1A: DT 9-2

GFR, deeper you go, sweeter it gets:
Renin-Ag II-->Zona glomerulosa--aldosterone

ACTH, CRH-->Zona fasciculata--cortisol

ACTH, CRH-->Zona reticulata--Sex hormones, androgens

Pregnaglionic Symp Nerves-->Medulla (Chromaffin cells)-->Epi, NE

Cortex: Mesoderm

Medulla: NCC

Children: Neuroblastoma
Adults: Pheochromocytoma

(Cholesterol-->Pregnenolone)
Pregnenolone-->17-hydroxypregnenolone (this is then shunted to Cortisol or T/E2 production)

OR

Progesterone-->17-hydroxyprogesterone (which is then shunted to cortisol, T/E2 production)

Deficiency results in:
-low sex hormones
-low cortisol
-inc'd mineralocorticoids (HTN, hypokalemia, pseudohermaphroditism--externally phenotypic female, but not internal reproductive structures due to MIF; in women causes externally phenotypic female w/normal internal sex organs but lacking secondary sex chars)

(Cholesterol-->pregnenolone-->Progesterone)
Progesterone-->11-deoxycorticosterone

OR

17-hydroxyprogesterone-->11-deoxycortisol(-->cortisol)

Deficiency -->most common form of dec'd cortisol (inc'd ACTH). Dec'd mineralocorticoids, inc'd sex hormones. Sx = masculinzation, female pseudohermaphroditism, HYPOtn, hyperkalemia, inc'd renin

Salt wasting, volume depletion

(Cholesterol-->pregnenolone-->Progesterone-->11-deoxycorticosterone)
11-deoxycorticosterone-->corticosterone(00>aldosterone)

OR

(17-hydroxyprogesterone-->21-hydroxylase-->11-deoxycortisol)

11-deoxycortisol-->Cortisol

Effect of deficiency: dec'd cortisol, dec'd aldosterone, dec'd corticosterone, inc'd sex hormones; inc'd 11-deoxycorticosterone (acts as mineralocorticoid)

Sx: masculinizaiton, HTN

3 beta-hydroxysteroid DH essential to formation of aldosterone, cortisol, testosterone, estradiol, so:

deficiency-->inability to produce gluococorticoids, mineralocorticoids, androgens, and estrogens

Results in early death and excessive salt secretion in urine

If 1 in first digit->HTN

ex: 11-beta-hydroxylase def
ex: 17-alpha-hydroxylase def

If 1 in second digit-->masculinization

Ex: 21-beta hydroxylase def
ex: 11-beta-hydroxylase def (doesn't matter if 1 is in first digit!!)

Cortisol is BBIIG

-Maintains BP (upregulates alpha-1 receptors on arterioles)
-Decreases bone formation
-Anti-Inflammatory
-Dec'd immune fn
-Inc'd gluconeogenesis, lipolysis, proteolysis

Regulation:
CRH (hthal)-->ACTH (pituitary)-->cortisol production in adrenal zona fasciulata

-Exogenous steroids (dec'd ACTH)
-Cushing's DISEASE--ACTH secretion from pituitary adenoma
-Ectopic ACTH from inon-pituitary tissue making ACTH (small cell lung cancer, bronchial carcinoids)--inc'd ACTH
-Adrenal adenoma

Presentation: HTN, weight gain, moon facies, truncal obesity, buffalo hump, hyperglycemia, striae

Dexamethasone (synthetic gluocorticoid) suppression test:

If healthy: dec'd cortiol after low dose dexamethasone

If ACTH-producing PITUITARY tumor: inc'd cortisol after low dose, dec'd cortisol after high dose

If eectopic ACTH-producing tumor (e.g., small cell carcinoma)-->inc'd cortisol after low and high dose

If cortisol-producing tumor: inc'd cortisol after low and high dose

ACTH production pituitary tumor

MOA: dec'd production of LKs and PGs by inhibiting phospholipase A2 and expression of COX-2

Ex: hydrocortisone, prednisone (anythign ending in -sone)

AE: Iatrogenic Cushing's, adrenal insufficiency if stopped after chronic use
Psychosis, insomnia, glaucoma, acne

Primary--aldosterone-secreting tumor resulting in HTN, hypokalemia, metabolic alkalosis, LOW RENIN

