,.

s.:::'*-..*, COMPLEME,NT CASCADE

:.: #. ..c.*i.3

,,

e
pathogen invades body

complement cascade
is activated as part of the
immune response in order to:

mark pathogens for elimination by other cells of the immune system

1yse pathogens directly

cascade is composed of serum complement

proteins produced mainly by hepatocytes

4
complement activation occurs in 3 ways

MB-lectin pathway

altemative pathway

both of these pathways occur without the heIp of anUbodies = innate immune response

classic pathway

t
complement protein Clq
binds antibody-antigen complex

acute phase protein called

complement protein C3 is

mannan binding lectin (MBL)

spontaneously activated

binds mannose residues

found on pathogen surface

(usually by pathogen surface molecules) via

found on pathogen surface

hydrolysis

Clq forms complement

MBL is then bound by

protein Cls

C3 directly binds pathogen surface

MBL associated serine protease (MASP)

i
pathogen-MBL-MASP
complex behaves just like Cl s

leading to the formation of

Cls cleaves complement

C3 forms

C3 0onverlase

proteins:
C4 into C4a =

anaphylatoxin
C2 into

C4 into

C2b

C4b

follows classic pathway from

C3a =

this point on

anaphylatoxin

C3b

C3b binds factor B

and forms C3bB complex

C4b and C2b join to form

C3 convertase

C3bB complex
is cleaved by factor D

C3 convertase cleaves

complement protein C3 into

p-

into C3bBb

C3a =
anaphylatoxin

C3bBb behaves just like

C3 convertase

produces many molecules of

C3b which amplifies the

complement cascade

follows classic pathway from

response

t
C3b coats pathogen
and marks it for phagocytosis =

this point on

C3b also binds

C4b2a to form
C4b2a3b or
C5 convertase

opsonization

C5 convertase cleaves

complement protein C5 into

C5a .

anaphylatoxin

cause more inflammation

r by binding and activating

other inflammatory cells

can lead to

' anaphylaxis

C5b - binds C6 - C5bC6 binds C7 - C5b67 binds - C5b678 binds C9

to form C5bC6

to form C5b67

C8 to form

fomming the

C5b678

membrane attack complex

a pore fonnsin - pore allows water and ions

membrane of pathogen

into organism causing

ce11 1ysis

COAGULATION CASCADE

: ,' t''1jD' ,

series of enzymatic reactions

that occur within

secondary hemostasis (see map)

in order to form fibrin

occurs on surface

of activated platelets
and vascular endothelium

divided into 2

interconnected pathways

intrinsic pathway abnormalities

in response

injury "within" blood

to tissue injury

vessels:

"outside' blood vessels

damaged vessel endothelium

intrinsic

measured by

in response to

extrinsic

damaged platelets

pathway

activated partial

extrinsic pathway

pathway -

abnormalIties

measured by

thromboplastin time (aPTT)

prothrombin time (PT)

begins by the creation

of a complex on vascular
begins by the creation

subendothelium between:

of a complex between:
factor VIl

this complex

factor X11 (aka Hageman factor)

this complex

calcIum

high molecular weight kininogen (HMWK)

activates

tissue factor (TF)

prekallikrein

factor X11 to XIIa

thromboplastin

I0

activates
factor VIl to VIIa

factor VIIa activates:

factor XIIa activates:

prekallikrein to kallikrein

kallikrein converts:

factorXtoXa

factor XI to XIa

factor XIa activates

factor IX to IXa

1Xa becomes a

part of a new complex

HMWK to bradykinin

plasminogen to

common pathway abnormalities

measured by both PT and aPTT

induding

1Xa 7 this complex

plasmin

Xa initiates the

VIlIa activates
leads to:

2 vascular permeability
smooth muscle constriction

common pathway

by forming a complex

X 3 XtoXa

activates complement

between:

component C3 to C3a
Xa

(see complement cascade map)

vascular vasodiIation

this complex

Va

cleaves

calcium

prothrombin (factor 11)

into thrombin

phospholipid
plasmin initates fibrino1ysis

-1

as it degrades fibrin into

thrombin

fibrin split products

6bnnotysis can be /

i
main role of

thrombin is to convert

measured in lab as an o

fibrinogen (factor I) to fibrin

d-dimer tevel

amplifies
the coagulation cascade

by activating factors:
V
VIll
X1
xm

stjmulates

fibrin is cross-linked

platelet aggregation

by factor X1IIa

and granule secretion

(see hemostasis map)

1
pennanent clot is
formed as fibrin
combines with

platelet
aggregates

0
first exposure to
antigen:

antigen is delivered to
secondary 1ymphoid tissue

intracellular
turnor cell

activation phase

lack of costimulatory

antigen presenting cell(APC)

displays antigen to naive T cell via peptide: class I MHC complex

APC also provides T cell ,

with costimulatory signal (B7 molecule)

signal causes anergy =

T cell unable to respond to anItigenic

stimulation

binds CD28 receptor on T cell

T cell activation orpriming

activated T cell

heIps T cell

undergoes proliferation, di#erentiation and cIonal expansion - activatedTcell - develop secretes IL 2

into antign specific effecto

promotes further
donal expansion

efFector functions

CD4 helper T cell

effector phase

releases cytokines such as: CD4 T cell further

:

differentiates into

1FN TNF
gamma
alpha

.0

1 of 2 T-helper cell types

cytotoxic CD8 T ce11 - travels to site -

of infection 8
t3

1FN gamma

releases cytotoxins such as:

enhances activation of

perforin

these 2 pathways are not always

macrophages

granzymes

mutually exdusive

kill infected

target cell by

if secretes a Th2 cell cytokine

inducing

if secretes a Thl cell cytokine profile

apoptosis in 2 ways

profile

cytotoxins

Fas ligand

humoral immune response

( see map)

