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)

How 'bout a little Lung Pathology

Good evening all! I'm trying to give some quick-hit reading and "to know" for those preparing for USMLE Step 1. This will continue for a couple more weeks. Most of those who will be taking this exam will be completing their preparation during the next 3 weeks and then entering the wards, where I could then become their intern when they rotate through their internal medicine clerkship at the University of Kansas. That is when the fun begins. Right now, it is time to focus on preparing to take THE test that either opens or closes future doors of opportunity. Sadly, this exam does weigh that heavily.

All of you preparing for this exam and have scheduled to take it in the middle to late June should be doing lots and lots of questions from a question bank, such as USMLE world or Kaplan. I would also recommend as you go back through your question bank to have your FirstAid book handy and write in the margins those explanations that really make it stick for you.

You should have or should be thinking about taking a full, mock exam. This will build your stamina for THE day and make you work that recall muscle I blogged about earlier this month.

Build your confidence, daily! Know you are in the right place, at the right time to do well.

Make sure you are exercising and eating right.

Make a plan, do your plan, believe in your plan and execute!

Alright... enough soap box stuff. As important as it is, here is some lung path to work your brain over.

Make sure to inhale! ;)



Interstitial Lung Diseases

Acute Lung Injury- rapid onset, short duration
- Diffuse Alveolar Damage (DAD)- specific cause, rapid progression-infiltrates
- Acute Interstitial Pneumonia (hamman-rich disease)- like DAD, only no specific cause, fulminant course- need biopsy
o The above two present with pretty severe respiratory symptoms

- Bronchiolitis Obliterans (BOOP)- only one with a good prognosis, air space disease- fibroid polyps filling airspaces

o Presents with fever, cough, dyspnea, bilateral infiltrates

Chronic Interstitial Pneumonia
- Usual Interstitial Pneumonia- varying histology- fibrosis, inflammation
o Infiltrates periphery, base
o Worse prognosis, older people 55

- Desquamative Interstitial Pneumonia- uniform, macrophages in airspace
o Better prognosis---younger 45

Honeycomb lung- dilation/mucous filling air spaces/cyst formation/obliteration of small airspaces to create big ones---end stage
- Acute lung injury- DAD
- Chronic- BOTH UIP, DIP
- Asbestos
- Interstitial glanulomatous diseases
- Eosinophillic granuloma


Hypersensitivity Pneumonitis= Extrinsic Allergic Alveolitis

Non-Necrotizing Granuloma: Hypersensitivity Pneumonitis
Necrotizing Granuloma: Wegener's granulomatosis

Cyclophosphamide
- UIP
- Wegener's Granulamatosis

Diffuse Pulmonary Hemorrhage Syndromes
- Goodpasture's Syndrome---young males, kidney too
o Hemorrhage in intraalveolar spaces

- Vasculitis assoc- both have good prognosis with treatment
o Wegener's granulomatosis-- 50 y/o males, kidney too--mostly other organs
Necrotizing granuloma in lung and vasculature (necrotizing vasculitis)
C-ANCA

o Chrug-Strauss- ASTHMA, P-ANCA, RARE kidney: skin, nerves, heart, looks like eosinophilic pneumonia

Pulmonary Eosinophilia
- eosinophills in BLOOD or SPUTUM…NOT IN LUNG TISSUE ITSELF
- DISEASES:
o Churg-strauss (see above)
o Eosinophilic pneumonias
Simple- LOEFFLER'S SYNDROME- transient infiltrates
Tropical- filiarial
Chronic- only one that needs biopsy, assoc w/ASTHMA
• Responds well to steroids, lots of diff causes

o Allergic bronchopulmonary aspergilliosis- NO BIOPSY
Hypersens to aspergillius (acute branching hyphae)
Ab to aspergillius, central bronchiectasis (dilation)

Immune, not infectious- treat w/ steroids

Pulmonary Eosinophilic Granuloma (histiocytosis X)
- is NOT A PULMONARY EOSINOPHILIA!!!!!!!!
- the eosinophils are located in the lung tissue, NOT the peripheral blood/sputum
- histocyte proliferation, with a pneumothorax (air in pleural cavity)
- langerhans cells w/ bierbeck granule(ovoid nucleus with central line, stain with S-100) CD 1+
- treatment: stop smoking, corticosteroids

Diseases associated with ASTHMATICS- all have pulmonary eosinophilia (makes sense)

- Churg-Strauss
- Chronic eosinophilic pneumonia
- Allergic bronchopulmonary aspergilliosis