Secondary: Kidney perception of low intravascular volume results in overactive renin-Ag system. Due to renal artery stenosis, chronic renal failure, CHF; HIGH PLASMA RENIN

Tx:
Sx to remove tumor, spironolactone (K+ spraing aldosterone antagonist)

Primary = Adrenal atrophy or destruction by dz (autoimune, TB, mets); deficiency of aldosterone and cortisol-->hypotn, hyperkalemia, hyperpigmentation (due to MSH, by-product of inc'd ACTH production from POMC)

Secondary adrenal insufficiency: dec'd pituitary ACTH production--no skin hyperpigmentation, no hyperkalemia

Acute primary adrenal insufficiency to adrenal hemorrhage associated w/Neisseria meningitidis septicemia, DIC, endotoxic shock

Tumor of adrenal medulla; derived from chromaffin cells (arise from NCC); secrete NE, epi, DA-->EPISODIC HTN

Urinary VMA, plasma catechols elevated

Tx: alpha-antags, esp PHENOXYBENZAMINE (nonselective irreversible alpha-blocker) followed by surgery to remove tumor

Presentation:
EPISODIC HTN, HA, perspiration, palpitations, pallor

Most common tumor of adrenal medulla in children

HVA elevated in urine, less likely to develop HTN

Assocd w/N-myc oncogene

MEN1: Pancreas, Pituitary, Parathyroid tumors

MEN2A: Pheochromocytoma, Parathyroid tumor

MEN2B: Pheochromocytoma, mucosal neuroma

ALL have Aut Dom inheritance

MEN2A, MEN2B

alpha: make glucagon
beta: make insulin
delta: make somatostatin

BRICK L
Brain
RBCs
Intestine
Cornea
Kidney
Liver

Nonenzymatic addition of glucose to molecules due to hyperglycemia (insulin)

Results in Small vessel dz (diffuse thickening of BM)-->retinopathy, glaucoma, nephropathy

Can also result in large vessel atherosclerosis, CAD, peripheral vascular occlusive dz, gangrene

Diabetic glomerulosclerosis--nodular; acellular ovoid nodules in periphery of glomerulus

Diabetic retinopathy--cotton wool spots, macular edema; can also be seen in HTN

Glucose + NADPH-->Sorbitol via ALCOHOL REDUCTASE

Sorbitol + NAD+-->Fructose via SORBITOL DEHYDROGENASE

Not all cells are equipped with sorbitol DH, so in setting of DM, there's inc'd sorbitol, which (via an osmotic effect) results in neuropathy and cataracts.

Cells that don't have aldose reductase:
-Schwann cells, lens, retina, kidneys

Pancreatic islet cells in DM1--islet cells entirely replaced by fibrosis

Assocd w/DM 1 mroe often than DM2; due to inc'd insulin requirements from stress (infection)

Excess fat breakdown and inc'd ketogenesis from inc'd FFAs which are made into ketone bodies (beta-hydoxybutyrate>acetoacetate)

Presentation:
Kussmaul respirations (rapid/deep breathing)
Delirium
Fruity breath (due to exhaled acetone)

Labs: Hyperglycemia, high H+, low HCO3-, inc'd blood ketone levels, hyperkalemia but depleted intracell K+ due to transcellular shift from insulin

Tx: Fluids, insulin, and K+; glucose if necessary to prevent hypoglycemia

Gli- (glyburide, glimepride, glipizide)

Close K+ channel in beta-cells, inc'd Ca2+ channel opening-->inc'd insulin release

AE: Hypoglcyemia

Biguanide--MOA unknown

Dec'd gluconeogenesis, inc'd glycolysis, inc'd peripheral glucose uptake (insulin sensitivity)

AE: lactic acidosis; contraindicated in renal failure (avoid if receiving IV contrast)

-glitazone

Inc insulin sensitivity in peripheral tissue; bind PPAR-gamma nuclear transcription factor

AE: Weight gain, edema, hetpatox, cardiotox

GLP-1 analog

Increases insulin, decreases glucagon release

metformin

sulfonylureas

metformin (first line)

metformin

glitazones
metformin

metformin

alpha-glucosidase inhibitors--acarbose, miglitol

glitazones
metformin

metformin

glitazones

alpha-glucosidase inhibitors--acarbose, miglitol

sulfonylureas

alpha-glucosidase inhibitors--acarbose, miglitol

TZDs (glitazones)

