10 pearls of Acid base

1. Normal pH, serum bicarbonate, and Pco2 levels do not necessarily exclude acid-base disorders. Final pH level is determined by the ratio of bicarbonate and Pco2. The terms “acidemia” and “alkalemia” represent only changes in pH, whereas the terms “acidosis” and “alkalosis” denote underlying pathological processes. Acidosis without acidemia and alkalosis without alkalemia can be seen. Remember to draw blood simultaneously for arterial blood gas measurement and for basic metabolic profile to ensure proper interpretation of acid-base disorders.

2. Always calculate the serum anion gap (AG); otherwise, acid-base disorders may go unrecognized. When calculating AG, pay attention to serum albumin values, which will influence AG significantly. For every 1 g/dL decline in serum albumin <4.4 g/dL, a 2.5 mEq/L reduction in AG occurs. In the case of increased AG, the ratio of AG and HCO3— should be calculated (Δ:Δ). The Δ:Δ<1 suggests mixed normal AG and high AG acidosis; Δ:Δ>2 suggests coexisting metabolic alkalosis. Increases in AG can be seen in nonacidotic states, such as metabolic alkalosis and respiratory alkalosis; however, increases in AG beyond 3 to 5 mEq/L are unusual.

3. Check for appropriate compensation to detect occult mixed acid-base disorders. Over- or undercompensation does not occur and is only indicative of another primary acid-base disorder. Any combination of acid-base disorder can occur, except for respiratory acidosis and respiratory alkalosis. In mixed acid-base disorders, therapeutic decisions should be based on the pH level.

4. Compensation formulas include:Expected compensation in metabolic acidosis:
Pco2 = 1.5 x HCO3— + 8 ±2
Expected compensation in metabolic alkalosis:
Pco2 = 0.6 x ΔHCO3—
Acute respiratory acidosis: ΔHCO3— = 0.1 x ΔPco2
Acute respiratory alkalosis: ΔHCO3— = 0.2 x ΔPco2
Chronic respiratory acidosis: ΔHCO3— = 0.35 x ΔPco2
Chronic respiratory alkalosis: ΔHCO3— = 0.4 x ΔPco2

Since you have to remember 4 formulas for expected compensatory changes in respiratory disorders, “1-4’’ can be used for quick recall.

5. The urinary AG (UAG) can be useful to differentiate between gastrointestinal (GI) and renal causes of a hyperchloremic metabolic acidosis. A negative UAG suggests GI loss of bicarbonate (eg, diarrhea); a positive UAG suggests impaired renal distal acidification (eg, distal renal tubular acidosis). UAG is not useful in volume depletion with urinary sodium <25 mEq/L.

6. In early stages of chronic kidney disease (glomerular filtration rate [GFR] <40 mL/min), normal AG metabolic acidosis can become evident, and as the disease progresses (GFR <20 mL/min), high AG metabolic acidosis can be seen. Serum bicarbonate <10 mEq/L and AG >20 mEq/L are unusual in renal failure and may be indicative of coexistent pathological processes, such as ketoacidosis or lactic acidosis.

7. Lactic acidosis that exceeds 4 to 5 mmol/L in a patient with acidosis is considered significant. The lactate level can exceed 12 mmol/L during grand mal seizures. Drug-induced lactic acidosis has been seen with metformin, isoniazid, and some antiretroviral agents.

8. In adults, salicylate overdose results in mixed metabolic acidosis and respiratory alkalosis; in children, only metabolic acidosis is seen.

9. Diabetic ketoacidosis, alcoholic ketoacidosis, lactic acidosis, and chronic renal failure—but not acute renal failure—are much more common causes of serum osmolal gap increases than are ethylene glycol or methanol intoxications. Serum osmolal gap can be seen without metabolic acidosis, for example, with isopropyl alcohol or with mannitol.

10. Serum osmolal gap of ≥25 mOsm/kg, in the absence of evident causes, strongly suggests methanol or ethylene glycol intoxication. Prophylactic therapy either with fomepizole or with ethanol can be initiated to prevent the formation of toxic metabolites while laboratory test results are pending. Once parent compounds are metabolized, the osmolal gap will disappear, but an increased AG will remain; hence, a normal osmolal gap does not necessarily exclude ethylene glycol or methanol toxicity.

Immunology nirvana... ahhhh

 


Courtesy of David B., whom I consider one of my closest friends and a trusted collegue.