, activates macrophages

- cell mediated inflammatory response

tion of effector T cell

activates endothelium

population

1
amplifies inflammatory

enables inflammatory
response to progress

response

via 1FN gamma and CD40 ligand

n
rn

K
rn

o expression
of MHC class 11
molecules and 87

bystander

tissue damage

3>

macrophages phagocytize
..

costimulatory signals

J
o antigen
presentation to T cells

(see acute inflammation map)

bacteria or other offending agent

1
granuloma forms
if macrophages
are unable to eliminate

amplifies immune
response

0.

antigen

(see sarcoid and TB maps)

;Z-

first exposure to antigen

elicits a primary adaptive immune response

humoral immune response

i
2 types of antigen
seen by B cells -

during thjs response

cannot begin without B and T cell cooperation

majority of antigens

antigen is

seen by B cells

processed and

thymus independent 1 T naive T cells

presented by APC to

antigens = B cells don't thymus dependent

need T cell heIp to

activate

antigens = B cells do

need T cell heIp to activate / antigen is bound by surface

CD4 helper T cells

activated

cell-mediated
secretes Thl cell
secretes Th2 cell

inflammatory response

cytokine profile

(see map)

cytokine profile:
especially IL 4

/ 2 1gM onna ve B cell

antigen is delivered

to 1ymph node where

it is recognized by
both B and T cells

antigen is intemalized,

linked recognition =

processed and then - activation of B cell requires antigen recognition

presented on a

by both B and T cells

MHC dass 11 molecule CD40 1igand on T cells

enables isotype switching

to Th2 cell

T helper cells produce

binds CD40 receptor on

CD40 1igand -

B cell and induces

and heIps the germinal center

to survive

activation of the B cell

1
B cells form a primary focus

within the 1ymph node

for cIonal expansion

B cells travel

(immediate response)

to primary 1ymphoid follicle

t
form a germinal center where

antjgen specific B cel!s called centroblasts proliferate

somatic hypermutation = creates a set of B cells

with varying ability to bind the same antigen

j
B cells which have a lesser

occursatthesame

time as isotype switching

results in a small number of these

*St*.

ability to bind the antigen

B cells that have a greater ability to

die off within the germinal

bind the antigen = affinity maturation

different classes of antibodies

center = negative selection

g'%3

specific for the same antigen

B cells with the highest affinity for the antigen

are produced

Ah:-S

are selected and give rise to both

k*g
memory B cells

4
provides body with

ability to fight future exposure

plasma cells
allow for

2 main effector functions

secretes antibodies into serum

of B cells to be carried out

tIP

jC
K
0

against antigen

to same antigen =

. r- .

secondary adaptive immune response

enable
neutralize

pathogens =

phagocytosis via
2 ways:

binding and preventing

opsonization

pathogens from

complement

entering cells

activation (see map)

0
infection

insult elicits an immediate response (in seconds to minutes)

trauma

exposure to physical or chemical agents

, by body's immune system =

acute inflammation

tissue necrosis

foreign bodies
hypersensitivity reactions (see maps)
endothelial injury

3 main components
cellular reaction =
vascular reaction =

1eukocyte extravasation

delivers plasma proteins

and immune cells to site
of infammation

and activation

- begins with
activation of endothelium

1eukocyte margination

bradykinin from
2. 9 blood flow and viscosity

activation of the

1eukocyte rolling and pavementing

mediated primarily by

kinin system

histamine

nitric oxide
1. increased vascular

1eukocyte adhesion

permeability via:
endothelial contraction

' , direct injury '

vasodiIation

1eukocyte induced injury

angiogenesis-related leakage

1
3. 1eukocyte migration or diapedesis
through endothelium

chemical signals for chemotaxis provided by:

bacterial products

exudate contains complement proteins

which can become activated .