Immunologic lung diseases
- Goodpastures
- Allergic bronchopulm aspergilliosis

Sarcoidiosis- multisystem granulomatosis disease
- multiple non caseating, non necrotizing granulomas, usu along lymph pathways (different from TB- which would caseate)
- black, female, 20-40 y/o
- bilateral infiltrates, hilar lymphadenopathy
- increased serum angiotensin converting enzyme
- increased 24 hour calcium secretion

Necrotizing Granulomas along blood pathways- Wegener's granulomatosis
Non-necrotizing granulomas along lymph pathways- sarcoidiosis

Pneumonconiosis
- non-neoplastic rxn in lung to inhaled mineral/organic dust
- Asbestos Diseases
o Asbestosis- pulmonary parenchymal interstitital fibrosis
o Pleural plaque
o Pleural effusion
o Bronchogenic carcinoma
o Malignant mesothelioma
o Laryngeal/extrapulmonary neoplasms

Lung Biopsies
- OLB- gold standard
- VALB- not good for central biopsy
- TBB- good for sarcoid, cancer, infections

o Bad for UIP, DIP

COPD/PFT

Chronic Obstructive Diseases
- Chronic Bronchitis
- Emphysema
o Above two are usually considered COPD
- Asthma
- Bronchiectasis


Chronic Bronchitis
- middle ages, smokers, males
- hallmarks:
o hypertrophy/hyperplasia of submucosal glands (ried Index)
RIED index- meas ratio of submucosal gland thickness to thickness of bronchial wall..>0.4 is bad
o goblet cell metaplasia in bronchi

Remember----terminal bronchiole---respiratory bronchiole---alveolus

Emphysema: enlargement of airspaces, distal to terminal bronchiole
- pathogenesis: protease/antiprotease balance
- defined in morphologic terms
- males, smoking, 50-80 y/o
Types
- centrilobular: most common, resp bronchioles, UPPER lobes
- panlobular: involves BOTH resp bronch and alveoli (whole acinus), LOWER lobes
o alpha-1-antitrypsin defiency (PiZZ genotype)
- localized - (paraseptal), enlargement distal acinus, upper lung, usu asymptomatic

o young adults- spontaneous pneumothorax
- Irregular (paracicatricial emphysema)- fibrosis
- Bullous- occurs w/ other emphysemas

Asthma:
- smooth musc contraction, mucous secretion, increased vascular permeability-edema---leads to bronchial obstruction
- thickened bronchial basement membrane of bronchioles, hypertrophy of bronchial smooth muscle, mucous plugs

Bronchiectasis
- irreversible dilation of bronchi- due to elastic/muscular elements in wall

- Immotile cilia syndrome
o Inherited non-obstructive cause
o Includes Kartagener syndrome: dextrocardia, bronchiectasis, sinusitis, rhinitis, nasal polyps, otitis media

Non Productive cough: Asthma
Productive Cough: bronchiectasis (mucopurulent sputum)

Middle Aged men
- UIP
- DIP
- Hypersensitivity pneumonia
Pulmonary fxn tests
- when have pulmonary function tests: the percent predicted is the "percentage that the "ideal" predicted value that the patient has achieved
- Forced Expiratory Flow :slope of line through volume/time graphs
o FEF 25-75%- small airway disease
o FEF 200-1200- large airway disease

Infectious Lung Diseases

Productive Cough: Bacterial Pneumonia

Bacterial Pneumonia
- Community Acquired Pneumonia: mild- bad if co-morbidities
- Nosocomial
- Opportunistic
- Abscess is complication of bacterial pneumonia
Viral Pneumonia: usu kids, immunocomp
- chronic interstitial pneumonia- lymphocytes
- diffuse alveolar damage- hyaline membranes
- Cytomegalovirus
o Immunocomp,
o Fever, non productive cough, diffuse infiltrates
o Intranuclear inclusion bodies, intracytoplasmic inclusions
Pneumocystis Pneumonia
- immuno comp
- fever, dry cough,
- inter-alveolar FOAMY exudates

Pulmonary Fungal Infections
- Histoplasmosis
o Soil, bird/bat droppings
o Granulomatous inflammation, small black budding yeast
- Coccidiodomycosis
o Southwest
o Necrotizing granulomatous inflammation

- Cryptococcosis - india ink stain
o Soil, PIGEON poop
o Mucin positive
- North american blastomycosis
o mid west river valleys
o pus forming (suppurative)/granulomatous
o BROAD based budding

- Aspergillosis
o Allergic bronchopulmonary aspergillosis- immunologic
o Aspergilloma- colonizes pulmonary cavity- fungus ball
o Invasive aspergillosis- opportunistic infection
Vascular invasion, thrombus + infarct
Can see hyphae and fruiting bodies