Some ANS pharm review

You can view it here in a better format!
http://docs.google.com/View?id=ddb246wq_9f8qm94

Parasympathetic Nervous System

Cholinoreceptor:

G protein-linked (Muscarinic): CNS, PNS-targeted tissues, vascular endothelium (not innervated by CNS)

- seven transmembrane domains (third cytoplasmic loop is coupled to G proteins)

M1 & M3: Gq everything except heart → activates the IP3, DAG cascade = ↑ Ca2+

M2 & M4: Giα → heart, inhibits adenylyl cyclase activity (inhibit cAMP & Giβ = ↑K+ flux)

Ion channel (nicotinic): “Neuronal” - ANS postganglions, some CNS neurons; “NMJ” - somatic motor fibers innervating muscles

- 4 subunits form cation-selective ion channels→ electrical and ionic changes→ depolarization

*Prolonged agonist occupancy→ "depolarizing blockade" abolishes the effector response→ can produce muscle paralysis


Direct Muscarinic Agonists:

CV: Direct effect = vasoconstriction; masked by NO-mediated vasodilation (requires intact endothelium) → reflex tachycardia

Pulm: Bronchoconstriction, ↑mucus secretion, *exacerbates asthma

GIT: ↑secretions (salivary, gastric, pancreatic & intestinal) & ↑peristalsis (contract longitudinal muscle while relaxing sphincters)

GUT: Promotes voiding: Detrusor contraction, relax trigone & sphincters

Eye: Miosis (iris contraction), Accommodation (ciliary contraction - facilitates aqueous humor outflow)

Secretory: ↑ secretion by thermoregulatory sweat glands (anomalous Muscarinic receptors of SNS)

Choline Esters - poorly absorbed & poorly distributed into CNS

Acetylcholine [Endogenous transmitter] – rapidly hydrolyzed - Affects both Muscarinic & nicotinic receptors

Low Dose: mostly vascular Muscarinic receptors→ NO→ vasodilation→ reflex tachycardia; cardiac effects hidden by baroreceptor response

High Dose: vascular + direct bradycardia (potential atrial flutter) * Can evoke SNS response thru ganglia (see when using Muscarinic antag)

Methacholine - Slightly resistant to AChE - Specific to Muscarinic (methyl group reduces potency @ nicotinic)

Bethanechol - Resistant to degradation by AChE - Specific to Muscarinic (methyl group reduces potency @ nicotinic)

Carbachol - Resistant to degradation by AChE

- Affects both Muscarinic & nicotinic receptors (i.e. can cause endogenous ACh release through ganglionic nicotinic receptors)

Alkaloids

Muscarine - Fungal (4° amine) alkaloid ACh mimetic

- Activates Muscarinic receptors, CNS activity

- Resistant to AChE

- No therapeutic use

Pilocarpine (ophthalmic) – (natural 3° amine) alkaloid ACh mimetic

- Used to treat glaucoma by allowing for fluid drainage from eye & atropine poisoning

- Resistant to AChE


Muscarinic Receptor Antagonists: Block action of ACh/agonists at Muscarinic receptors;

CNS: Minimal effects – Toxic doses→ agitation, hallucinations & coma; often used w/ dopamine precursor in Parkinson’s, also relieves vagal syncope

CV: Tachycardia (blocks PNS tone @ SA node), few hemodynamic effects

Pulm: Bronchodilation & ↓mucus secretion (not as useful as B2 agonists in asthma)

GIT: ↓motility & secretions – useful for mild GI hypermotility, excessive salivation, or as pre-op adjuvant before abdominal surgery

GUT: can cause urinary retention, especially w/ BPH

Eye: Mydriasis (dilated pupils); Cycloplegia (paralyzed ciliary muscle) – good for ophthalmic exam; Acute glaucoma (narrow anterior chamber angle)

Secretory: “atropine fever” - ↓ thermoregulatory sweating (anomalous Muscarinic receptors of SNS); helpful in hyperhidrosis

Contraindications: Glaucoma (especially closed angle), Prostatic hyperplasia, may ↑ gastric ulcer symptoms

3° Amine – Used for effects in eye or CNS

Atropine [Prototype] – reversible (competitive) blockade with relatively long duration of action; non-selective between M1, 2 & 3

- classic antidote to organophosphate poisoning

- “Atropine Poisoning”: dry (as a bone) mouth, mydriasis (blind as a bat), tachycardia, flushed skin (red as a beet), delirium (mad as a hatter)