(see complement cascade map)

blood viscosity 0

anaphylotoxins (C5a)

as exudate escapes
into surrounding tissue

1eukotrienes

chemotaxis toward cytokines

site of injury or infection

elaborates the acute

blood stasis

infammatory response vIa:

allows 1eukocytes to

0 vascular permeability

1eukocyte adhesion, chemotaxis and activation

collect aIong vascular

endothelium
Sk-

phagocytosis via opsonization

3>

, leukocyte activation

rh

and phagocytosis

C
-4

elimination of offending agent

tissue injury
K

leads to 1 of 3 outcomes:
resolution

healing with fibrosis

E.
0
Z

progression to chronic Inflammation (see map)

CHRONIC INFLAMMATION

etiologies include:

ongoing infection

regardIess of etjology

acute inAammation

antigen is unable to

tissue damage from chronic disease

be cleared by immune

toxic exposure

system

autoimmunity

malignancy

1eads to a state of chronic inflammation

continuous activatjon of T cells

release of

1FN gamma

accumulation and activation of

rnacrophages

o inflammatory
. cell recruitment and

exacerbates inflammatory response -

adhesion

release of

TNF a -

release of

cytokines released 4

tissue wasAng

reactive oxygen specIes

o microbicidal

9 cytokine release

M9HeCus - eheng cell

funcdons

and reactIve nitrogen species

fibroblast proliferation

tissue damage

collagen production

fibrosis

alters structure
and function of
involved tissues

RENIN-ANGlOTENSIN-ALDOSTERONE SYSTEM
- ...,.-2.-*I:'A.:'...-.*.C. 42--.-

kidneys sense

8 in circulating

8 blood volume

' via 3 main

blood volume due to:

mechanisms

hypovolemia

8 total peripheral resistance (TPR)

congestive heart failure (CHF)

8 stretch of

8 stretch of

11 NaCI delivery

baroreceptors

renal baroreceptors

and reabsorption

in central arterial

in afferent arterioles

across m:cula densa

dculation 1

0 sympathetic outflow

causes 8

to beta receptors on

in calcium concentrabon

juxtagIomerularceIsCJGA)

leads to renin released

ATII

by JGA celIsinto .
circulation

suppresses renIn

release

renin is cleaved

kininogen

kallikrein -

by angiotensinogen
into angiotensin I
(inactive form)

bradykinin - ACE cleaves-

AT I tIavels to lungs

1/ bradykInin

where it is cleaved by ACE

bradykinIn:

into AT 11 (active form)

vasodiIates

decreases platelet

peptides

aggregation

AT I receptor located in:

ATII receptors located in:
vascular endothelium

vasculature

kidney
adrenals

hypedrophy of myocytes

worsens

0 matrix formation

heart failure

fibrosis

(see map)

fibrosis

worsens chronic

inflammation

kidney disease

hypertrophy

(see map)

brain
hean

adrenal glands

brain 1

opposite affect of AT I

1ongterm physiologic actions 1ead to structural changes

and disease

o bradykinin

thrombosis

worsening hypertension

nitric oxide

hypertrophy ,

and vascular disease

cydiC GMP

vasoconstfiction

(see maps)

2 in:

intimal thickening
stimulation of the AT I receptor

hypertrophy of smooth musde cells

causes multiple

other

short-term physiologIc '

effects

actions which fl

- the circulating volume

acts ort
hypothalamus
to stimulate thirst

and ADH release

o in

4/
u plasminogen activator inhibitor-1 smooth musde

actson

enhances

constriction

release of catecholamines

Of adrenal cortex

in systemic

from adrenal medulla

to release

vasculature

(PAl-I)

zona glomerulosa

aIdosterone

inhibits:

causes constnctIon of

total body efferent

arterioles
free
water
more than afferent arterjoles

0 sodium
reabsorption

TPA
UPA

protein C

to 2 perfusion pressure

o risk of
o water and

reabsorption

0 adrenergic
tone

vascular
resistance

0 myocardial

at distal tubules

9 11uid

o peripheral

sodium
reabsorption

atheroscIerosis

blood clots

9 afterload
on heart

contractility

i
Unsk of
ahythmias

0
normal hemostasis =
balance between

anti- and pro-thrombotic

functions

anti-thrombotic functions

pro-thrombotic functions -+ occur In response to

injured vascular
endothelium

the preferred state under

normal conditions

synthesizes

local neurohumoral factors

allows for 1Iquid blood flow via

tissL e factor

cause transient arterial

3 major mechanisms

vasoconstriction

1. anti-platelet functions

2. anti-coagulant functions

3. fibrino1ytic

thrombogenic substances of

functions

the subendothelial extra cellular matrix

t
normal endothelium
f tissue factor

does not allow

pathway inhibitor

inactivated platelets
to adhere

synthesizes tissue type

plasminogen activator (t-PA)
which heIps to clear fibrin deposits

from the endothelium by activating

thrombomodulin binds

exposed to blood flow

plasminogen to plasmin

U>

platelets adhere via vWF to injured

endothelium and become
activated

and converts thrombin into

endothelium synthesis of

an anticoagulant

nitric oxide and prostacyclin (PG12)

causes:

vasodiIation

endothelium membrane

associated heparin-like

secrete granuIes containing

molecules augment

ADR thromboxane A2

antithrombin 111

inhibition of platelet aggregation

j
activation of protein C

inactivate

(see coagulation

coagulation factors:

cascade map)

Xa, 1Xa, XIa, XIIa

thrombin

coagulation
, cascade

(see map) 7

which lead to:

1 1

cascade ultimately

recruitment of

formation of a

more platelets and

hemostatic

platelet

PlUg

aggregation

activates thrombin

thrombin converts fbrinogen into fibrin

14%*

expression of adenosine
diphosphatase which degrades ADP
and prevents platelet aggregation

primary hemostasis

inhibits coagulatjon cascade

factors

VIlIa -

local fibrin deposition occurs

Va

at the site of vascular injury

allows for

o fbrino1ysis

E I

thrombin also
recruits more

8 thrombin formation

platelets and 1eads to further

rn

fibrin and platelet aggregates

combine to form

a permanent plug

granule release
prevents further
hemorrhage

/0

Cardiovascular Disorders

0
cardiac insult
MI
HTN

virus
toxin

compromises

heart cannot fill or eject

. cardiac

blood properly

output

leads to compensatory
mechanisms

sustained

adrenergic
functional response

drve can

exacerbate

proliferative
signals

Frank Starling

activates

mechanism

neurohumoral

initiates

proliferative response s

' induding:
TNF-a

mechanisms

endothelin

0 preload
9 norepinephrne

activates

RAAS
stretches ,
heart chambers

(see map)

0 end

heart rate

BNP= brain natriuretic peptide

vasopressin

0 power of

(ADH)

myocardial

compensatory
mechanisms

remodeling

more 3roliferative

and hypertrophy

signaIng

(with or without

t
augments
contractile

, initially normalizes
wall stress

force of myocardium

contraction

i
leads to

myocardial

chamber diIatation)

e contractility and
release of

ANP= atrial natriuretic peptide

AT1 receptors and

TGF- receptors

diastolic
volume

releases

angiotensin 11
1 stimulates

vicious cycle -

maintains
cardiac

output

induding:
o naturesis
vasodiIation

suppresssion of renin-angiotensin-aIdosterone system

suppression of sympathetic nervous system

maintains arterial

pressure by o
vasoconstriction and

fluid retention

1
maintains

perfusion of vital

occurs over weeks

but eventually

to months and

shortens myocyte

becomes the

survival

causes an 9
, in overoad on

surviving myocytes

longterm

4%,

adaptation

%,=,

orgaT
occurs over

r secondsto minutes
= short4erm

adaptation

0
Z

asymptomatic ' heart failure

Cl

signs

eventually
both forms of

and symptoms of

adaptation

heart failure occur

ultimately

(see heart failure maps)

-1

<
rn

fail

I
rn

3>

symptoms:

signs

dyspnea

pulmonary rales

orthopnea

pleural effusions

paroxysmal noctumal dyspnea

ascites

fatigue

hepatomegaly

!Fr
C

jaundice
cardiac cachexia

r rri

: jA4..s , RIGHT-SIDED HEART FAlLURE

e
2 major types of heart failure

1eft-sided
heart failure '

, rightsided
heart failure

(see map)

0 afterload
placed on right
ventricle

causes:

1eft-sided heart failure (most common)

' right-sided MI
cor pulmonale (see map)

right-sided
ventricular strain

heart attempts to maintain

systolic function by
e preload in right ventricle

0 right ventricular
this compensation

: output due to -

fails if myocardium

8 venous return
to left side of heart

decompensation

becomes weakened

can shift

, interventricular

o blood volume in

pressure builds up in

septum

right ventricle causes hypertrophy

right ventride and travels

to the left

back to right atrium

4 preload on
1eft ventride

right ventricular

hypertrophy develops J
leads to congestion
of systemic vasculature

distorts valvular
architecture

. portal system is
especially affected
right ventricular

8 1eft-sided

heave

cardiacoutput

9 jugular venous distention (JVD)

tricuspid valve insufficiency

peripheral edema

pulmonary valve insufficiency

(see valvular regurgitation map)

hepatospIenomegaly
hepatojugular rellex
asciles

jaundice
nausea
anorexia

chest x-ray
6 retrostemal

airspace (on lateral view)

elevated 1iver enzymes:

AST
ALT
LDH
bilirubin

ECG

right axis deviation

deep S wave in lead V6

large R wave in lead V1

peaked P wave

fatigue
anorexia

shortness of breath

4SBM

LEFT-SIDED HEART FAlLURE

-

2 major types )f heart failure

right-sided
1eft-sided .

. heart failure

heart failure

(see map)

hemodynamic
dysfunction can
occur as either or

both
diastolic - most common cause

common causes

MI

hypertension

systolic

dysfunction hypertension

dysfunction

virus / toxin
hear cannot

heart cannot

relax because it is

contract properly

less compliant

due to either or

both

stiff ventricle

impairs

9 afterload

. causes S4

ability of ventricIc

8 contractility

heart sound

to accommodate

o pressure

stress from -

of dastole

fil ing
8 stroke

attheend -

pressure
oveMoad

concentric

hypertrophy

. 8 cardiac output

volume

combInes

wIth incomIng

0 end systolic volume -+ blood from

next diastolic

o end diastolic volume

--- volume - oveMoad

distorbon of

compensatory

left atrial -

mechanisms

filling

/ enIargement

temporarily

interferes with

action potentials

maintain cardiac output

untiI decompensation

myocyte architecture -

- pressure from

occurs (see CHF map)