Infection

Non-enzymatic glycosylation

Hypoglycemia
Lipodystrophy
Weight gain

3/5 of:

Abdominal obesity (men waist >40 in, women >35 in)

TGs >150
HDL <40 in men, <50 in women

BP >135/85

Fasting serum glucose >100

Anti-diuresis-->retain free water, decreased serum sodium

Excessive water retnetion, hyponatremia, urine osmolarity > serum osmolarity

Causes: ectopic ADH (small cell lung cancer), CNS disorders/head trauma, pulmonary disease

Tx: Demeclocycline or water restriction

CORRECT SODIUM LEVELS SLOWLY

Intense thirst, polyuria, inability con concentrate urine owing to LACK OF ADH (central DI--pituitary tumor, trauma, sx) or to lack of renal response to ADH (nephrogenic DI--hereditary or due to hypecalcemia, Li, demeclocycline (ADH antag))
Tx: adequate fluid intake; for central DI: intranasal desmopressin (ADH analog), for nephrogenic DI--HCTZ, indomethacin, amiloride

Gastrin-secreting tumor of pancreas or duodenum

Stomach shows rugal thickening with acid hypersecretion

Causes recurrent ulcers

Assocd w/MEN I

Tx w/PPI, H2RA, Octreotide

Occlusion of PICA (posterior inferior cerebellar aa)-->unilateral infarct of lateral portion of rostral medulla

Results in loss of pain and tamp over contralateral body
Loss of pain and temp over ipsilateral face
Hoarseness, difficulty swallowing, loss of gag reflex
Vertigo, nystagmus, n/v

2

1 (2 is a possibility but less likely)

2

1

I: Pancreas, pituitary, parathyroid

IIA: Medullary thyroid carcinoma, pheo, parathy

IIB: medullary thyroid carcinoma, pheo, mucosal neuroma

Inc'd skin pigmentation
hypotn
maliase
anorexia

autoimmune-->adrenal atrophy; dec'd aldosterone, cortisol

Metformin

Sulfonylureas

Sulfonylureas

alpha-glocusidase inhibitors

glitizones

Absnce of iodination of tyrosyl groups

Dec'd thyroid hormone synthesis

Disrupts peripheral conversion of T4 to T3

METHIMAZOLE works this way

AE: Agranulocytosis, aplastic anemia

PTH; chief cells of parathyroid

Calcitonin: parafollicular C cells of thyroid

MEN IIA
MEN IIB
Medullary thyroid carcinoma
Papillary thyroid carcinoma

Hypotn
Masculinization

Hypertn
Masculinization

Elevated cortisol

Elevated aldosterone

Dec'd aldosterone AND cortisol

Inc'd T4

Subacute (de Quairvain's--sp?) thyroiditis

Toxic thyroid adenoma

Toxic multinodular goiter

Graves'

A fib

Bacteroides fragilis

Endometrial carcinoma

Rhabdomyoma

Invasive ductal carcinoma

Precursor to squamous cell carcinoma

Cushing's ulcer (inc'd ICP stimulates vagal gastric secretion)

Curling's ulcer (greatly reduced plasma volume results in sloughing of gastric mucosa)

Skip lesions--Crohn's dz

HTN

Atherosclerosis

Teriary syphilis, Marfan's syndrome

Wernicke's encephalopathy (thiamine def. causing ataxia, ophtalmoplegia, confusion)

Sickle cell anemia

H pylori

Neisseria meningitidis

Group B strep (newborns)
Strep pnuemo/Neisseria meningitidis (kids)

Spitz nevus--most common in first two decades

Bernard-Soulier disease (defect in platelet adhesion to vWF)

Supratentorial: mets > astrocytoma (including glioblastoma multiforme) > meningioma > schwannoma

infratentorial: medulloblastoma (cerebellum) or supratentorial: craniopharyngioma (cerebrum)

Infiltrating ductal carcinoma (in US, 1 in 9 women will develop BrCa)

1. fibrocystic change
2. carcinoma--in postmenopausal women

Fibroadenoma

Rhabdomyoma

Libman-Sacks endocarditis (nonbcaterial, affecting mitral)

1. Mets
2. Primary myxoma

Chiari malformation (often presents with progressive hydrocephjalus or syringomyelia)

A fib (assocd w/high risk emboli)

Predisposition to gastric carcinoma--can also cause pernicious anemia