Treat with Physostigmine or symptom management

Scopolamine - has a relatively long duration of action, better CNS, motion sickness

Homatropine

Pirenzepine - M1-selective (nerves)

Tropicamide

Tolterodine - M3-selective (urinary urgency, frequency & incontinence)

4° Amine – Only peripheral effects, cannot penetrate CNS (due to charge) – NOT used to reverse cholinergic poisoning

Atropine Methyl Nitrate

Methscopolamine

Ipratropium - asthma

Propantheline

Glycopyrrolate

Indirect Cholinomimetics: ACh-esterase inhibitors (also inhibit ButyrylCh-esterase) → amplify effect of endogenous ACh (modifies PNS tone)

Prominent effects on CV, GIT, eye & skeletal muscle; but NO effect on peripheral vasculature

@ NMJ: low conc. → ↑force of contraction; high conc. →depolarizing neuromuscular blockade

Clinical Uses: Atropine or TCA (tricyclic antidepressant) intoxication/overdose

CNS: Mild to moderate Alzheimer’s disease

GIT & GUT: ↑smooth muscle activity – postop ileus, congenital megacolon, reflux esophagitis, neurogenic bladder, urinary retention

Eye: Glaucoma (closed angle) - ciliary contraction →↑ aqueous humor outflow→ ↓intraocular pressure

NMJ: Myasthenia Gravis

Toxicity: SLUDGE = Salivation, Lactation, Urinary incontinence, Diarrhea, Gastrointestinal cramps & Emesis – reversed by atropine (& 2-PAM)

Simple Alcohol Esters (simple alcohols bearing a 4° ammonium group)

Edrophonium – [very short half-life] - Diagnostic Test for myasthenia gravis

Carbamates (carbamic acid esters of alcohols bearing 3° or 4° ammonium group)

* Undergo 2-step hydrolysis (covalent bond formed w/ enzyme is resistant to hydration; inhibition is longer (30 minutes - 6 hours)

Ambenonium (Mestinon)

Carbaryl – high lipid solubility (rapid CNS effects)

Demecarium- Used to treat glaucoma

Neostigmine – (4° amine - permanent charge renders them relatively insoluble in lipids – poor absorption/CNS distribution)

* Used to treat myasthenia gravis, ileus (severe abdominal cramping due to obstruction)

* Has both indirect & direct effects in PNS (inhibits AChE & stimulated Muscarinic receptors)

Physostigmine – (3° amine - well absorbed, CNS distribution); duration of effect is determined by stability of inhibitor-enzyme complex

- Used to treat glaucoma, myasthenia gravis & atropine overdose

Pyridostigmine - Used to treat myasthenia gravis

Organophosphates - well absorbed topically w/ good CNS distribution (except Echo); * Before aging, pralidoxime (2-PAM) can restore enzyme fxn

bind→ hydrolyzed/phosphorylated AChe active site – extreme stability (strengthened by “Aging”) → lifetime inhibition

Diisoprophylfluorophosphate (DFP) - Can cause cumulative overdose due to extremely long duration of action

Donepezil

Echothiophate – poorly absorbed, very long half-life (~100 minutes) - Used to treat glaucoma

Isoflurophate (ophthalmic) - Used to treat glaucoma

Malathion – [irreversible] - converted to phosphate derivative, used as insecticide

Parathion – [irreversible] – converted to phosphate derivative (Active only after biotransformation), used as insecticide

Sarin

Soman - Immediately & completely binds AChE (no aging) - Potential biological weapon

Tacrine - anticholinesterase and cholinomimetic actions – used for mild/moderate Alzheimer’s disease


Cholinesterase Regenerator

Pralidoxime (2-PAM)

Direct Nicotinic Agonist: Mostly targets ganglia; ↑SNS & PSNS: predominant tone determines effect (SNS = vasculature, PSNS = everything else)

Toxicity: CNS stimulation→ convulsion, coma, resp arrest (NMJ depolarization block); HTN & arrhythmias – Tx w/ Muscarinic Antag. & mech. resp

Nicotine – (natural 3° amine)

Lobeline – (natural 3° amine) a plant derivative similar to nicotine


Ganglion-Blockers (Nicotinic Antagonists): Block action of ACh/agonists at nicotinic receptors in SNS & PSNS ganglia; All are synthetic amines

Blocks homeostatic reflexes (e.g. baro & sweating), but effector cell receptors are NOT blocked; End-Organ effects depend on predominant ANS tone