0 riskof atrial
fibrillation and
dotformation

o riskof stroke

1eft ventricle

(see map)

travels
back to left atrium

o preload stretches
to pulmonary

myocytes

veins and capillaries

1eft ventricular

remodeling characterized

9 pulmonary

capillary hydrostatic

by new sarcomeres

9 venous

laid down in senes

with old sarcomeres

pressure

eccentric

fluid extravasates

hypertrophy

into interstitial space

of lung parenchyma

heart can become

diIated = diIated cardiomyopathy

pulmonary
edema

, 9 work of breathing

9 risk of mitral

regurgitation
(see map)

chest x-ray shows:

KerIey B lines

orthopnea

pressure relative to - return when -+ paroxysmal noctumal dyspnea

patient is supine nocturia
plasma oncotic

peribronchial cuffing
fluid in fissures

pleural effusion

rales

dyspnea
on exertion

33,4 1 . VALVULAR STENO.SlS

' 1.....Al.dNal'...' ..-. -.....-

0
2 major types of
valvular heart disease

valvular regurgitation

(see map)

maJor causes

SLE (see map)

calcification
rheumatjc heart disease

1
major causes:

valvular

congenital

. mitral stenosis

stenosis

calcific

rheumatic heart disease /

creates low

narrow valve

obstructs , pitch diastolic

outflow

rumble and

from LA

opening snap

aortic stenosis

outflow from
the left ventricle

atrial

O blood volume

into aorta is

in LA -

LA dilates - arrhythmias -+

1 1

obstructed

palpitations

blood . predispose to

pressure travels

4 cardiac
output

as blood is pushed

- through smaller
valve opening

g blood volume collects

thrombus
formation

backward

in left ventride(LV)
embolization

at end of systole

to CNS

into pulmonary
veins and capillaries

8 cerebral

perfusion

stasis

neuro symptoms =
stroke

creates turbulent

9 afte11oad

pulmonary -

blood flow

congestion and HTN

heart failure

midsystolic

syncope

right-sided

dyspnea on exertion

combines with

mumnur Is

filling from

crescendo

next round of

decrescendo

diastole into LV

orthopnea

paroxysmal noctumal dyspnea

hemoptysis

pulsus
parvus

et tardus

pressure works

o LVend - back into pulmonary diastolic pressure

concentric

displaced ,

- dyspnea

, 5 compliance

hypertrophy

PMI

pulmonary
edema

capillaries

of LV
\ congestive
heart
faiture

oxygen supply

o oxygen

is reduced because

demands

hypertrophy
compresses
blood vessels

LA systole

(see map)

now responsible

for filling
the LV

- ischemia produces S4 heart sound

as it contracts

angina

into noncompliant LV

(see map)

2 majortypes
of valvular heart
disease

valvular

valvular

regurgitation

stenosis

(aka insufficiency)

(see map)

major causes include:

aortic regurgitation - ' rheumatic heart disease

mitral regurgitation

endocarditis

Marfans syndrome
blood flows back syphilis
causes o

- from aorta into left ventricle (LV)

in aortIc pressure

blood flows back

during systole

holosystolic high pitched

from LV into LA

classically presents with

. 1'blowing"

murmur

during systole

early high pitch "blowing"

diastolic murmur

wide pulse

9 LV end systolic volume

regurgitated blood

combines with blood

combines with

pressure

from 1eft atrium (LA) during - 3 murmurs -Austin Flint murmur =

venous return

nexti diastole middiastolic rumble

0 blood

mid-systolic flow

9 stroke

9 LV end diastolic volume

volume

MI (see map)

how quickly this

how quickly this

occurs determines

occurs determines

clinical prsentation
if acute onset =
no tIme for heart

to adapt
symptoms develop immediately
as LV volume and

pressure travel
backward to LA

to pulmonary

veins and capillaries

causes pulmonary

mitral valve prolapse

rheumatic heart disease

clinical presentation

\ if chronic onset:

if chronic onset =

ruptured chordae -

to adapt

i
eccentric

hypertrophy -

volume overload

maor cause ls

time for heart

if acute onset

sudden volume

cardiacoutput

load cannot be

untiI compensation

accommodated

neurologic

atrial -+

blood stasis . symptoms include

can lead to

fibrillation

and palpitations

clot formation

displaces

point of

1eftsided

largerblood

maximal impulse

heart failure

volume

walls are not diIated

stroke

but q

accommodates

forces even more

ischemic

(see map)

by LV because

, volume load returned to LV duMng next

S3 =

rapid filling
of LV

atrial contraction

blood volume back

into the LA
CHF

less pressure

(see map)

works its way

9 pressure

dyspnea

valve dysfunction
can lead to

muscle

maintains

, exacerbates

on LA diIatation

tendineae or papillary

(PM1)
edema

major causes include:

volume in LA

murmur

<

LV diIates

back to lungs

travels back into

C

pulmonary capillaries

0 forward

less pulmonary

cardiac output

symptom early on

"flash"

pulmonary edema

eccentric

hypedrophy

untiI decompensation
occurs

fatigue

eventual

weakness

pulmonary HTN
dyspnea
0dhopnea

paroxysmal nocturnal dyspnea

P::
r'

4cn

iC

systolic

dysfunction

right-sided

heart failure - CHF

(seemap)