Tuburculosis
- Gohn complex: peripheral granuloma, involvement w/ mediastinal lymph node

Stuff that forms Granulomas
Necrotizing
- TB
- Coccidiomycosis

Non-Necrotizing
Lung Cancer
Men, 60-70 y/o
Central Tumors
- small cell carcinoma
- squamous cell carcinoma
- branchial carcinoids
Peripheral Tumor
- adenocarcinoma
- hamartoma

Malignant
Epithelial Tumors
- squamous cell carcinoma
o smoking males, central lung- keratin pearls
o hemotypsis, symp due to obstruction
o superior vena cava syndrome- compression, dilation of upper body veins
o pancoast syndrome- shoulder pain- ulnar distribution: b/c tumor at apex compresses parts of brachial plexis
o Horner syndrome- b/c pancoast tumor that involves cervical symp plexus- ptosis, miosis, anhydrosis, endopthalmosis
o Massive hemorrhage, dilated bronchi mucopurulent secretions,
o 5 years, 15%

- adenocarcinoma
o peripheral, assoc with scars
o 5 year 15-20%
o Types
Acinar adenocarcinoma
• Gland arrangement, mucous secretions
Broncho-alveolar carcinoma
• Male female 1:1, 5 year 42%, multicentric/diffuse forms worse
• Neoplastic cells line "normal" alveolar architecture
• Types
o Solitary mass
o Multiple nodules- resembles metastatic cancer
o Multicentric diffuse infiltrate- resembles interstitial disease
Solid carcinoma w/ mucous cell formation
• Undifferentiated, anaplastic
Papillary adenocarcinoma
• Papillary structures with central fibrovascular core

Neuroendocrine Carcinomas (small and large cell carcinomas): acts like neuroendocrine system

Small cell carcinoma
o Males, smoking
o Worst prognosis 5 yr 4%, already metastatic by time of diagnosis
o Best response to cancer- important to ID as small cell for TX
o Central
o Types
Oat Cell
Intermediate
• Similar clinically
Combined- oat cell + any other type of tumor (squamous or adenoma)
• Perform surgery to remove

- Large cell carcinoma
o Poorly differentiated- no observable org via light microscopy
Electron microcsopy shows some organization
o cells with lots of cytoplasm (+ lymphocytes…not oat cells)
o Treat with SURGERY NOT CHEMO

Bronchial Carcinoids
- M=F, 45 y/o
- Central, peripheral, atypical
- Central
o GOOD PROGNOSIS- 5-10 y 50-95%!
o Maj metast to lymph, minor to liver
o YELLOWISH color
o Mass invading lumen of larger bronchi (more central)
o Invade bronchial wall into lung tissue
o Uniform cells, strippled chromatin, positive stain for chromogranin
o Can UNUSUALLY cause carcinoid syndrome (via seretonin secretion- skin flush, broncho const, cyanosis, R heart prob, hypotension,edema)

Metastatic Tumors
- lung 2nd most freq after lymph node
- Types
o Multiple- usu late stage cancers
o Lymphangitic- usu from adenocarcinoma
o Solitary- must distinguish from primary tumor
- usu from stomach, breast, colon, uterus, pancreas
Malignant Mesothelioma
- males, 40-70 y/o
- increasing in freq
- asbestos exposure (20-40 year lag)
- PLEURAL EFFUSION
- Pleural tumor encasing the lung- can extend to diaphragm
- Biphasic: epithelial/spindle
Benign
Hamartoma
- Peripheral, well defined
- hamartoma means like tumor, but due to faulty development
o microscopically can reproduce any component of bronchial tissue- cartilage, muscle, fat, cleft like spaces
Putting it all together….

Small cell carcinoma: major one for chemo
All other tumors- surgery is treatment of choice!!

Overall cancer survival rate: 5 years, 8-10 %
In order of better to worse
- squamous, adeno, small, large
Squamous cell, adeno= better prog
Small/Large cell= bad prog
Metastasis: most likely to least likely: lymph nodes, liver, adrenal, bone, brain

Paraneoplastic syndromes
Squamous cell carcinoma: hypercalcemia- PTH
Small cell carcinoma: cushing's (ACTH), inapprop ADH, carcinoid, gyneocmastia, acromegaly
Squamous cell and adenocarcinoma ( prob most frequent and increasing!)are most frequent lung tumors
- small cell and large cell also considered frequent

Drugs with Lung Toxicity:
Bleomycin
Busulfan
Amiodarone
Cyclophosphamide
Methotrexate and methysergide
Nitrosourea and nitrofurantoin