CV: ↓SNS tone→↓BP & orthostatic hypotension (no baro); ↓PSNS tone @ SA node→ mild tachycardia

GIT: ↓PSNS tone→↓secretions & motility→ constipation & xerostomia (dry mouth)

GUT: Hesitancy or urinary retention (esp. with Prostatic hyperplasia); Impaired sexual function (requires both SNS & PSNS)

Eye: ↓PSNS tone→ cycloplegia (paralyzed ciliary muscle) & moderate pupil dilation (Normal Input: PSNS>SNS)

Tetraethylammonium (TEA) [prototype] - short half-life; used to manage HTN

Hexamethonium

- No therapeutic use currently

Mecamylamine – readily enters CNS→ sedation, tremor, choreiform movements, mental aberrations

Trimethaphan (IV) – 4° Amine →lacks CNS effects

- Extremely short acting

- Can be used to treat acute dissecting aneurysm or autonomic hyperreflexia

Sympathetic Nervous System

Adrenergic Neuron Blockers:

Reserpine - non-selective blocker of uptake & storage of amines

Guanadrel - similar to reserpine


Adrenoreceptor Agonists:

A1- forms IP3, DAG & activates phospholipase C; A2 - presynaptic autoregulation of SNS outflow, inhibits cAMP formation

B1 & B2 - activates adenyl cyclase;


CV: A1→ vasoconstriction, ↓renin secretion; B1 – Ca++ influx into cells (↑ino & chronotropic), ↑renin secretion

Pulm: A1in vessels of URT mucosa→ contraction→decongestion

GIT: A2→↓PNS tone on enteric system; Beta on smooth muscle mediates relaxation

GUT: A1→contract bladder base & urethral sphincter; B2→relax bladder wall smooth muscles – both actions promote urinary retention

Eye: Alpha→ radial dilator contraction→ mydriasis (dilated pupil); Beta→↑aqueous humor production by ciliary epithelium→ ↑intraocular pressure

Exocrine: A1 on aprocrine (stress) sweat glands→ sweating on palms, brow & upper lip

Metabolic: A2→↓ insulin release; Beta→ ↑lipolysis, ↑glycogenolysis, ↑glucose release, ↑insulin secretion

Toxicity: Extended effects – hypertension, tachycardia, CNS – restless, tremor, insomnia, anxiety, paranoia


Catecholamines:

Epinephrine – A1, A2; B1, B2: skeletal muscle arteriodilation & ↑venous capacity (mixed TPR effects)

Norepinephrine - A1: ↑TPR, A2; B1: Heart effects overcome by vagal reflex; = ↑Sys, Dias; High doses = ↑HR

Isoproterenol - B1= ↑CO; B2: skeletal muscle arteriodilation & ↑venous capacity = ↓Dias & MAP

Dolbutamine (B1; A1 @ high doses) - Uses: Heart failure/cardiac decompensation (short-term) – limited by tolerance/desensitization

Dopamine - D1 stimulates adenyl cyclase in renal vasculature→ renal vasodilation→ ↑GFR; A1; B1 @ high doses


Alpha-1 Specific – mydriasis (fundoscopic exam) & decongestant, can ↑BP;

Uses: nasal congestion, hypotension, paroxysmal atrial tachycardia

Phenylephrine [prototype] – not a catechol derivative, thus not inactivated by MAO/COMT; longer duration of action

Methoxamine

Oxymetazoline & Xylometazoline – used as topical decongestants


Alpha-2 Specific – Use as anti-HTN

Clonidine

Methyldopa

Guanfacine

Guanabenz


Beta-1 Specific – ↑CO w/ less reflex tachycardia;

Dolbutamine

Prenalterol (partial)


Beta-2 Specific – bronchodilation; Uses: Asthma & bronchial constriction

Albuterol

Salmeterol

Terbutaline

Ritodrine - uterine relaxation in premature labor


Indirect Sympathomimetics:

Ephedrine – first orally active

Pseudoephedrine [also direct] – cause release of endogenous NE; widely available OTC decongestant

Cocaine - block uptake1 (potentiates effects of NE) - Used as local anesthetic

Tyramine – enter thru uptake1, displace stored catecholamines→ hypertensive crisis; potentiated by MAO inhibitors * fermented foods (cheese)

Amphetamine (NOT a catecholamine) – mech=same as tyramine; ↑mood & alertness; ↓appetite *Common Drug of Abuse – Used for narcolepsy