E-1
0
Z

-....-

MYOCARDIAL 1SCHEMIA AND INFARCTION I

0
most commonly
caused by

atheroscIerosis (see map)

when 02

myocardial

supply cannot

' ischemia

meet 02 demands

stable angina or angina wilh exercise = (-75% occlusion)

incomplete occlusion
plaque occludes

causes

coronary artenes

transient ischemia

or

unstable angina or angina at rest = (-90% 0cdusion)

8 oxygen supply

0 02

. can be caused by-

delivery to

either

due to:
anemia

myocardium

hypotension
vasospasm

if 02 is not

. cell injury

restored

9 0xygen demand

if plaque ruptures

due to:

thyrotoxicosis
1eft ventricular hypertrophy
compromises

myocardIal
function

thrombus

forms over plaque

ischemia contInues

coronary

vasoconstriction >

-30 min

1 1

myocardial

total occlusion

ofartery '

dnfe MI with or
without

right ventric]e infarct

, complications of MI

infarction

leads to signs
- RCA - clinical presentation

myoc*e

depends on necrosIs

AV node conduction
abnormalities

and-

symptoms of MI

chest/arm4aw pain
diaphoresis

pallor

location of

tachycardia/bradycardia

occlusion

hypotension

causes:

nausea

releases

reflected in

vomiting

gardiaterizymes:

ECG via:

anxiety

ST changes

dyspnea

anterior / septal MI

CK-MB T wave changes

Q waves

ventricular 3neurysm
CHF (see map)
cardiogenic shock
cardiac rupture

circumfIex artery

if lefl main artery ,s

pericarditis (DressIer's syndrome)

involved:

AV node dysfunction

sudden death
LV failure

tamponade

causes:

arrhythmias

lateral M1

ventricular tachycardia

AV node conduction abnonnalities

ventricular fibrillation

LV dysfunction

mitral regurgitation (see map)

ATHEROSCLER05lS

0
risk factors for ATH:
cholesterol

smoking

HTN

e tendency

, toward arterial
endothelial injury

DM

positive family history

injury leads to
chronic inflammation

endothelial

dysfunction 0 permeability

0 1eukocyte
adhesion

allows oxidized LDL

to be deposited
into vessel wall

monocytes enter in'ima

9platelet

of vessel wall

adherence leading to
microthrombi

oxidized LDL

stimulates

inflammatory cytokine

, release factors

release and

that attract smooth

8 nitric oxide

muscle cells into the

monocytes

subendothelium

turn into macrophages

macrophages ingest oxidized

smooth muscle cells

' LDL via scavenger

deposit and proliferate within

receptors

extracellular matnx

i
macrophages tum into
foam cells

. L comis a

fatty streak

apoptosis of macrophages
andother

mononuclear phagocytes
contributes
lo necrotic core

atheroma can develop

with thrombogenic 1ipid core

can evolve into

fibrous plaque or
fibroatheroma

thrombotic
emboli

platelets release:
thromboxane A2 - vasoconstriction --,
serotonin

others

thrombosis
forms

calcification and

, contributes to - narrows vessel size of plaque

lumen further

1
ischemia

inflammation make

if occurs transiently
can lead to transient symptoms =
unstable angina
if evolves into
fixed occlusion can lead

to constant and progressive symptoms =

stable angina

plaque prone to
rupture

renal artery stenosis =

chronic renal failure (see map)

unstable

clinical manifestations ,

plaque

specific to location

ruptures

aneurysm

of stenosis \
cholesterol
emboli

peripheral vasculature =
daudication and

peripheral vascular disease

central nervous system =
ischemic stroke (see map)
coronary arteries =
myocardial ischemia
myocardial infarction
(see map)

',1 fS}3131t COR PULMONALE

respiratory system
abnormality:

COPD (most common)

alveolar vasoconstrIctIon

respiratory acidosis
emphysema

pulmonary embolism
interstitial lung disease
polycythemia vera

primary pulmonary HTN

9 pulmonary arterial
pressure = pulmonary
hypertension

1
pressure works its way back
into the right ventricle

0 systolic pressure

o afterload into the

right ventricle

, in right ventricle causes ,

right ventricle fails-

ventricular hypertrophy

and diIatatIon

pressure travels

right ventricular

myocardium cannot
adjust to afterload

back to right atrum

interventricular septum

8 right ventricula

heave 1sdispl1eft
acedventri
int de output i

increases

leads to congestion - jugular venous distention (JVD)

of systemic vasculature

hypertrophy

distorts valvular

8 blood

architecture

delivered to the left ventricle

tricuspid insufficiency

peripheral edema

affects

fatigue

portal system

anorexia

8 LVvolume

pulmonary insufficiency

shortness of breath

leads to

8 cardiac output

rate of onset determines

acute or chronic

clinical presentation

hepatospIenomegaly

hepatojugular rellex

most common causes are

ascIles

pulmonary embolism and ARDS

jaundice
nausea

acute

chronic

anorexia

- CXR:
\ enlarged pulmonary arteries

RV hypertrophy
echocardiogram
shows RV pressure overoad
9 thickness of RV

septal bulge into LV

EKG abnormalities
RVH
RV strain

right axis deviadon

Pulmonary Disorders
6, .. -:f6sL

1'j4*240*19

4
CHRONIC 0BSTRUCTIVE PULMONARY DISEASE
..,.

.-.'

