occur d/t sml cell lung cancer?
Ectopic ADH
Ectopic ACTH
Lambert-Eaton syndrome (proximal musc weakness d/t auto-Ab to presynaptic Ca2+ chnls)
Why is the serum sodium so low in SIADH?
Retaining more water means the Na+ basically gets diluted. (serum osmolarity goes down)
But, in addition, the body reduces its aldosterone secretion to stop retaining water. But in order to do that, it stops retaining Na+. So, the Na+ is extra low bc of low aldo.
Low Na+ can cause seizures- correct slowly
Nephrogenic DI is unresponsive to ADH at what place in the kidney?
Collecting tubule
What is Carcinoid syndrome?
Caused by carcinoid tumors that secrete high levels of serotonin. Rare.
Carcinoid tumors come from the neuroendocrine cells of the GI tract.
If the tumor is limited to the GI (as in carcinoid tumors of the appendix), there will be no Sx bc the serotonin will undergo 1st pass in the liver.
But, if the tumor metastasizes or is not in GI (eg in lung), then will see excess serotonin.
Most commonly site = GI tract- sml bowel tumors. Carcinoids are the most common tumor of the appendix, but the appendix is not the most common site (sml bowel is). Also found in lung.
See increased 5-HIAA in urine. 5-HIAA is a breakdown product of serotonin.
Sx: B FDR Bronchospasm (asthmatic wheeze) Flushing Diarrhea Right-side valvular dz.
Rule of 1/3s:
1/3 metastasize
1/3 present w a 2nd malignancy
1/3 multiple
Rx: octreotide (SS analog)
Zollinger-Ellison syndrome
Gastrin-secreting tumor of the pancreas or duodenum.
Gastrin stim’s gastric acid secretion- so see thickening of rugae in stomach.
Causes recurrent ulcers
May be assoc w MEN 1
(MEN 1 = Parathyroid, Pituitary, and (!)Pancreas)
Rx: PPIs
Octreotide works in some tumors to decrease gastrin, but not all are responsive
What are the breakdown products of Dopamine, NE, Epi?
Dopamine –> HVA
NE –> VMA
Epinephrine –> Metanephrine
Where in the body does pheochromocytoma occur? Derived from which cells?
Adrenal medulla (most common adrenal med tumor in adults) Derived from chromaffin cells (which are from neural crest).
Labs and genetics in pheochromocytoma
Most tumors secrete Epi, NE, and Dopamine (which all cause the episodic HTN), so plasma catecholamines are high.
Also, urinary VMA (breakdown product of NE) is high.
Pheo is assoc/w NF, MEN 2A and 2B
Rx for pheochromocytoma
a-agonists, esp phenoxybenzamine (non-selective, irreversible a-blocker)
Can also give B-blocker, but also give the a-blocker 1st!
Sx of Pheochromocytoma
Episodic hyperadrenergic sx: Prs (elevated BP) Pain (headache) Perspiration Palpitations (tachycard) Pallor Panic attacks
Also a/w increased EPP (which can cause polycythemia).
Can be a/w DM.
How is epinephrine made?
Phenylalanine –> Tyrosine –> L-dopa –> Dopamine –> NE –> Epi
What is an adrenal neuroblastoma? What are the markers for it?
Most common adrenal medulla tumor in kids. (Can also occur anywhere along the sympathetic chain).
See increased HVA (breakdown product of dopamine) in urine.
Not so much HTN (unlike pheo in adults)
See Homer-Wright pseudo-rosettes on histo
N-myc oncogene
Bombesin is the tumor marker
Stain w Neurofilament stain
Increased urinary VMA
VMA is a breakdown product of NE.
Increased VMA in urine is seen in pts w pheochromocytoma
Increased urinary HVA
HVA is a breakdown product of dopamine.
Seen in urine in kids w adrenal neuroblastoma.
Lateral Medullary Syndrome (Wallenberg’s) occurs as a result of dmg to what?
Occlusion of one of the PICAs (which come off of the vertebral artery).
This causes unilateral infarct of the lateral portion of the rostral medulla of the brainstem
Aka PICA syndrome
What are the Sx of lateral medullary syndrome?
Spinothalamic tract dmg: Loss of body P/T contralaterally
Trigeminothalamic tract dmg: loss of P/T over ipsilateral face
Nucleus ambiguous (glossopharyngeal and vagus) dmg: difficultly swallowing, loss of gag, hoarseness
Descending symp tract dmg: Ipsilateral Horner’s syndrome
Vestibular nuclei dmg: vertigo, nystagmus, naus/vom
Inf cerebellar peduncle dmg: ipsilateral cerebellar deficits- ipsilateral ataxia, past pointing
What is Horner’s?
PAM:
Ptosis
Anhydrosis
Miosis
A/w SC lesion above TI- brainstem, trauma to thoracic SC, T1/T2 nerve roots, symp chain, or carotid plexus.
What hormones are decreased in Addison’s?
Primary deficiency of cortisol and aldosterone
d/t adrenal destruction/auto-immune dz
Most common breast cancer?
Invasive ductal carcinoma
Most common gynecological malignancy
Endometrial carcinoma