Methamphetamine – similar, but w/ ↑ratio of central to peripheral effects

Methylphenidate - used to treat ADHD

Adrenoreceptor Blockers:

Alpha Receptor Antagonists - * Nitrates are preferred in hypertensive crises

Non-selective Alpha Antagonists

Phentolamine [prototype] – reversible, competitive; ↓TPR & MAP→reflex tachycardia

Tolazoline – similar to phentolamine;

Phenoxybenzamine – irreversible, slightly alpha-1 selective; Uses: Pheochromocytoma, limited by postural hypotension & reflex tachycardia

*Excessive release of NE & Epi from adrenal medulla

Alpha-1 Selective Antagonists: Uses: HTN & BPH - ↓TPR & BP, May cause postural hypotension & reflex tachycardia

Prazosin

Terazosin

Trimazosin

Doxazosin – longer half-life

Tamsulosin & Alfuzosin – competitive; Uses: BPH (prostate subtype selectivity)

Labetalol - also non-specific beta blocker


Alpha-2 Selective Antagonists

Yohimbine - no established clinical role, has been used in ED


Beta Receptor Antagonists – well absorbed orally

CV: ↓SNS tone to heart → slower AV conduction & ↓BP, but NOT hypotension; ↓SNS tone to kidney→ ↓renin secretion

Pulm: B2 block→ ↑airway resistance

Eye: ↓aqueous humor production by ciliary epithelium→ ↓intraocular pressure

Metabolic/Endocrine: ↓SNS stimulation of lipolysis & glycogenolysis; Use with caution in IDDM patients; Chronic use→ ↑VLDL & ↓HDL

Clinical Uses: HTN (w/ diuretic or vasodilator);

Ischemic Heart Disease - ↓angina frequency, cardiac work/oxygen demand; improves exercise tolerance; prolongs post-MI survival

Cardiac Arrhythmias (atrial & ventricular) - ↑AV refractory period, ↓ventricular response in A-fib, ↓ventricular ectopic beats

Glaucoma – refer to Eye above, better tolerated than Epi or Pilocarpine in open-angle glaucoma

Hyperthyroidism – limits excessive catecholamine activity

Toxicity: Minor= F, rash, depression, sedation; Major= exacerbates asthma, cardiac decompensation, supersensitivity (taper), hypoglycemia in IDDM

Non-selective Beta Antagonists - used to treat: HTN, angina, arrhythmias, glaucoma, and migraine; do NOT use in asthmatics

Propranolol [prototype] – extensive hepatic (first-pass) metabolism, low bioavailability

Nadolol – very long duration of action

Timolol – very long duration of action

Partial Agonists – may prevent bradycardia, changes in lipid profile & precipitation of asthma

Dichloroisoproterenol – first beta-blocking drug

Pindolol

Cartelolol

Penbutolol

Labetalol – reversible alpha-1 antagonist; → hypotension w/ less tachycardia than alpha-blockers


Beta-1 Selective Antagonists - treat HTN; Can also ↑airway resistance when used in asthmatics

Metoprolol

Esmolol – rapid hydrolysis by esterases in RBCs: half-life = 10 min.

Atenolol

Acebutolol – intrinsic sympathomimetic effects

Betaxolol

Bisoprolol


Beta-2 Selective Antagonists

Butoxamine - no clinical use

Pathology

Short post to keep you busy over the weekend!

Good luck everyone!

http://spreadsheets.google.com/pub?key=pp596LBw4L1OLWFbYaPSGaA&output=html

Make your micro list and check it twice...gonna find out who's naughty & nice! :)

Micro is heavily tested on THE test. Knowing how to differentiate bugs and their virulence factors, how they cause disease and their presentations is critical to scoring well on Step 1. This little list is courtesy of a classmate of mine, Kallie. She used to come up with some of the best ways to re-organize material into concise, manageable bites. Thanks Kallie!

I used this list as I prepared by taking it with me on walks at night and focusing on a few of them, making notes to the side and really getting to know micro. I probably answered 15 questions based just on the info here. It enabled me to narrow down and zero in.

Some Classification Lists

Mimics Appendicitis
Yersinia entericolytica
Salmonella typhi

Cause Fever (same as those that invade host tissues)
EIEC
Shigella
Salmonella enteridis (1/2 the time)
Salmonella typhi
Yersinia
Campylobacter jejuni
Listeria

Survive at Cold Temperatures
Yersinia
Listeria monocytogenes (4C!)