U.'.....r.v-*+114.

risk factors:

smoking (most common)

passive smokIng
occupational exposures

respIratory Infections
air pollution
genetics (ex. a 1 anti-trypsin deficiency)

, leads to a chronic
inflammatory response

\
recruitment

activation

and actjvation

of lung

of macrophages

epithelial

in the lungs

cells

macrophages 1 1
small aitway

accumulate

inflammation III

release:

in lung parenchyma

neutrophil chemotactic factors

IL 8

.LT84

irritants

proteases

. proteinase / antiproteinase

and release

imbalance leads to

Proteases

u proteinase

columnar

hypertrophy

8 ciliary

func8on

*2wd
leading to

activity

mucus

with squamous

breaks down

long lifespan
to release proteases and exacerbates
1ong-term tissue damage

accumulation

metaplasia

connective

of macrophages enables them

infiltrate

cell hyperplasia
epIthelium - - 0 mucus production 1

muscle cell

neutrophils arrive

inflammatory

pseudostratified

smooth

become

for released

goblet

ciliated

TNF-u
reservoIrs

-chronic

destruction of

tissue
narrowed

(especially elastin)

airways

become

in combination with impaired repair

obstructed

mechanisms leads to

irreversible

destruction of lung parenchyma

chronic

productive
fibrosis

cough with

luminal

sputum occurs

narrowing

for 3 months during

1 year for at 1east 2 years

i
chronic bronchitis

destruction of
airspace

alveolar walls
and loss of a]veolar

tethering

enlargement =

8 airflow

emphysema

characterized by:
4 FEV1
4 FVC
o FEV1/FVC

8 surface area

for gas exchange

progressive

abnormal

loss of elastic recoil

irreversible or

causes premature

partially

expiratory collapse

irreversible

function

of airways

airflow

tests renect

WQ mismatch =

-dyspnea - pulmonary

limitation

perfusion without
ventilation

leads to air trapping

o air trapping

chest

and hypernflation

characterized by:
o residual volume

of lungs

hypoxia

barrel

o totallung capacity

right-sided

stimulates erythropoletin

C02 retention

heart failure

release from kidneys

causes respiratory

(see CHF map)

acidosis with

compensatory
polycythemia

metabolic alkalosis

(see maps)

chronic

obstructive

pulmonary
disease

2:14-dst:,', s ',3.''33%{B3*4**42,*;<ASTH

0
potential triggers: upon 1st exposure:
exerdse -

air pollution
viral infection
aspIrIn

allergen attaches to --*

APC travels

to 1ymph node

antigen presenting cell

(mainly dendritic cell)

presents

antigen to both -

B cells

B cells activation occurs via:

CD4 T cells

IL4 and IL-13

bybinding to T cell
T cells differentiate

leads to synthesis

down the Th2 pathway (see map)

of lgE

2nd exposure

Th2 cytokines

IL-5 recruits

lgE enters circulation

released

eosinophils

and binds mast cells - to same 7

in lung mucosa/submucosa allergen occurs

from bone marrow

allergen binds

1gE on mast cell

eosinophils

travel to lungs

lgE cross-links and

eosinophils secrete:

activates mast cell

maJor basIc proteIn

proteolytic enzymes
1ipid mediators

release of preformed

oxygen metabolites
other 1eukocytes contribute

e airway permeability

mediators

more cytokines

histamine

allows more antigen

including:

1eukolrienes

neutrophils

more cytokines including IL-5

1-

monocytes
1ymphocytes
basophils

into lung parenchyma

late phase response =

4 to 6 hours after early ,
response

acute early phase response

- response

can

lead to

vagal receptors

starts within minutes

i
contributes
characterized

characterized by

by:

airway inflammation

i
stimulates

acute early

to bronchoconstriction

bronchoconstriction

o bronchial hyperresponsiveness

edema
, mucus secretIon

lead to

- reversible

airway obstruction
clinical manifestations

repeated attacks lead

of asthma

to chronic asthma

i
hypoxemIa
wheeze

lung function tests

cough

show:

chest tightness

8 FEV1

dyspnea

8 FEV1/FVC

V/Q mismatching -+ leading to

hyperventiIation

due to

g residual

volume = air trapping

paradoxus

airway remodeling =
thickening of small and
large airways

respiratory alkalosis

due to:

(see map)

goblet cell hyperplasia/hypertrophy

i
but continued

respiratory distress
leads to alveolar

pulsus

characterized by

hypoventiIation and

respiratory acidosis
(see map)