Survive at Hot Temperatures
Campylobacter (42C)

Invade Intestinal Epithelium
Shigella
EIEC
Salmonella enteritidis
Listeria

Invade Lymph Nodes, Bloodstream (systemic sx)
Salmonella typhi
Yersinia
Campylobacter jejuni

Bloody Diarrhea (the invaders!)
Salmonella typhi
Yersinia
Campylobacter
EHEC (does not invade, uses Shiga toxin)
EIEC
Shigella

Gram Positive
--- 6 cause disease
Cocci
Streptococcus
Staphylococcus


Rods
Spore-forming
Bacillus
Clostridium

No Spores
Corynebacterium
Listeria (make endotoxin)

Facultative Intracellular Organisms
Listeria monocytogenes
Salmonella typhi
Yersinia

Non-mobile
Shigella

Only G+ w/ Endotoxin
Listeria monocytogenes

Human = Only Host
Salmonella typhi
Shigella

Bactericidal Antibiotics
penicillins
fluoroquinolones
vancomycin
metronidazole
aminoglycosides (can be both –cidal, -static)

Bacteriostatic Antibiotics
tetracycline
sulphonamides
trimethoprim
chloramphenicol
macrolides
lincosamides
aminoglycosides (both)

Facultative Anaerobes
Staphylococcus (G+)
Listeria (G+)
most G- rods
Mycoplasma

Microaerophilic Bacteria
Streptococcus (G+)
Spirochetes (G-)
Campylobacter (G-)

Obligate Anaerobes
Clostridium (G+)
Bacteroides (G-)

Lactose Fermenting
E. coli

Non-Lactose Fermenting
Shigella
Salmonella typhi
Yersinia
V. cholera

Produces H2S
Salmonella typhi

Sterols in Cell Membrane
Mycoplasma

Not a Normal Part of Flora
Shigella
Salmonella

No Cell Wall
Mycoplasma

Stain Acid-Fast
Mycobacteria

Visualize via Darkfield Micro
Spirochetes

Shiga Toxin (AB)
Shigella
EHEC
EIEC
LT
ETEC
V. cholera (cholera toxin)
Campylobacter jejuni

ST
ETEC
EAEC
Yersinia

Resistance Encoded by Plasmid (modify antibiotic, efflux pump?)
Vancomycin (D-ala-D-ala  D-ala-D-lactose)
Aminoglycosides (modify drug)
Tetracycline (efflux)
Macrolides, Erythromycin (methylation of rRNA)
Sulfonamides (altered permeability)

Resistance Encoded by Chromosome (altered target, altered permeability?)
Quinolones (altered DNA gyrase, topo IV)
Sulfonamides (altered dihydropterate synthase)

AB Toxin
Shiga
E. coli (LT toxin)
V. cholera

TTSS
EHEC
Salmonella
Shigella
Yersinia

HUS
EHEC
Shigella dystenteriae

Invade M Cells
Yersinia
Shigella
Listeria

Endocrine... Challenging & Important

Endocrine

Multiple Endocrine Neoplasia I
- parathyroid- primary hyperparathyroidism
- pituitary- adenomas

Multiple Endocrine Neoplasia II
- parathyroid hyperplasia
- medullary carcinoma of thyroid
- pheochromocytoma- adrenal medulla tumor

Pituitary
Anterior lobe- hormone producing (all the troph cells)
- corticotrophs- ACTH, MSH

Posterior lobe- hormone storage
- supraoptic nucleus- ADH

- paraventricular nucleus- oxytocin (stimulates uterine smooth muscle, lactation)




Anterior Lobe Hyperpituitiarism
Major Cause
- Pituitary Adenoma-
o Benign, uniform cells, stain uniformly
o pituitary apoplexy
o can eventually lead to hypopituitarism if destroy enough of the gland
o MEN I
o Common Types
Prolactinomas- most common
• Treated surgically, and w/ bromocriptime-
• See calcium deposits mico w/ uniform staining
Growth Hormone Adenoma (of somatotrophs)
• GSP oncogene
• Prolactin can be present sometimes
• GH can cause hyperglycemia
o (side note- both GH and cortisol cause hyperglycemia)
• kids- giantism
• adults- acromegaly
Corticotroph adenoma
• ACTH- cushing DISEASE
o Remember: cushing disease involves pituitary, cushing syndrome involves ACTH hypersecretion outside of pituitary
• Nelson syndrome- cushing symptoms, remove adrenal gland, persistant signs of hyperpigmentation- due to MSH of corticotroph adenoma

Anterior Lobe Hypopituitarism
- pallor

- Causes
o Tumors
pituitary carcinoma
• non functional, only diagnosed when metastasize
rathke's cleft cyst
• benign, ciliated cuboidal epithelium, remove surgically
suprasellar tumors- can grow and squish the pituitary
• gliomas
• germinomas: germ cell tumor, midline, look like gonads histologically, Japanese men, AFP elevated
• craniopharyngiomas: benign aggressive remnants of rathke's pouch
o kids: endocrine prob, adults:visual prob (optic chiasm)
o adamantinomatous: wet karatin, calcifications, cholesterol rich fluid in cyst
o papillary: no cystic, keratin, or calcification
o remove surgically
o ischemic necrosis
Sheehan syndrome: ant gland hyp during pregnancy, hypoperfusion postpartum, post gland more resistant
Other causes…results in ischemic necrosis
o empty sella syndrome
o Apoplexy- hemorrhage
o Hypothalamic disease- sarcoidiosis, TB
o Congenital Hypopituitarism- Pit-1 mutation


Posterior lobe syndromes
- ADH
o diabetes insipidus: impaired ADH, excessive urination
o syndrome of inappropriate ADH secretion- excessive ADH, hyponatremia (because resorption of escessive amounts of free water), increased in total body water, but blood volume stays the same
- oxytocin- no clinical symptoms

Adrenal

Cortex: zones GFR, products-sweeter as you go deeper
- glom- mineralocorticoids- aldosterone- controlled by angiotensin

- fasc- glucocorticoids- cortisol

- retulari- estrogen/androgen
o G/R- controlled by ACTH
o So remember, ACTH hypersecretion will only affect cortisol, estrogen

Diseases of Cortex
- Hypocorticism
o Acute
Waterhouse-Friderichsen syndrome
• Usually~ neisseria meningitis (meningococcus)- will see bacterial CSF
• Hypotension
o Red infarct of adrenal gland
• Schwartzman syndrome- breakdown of platelets, accumulation of fibrin- leads to DIC---
o diffuse petechial hemorrhages
o fibrin clumps in glomerulus of kidney
o chronic
Addison's disease
• Hypoglycemia, hyponatremia
• Focal hyperpigmentation- b/c high ACTH due to loss of cortisol neg feedback and ACTH stimulates corticotrophs to produce MSH- melanocytes
• Mostly idiopathic ATROPHY (lymphocytes), OR caused by TB-adrenal granulomas
• Feared complication: Adrenal Apoplexy- adrenal "collapse"---treat w/steroids

- Hypercorticism
o Cushing Syndrome: elevated cortisol
Hypernatremia, hypophos, increased gluconeogenesis---leading to diabetes, lymphopenia/eosinopenia- cortisol depresses lymphocyte generation
Trunkal obesity, buffalo hump, round face
Causes
• Iatrogenic-corticosteroid therapy
• Pituitary--cushing's Disease
• Adrenal cortical adenoma/carcinoma/hyperplasia
• Ectopic ACTH- lung, etc

Congenital Adrenal Hyperplasia
o 21 hydroxylase deficiency- shunts pathway to testosterone
o clitoral/penile enlargement
o hyperplasia in ZONA RETICULARIS (b/c excessive testosterone prod)
o treat- give cortisol

- Conn's syndrome (hypermineraloadrenocorticism)
o Increase in aldosterone (mineralcorticoid) W/O increase in cortisol (glucocort)
o Hypertrophy in zona glomerulosa
o Clinical: severe HTN, loss of renal K+, sodium retention
o Causes
Cortical adenoma: which is a treatable form of HTN
Nodular cortical hyperplasia/adrenocortical carcinoma

Diseases of Medulla
- Neuroblastoma: adrenal MEDULLA tumor
o Kids,
o abdominal mass, hemorrhagic tendencies, increase in urine VMA
o tumor secretes epi/norepi, histo forms rosettes
o Better prog in kids 1 year- because will progress to ganglioneuroma- benign form

- Pheochromocytoma: neoplasm of chromaffin cells
o 30-50 y/o
o secrete epi/nor epi
o MEN II- medullary cancers of thyroid and adrenal glands
o UNILATERAL, benign, will show HTN and increase in VMA

Thyroid

- Thyroid hormone
o Uncouples oxidative phosp: decrease ATP, greater heat release
o Increase
Cardiac output and SYSTOLIC blood pressure (will cause a widened pulse pressure)
GI motility
O2 consumption----atrophy, spastic muscle
Hyperthyroidism
- Grave's disease
o Ab to TSH receptor-autoimmune
o Diffuse goiter, hyperthyroidism, exopthalmos (not due to inc. TSH, doesn't recede when treat Grave's disease)
o More females
o Clin: increase in systolic blood pressure, heat intolerance, diffuse non-nodal thyroid enlargement, red color
o Maj complications
Exopthalmos
High output heart failure
Thyroid storm- collapse, heart failure shock

Hypothyroidism
- Cretinism- kids: tongue, short, mental retardation

- Myxedema- adults: periorbital edema, NON-PITTING EDEMA, infiltration of glycosaminoglycans into subcutaneous tissue


Thyroiditis- inflammation of thyroid
- Hashimotos
o females
o Autoimmune: Ab to thyroblobulin in colloid (anti microsomal Ab in follicle cells)
o Thyroid enlargement due to Lymphycyte infiltration
o hypothyroid

- subacute (granulomatous, deQuervains)
o formation of granulomas in thyroid
o usually ~ post febrile/viral illness- usu. self-limiting

- Riedel's struma (chronic, woody)
o Heavy fibrous infiltration of thyroid, must distinguish from cancer

Thyroid Tumors
- Benign colloid goiter
o Euthyroid fxn
o Non-uniform nodular enlargement w/ non functional enlarged follicles of colloid

- Benign Adenoma of Thyroid
o Mass w/capsule…capsule keeps it benign
o Microscopic- follicular adenoma

- Thyroid carcinoma
o Papillary- most common, best prog
NO CAPSULE, papillary formation, diffuse

o follicular carcinoma-
probably a follicular adenoma that invaded a capsule..remnants of capsule present with evidence of invasion (capsules and blood vessels)
bad prognosis---metastasizes to bone marrow

- Giant Spindle Cell carcinoma of thyroid
o BAD prog- 6 mo to live
o Rapidly growing- can compress trachea
o Contains BOTH Spindle cells and malignant giant cells

Parathyroid
- chief cells- secrete PTH

- waterclear cells (vasserhelle cells)- chief cell at different stage of secretion

- oxyphil cells- red granules, cytoplasm full of mitochondria

- parathyroid hormone: stim by low calcium
o increase Ca2+
indirect osteoclast resorption (via RANK-L)
stimulates 1 hydroxylation of 1, 25 Vit D in KIDNEY

o decrease phos via decreasing renal tubular resorption of phosp
urine PO4 up, serum PO4 down

o increase in alkalinephosphatase- b/c stim osteoclasts

- calcitonin- from parafolicular cells of thyroid, stim by high calcium
o direct inhibition of bone resorption

Diseases
Hypercalcitonin
- Medullary Carcinoma of thyroid
o tumor secreting calcitonin
o low calcium, high phosphate

Hyperparathyroidism
- symptoms
o resorption of distal phalanges
o high Ca2+, high alk phos
o osteitis fibrosa cystica- bone loss with Ca2+/phos release, anchovy paste
o metastatic calcification of kidney- via calcium phos

- Primary hyperparathyroidism: arising in parathyroid gland---high Ca2+, low phos in serum
o PT adenoma- benign, main cause, uniform chief cells
o PT hyperplasia- clear cell hyperplasia
o PT carcinoma- rare

- Secondary Hyperparathyroidism
o Chronic Renal Disease- big sign…high PTH, low Ca2+, high phos in serum
o Defective Vit D formation-impairs Ca2+ absorption
o Low serum Ca2+- chronic PTH secretion- diffuse hyperplasia of PT glands
o High serum phosp- b/c kidney can't effectively excrete phosphate even when PTH stimulates it to


NON-PTH Hypercalcemia
- coma is main cause of death
- high calcium, NORMAL PHOSPHATE (b/c not PTH induced)
- usu due to variety of tumors (lung, breast)
- malignant cells secrete PTH-Related Peptide

Hypoparathyrodism
- symptoms-
o hypocalcemia: tetani, hyperreflexia
o hyperphosphatemia
- causes:
o accidental removal of PT gland during surgery, Di George, autoimmune,
o pseudohypoparathyroidism
end organ resistance
hereditary- short stature, short neck, rounded face, short fingers
hyperplastic parathyroids (b/c PTH keeps trying to secrete/cause changes)