}
aka status asthmaticus

collagen deposition and subepithelial fibrosis

smooth muscle hyperplasia/hypertrophy
o vascularity

1
causes nonreversible

airway obstruction

DEE P VE I N TH ROMBOSIS AND PU LMONARY EMBOLIsM 3Eh

local trauma

hypercoagulability

venous

to vessel stasis
\ Virchow's k-triad

contributes to the

development
of a thrombus

i
thrombus begins
in areas of flow
turbulence
A

platelets

release mediators

aggregate

serotonin

- thromboxane A2
initiates coagulation
cascade (see map)

formation of thrombus =
blood clot still attached -

from here thrombus

can do 1 of 3 things:

to wall of vessel

most commonly in
deep veins of legs:
iliac veins

resolveor

keep

embolize or - enters vena - into right side of

partially resolve

extending

break off

femoral veins

cava

into circulation

popliteal veins

once embolus enters pulmonary

artery = pulmonary embolism (PE)

extremity is:

hean

red

PE becomes trapped

swollen

within pulmonary vascular tree

warm

1
embolus reduces or completely blocks - sudden death

blood flow to a portion of the lung

changes in blood . 9 pulmonary ,

hypoperfusion 4

arterial pressure

- flow and ventiIation

0 pulmonary vascular resistance

surfactant production

by becoming

by alveolar type 2 cells

overperfused while

embolism blocks blood flow

pulmonary
infarction

8 perfusion while

continues nomIally=
alveolar collapse =

9 right
ventricular pressures

to affected area causing

ventiIation

pressures work back

into pulmonary capillaries

healthy lung compensates

decreased

can occur

ventiIation continues normally =

low V/Q ratio

hemoptysis

high V/Q ratio

atelectasis

pleural rub
pleuritic chest pain
Hampton's hump on CXR

but overperfused lung

pulmonary edema

segments cannot

this creates

adequately oxygenate

alveolar dead space

all this blood

acute

creates venous admixture

9 areas

of low V/Q

blood travels from the

hypoxia

(see map) '

hypercarbia

right to left side of heart without

being adequately oxygenated

right ventricular

cor pulmonale

causing right to left shunt as

V/Q mismatch

RV pressures increase

severe hypercarbia
can progress lo

w e A-a gradient

respiratory acidosis

strain

as compensatory mechanisms

fail leading to right-sided

diIatation

EKG shows
S wave in lead I
Q wave in lead lII
inverted T wave in
lead 111

(see map)

hypoxemia =
Impaired gas exchange
8 cardiac outpul
chemoreceptors detect hypoxia
and hypercarbia

tachycardia

2 minute volume or tachypnea

acute murmur of tricuspid regurgitation

results as a compensatory mechanism

right-sided heart failure

1
respiratory alkalosis
(see map)

hypoxia

ACUTE RESPIRATORY DISTRESS]5YNDROME

0
insult

to lung occurs as
either

ill

direct injury:

indirect injury:

pneumonia (see map) sepsis (see map)

aspiration

multiple blood transfusions

lung trauma hypovolemic shock

smoke inhalation

reperfusion injury

near drowning acute pancreatitis (see map)

note: these are non-cardiogenic causes

which can be identified by nonnal pulmonary capillary wedge pressure

1
leads to diffuse alveolar damage
consisting of a 3-phase response

initjates vicious cyde

release proinflammatory
mediators and exacerbates

lung injury

accumulation of

1st phase = exudative phase

. neutrophils in lung

which includes injury to both

parenchyma

epithelium and endothelium

signs and symptoms:

inspiratory crackles

bronchial and

tachypnea

epithelial cells

tachycardia

sIough off causing

dyspnea

e permeability ,

protein Mch
fluid foods both

chest x-ray shows bilateral pulmonary

alveoli and interstitium

infiltrates which are indistinguishable from

= pulmonary edema

cardiogenic pulmonary edema

inactivates

surfactant leading
to atelectasis

development of

death usually associated

hyaline membranes

with concomitant

/multiple organ dysfunction syndrome

1 of 2 dinical
abnormal

(see sepsis map)

outcomes at this

leads to:

blood gases and - intrapulmonary shunting

8 Pa02/F102 ratio dead space ventiIation
loss of lung compliance

provides structural

point of ARDS

framework for future fibrosis to

process

continue on to 3rd phase =

develop

resolution phase occurs

V/Q mismatch

as hypoxia resolves

i
refractory hypoxemia

11
initially respiratory alkalosis
occurs (see map)

acute respiratory distress syndrome (ARDS)

longterm sequelae:

defined by

microfibrosis

impaired oxygenation

residual pulmonary function

abnormalities including
low diffusing capacity

bilateral pulmonary infiltrates

normal pulmonary wedge pressure

impaired oxygen exchange

non-cardiogenic eljology

restnctive or obstructive disease

continued injury

e dead space ventiIation

2 work of breathing
hypercarbia

10 1ung parenchyma
1 of 3 clinical outcomes

ifinJury Is severe

at this point of ARDS - enough progress to

process

2nd phase =-

fibroproliferative phase

then respiratory

e map) all ARDS deaths

can lead to respiratory failure

despite supplemental oxygen

persistent hypoxemia
0 dead space

9 lossoflung compliance
pulmonary hypertension

acidosis forms

characterized by:

death =

resolution

33 10 50% of

(see 3rd phase)

development of pulmonary fibrosis

occur during this

chest x-ray shows

phase

evolving fibrosis

\
cor pulmonale or
right-sided heart
failure can result

(see maps)

-./4ORe

PNEUMONIA

. .1.f*'4:2&3:

bacteria, virus, fungi

can cause infection of the lung

2 major categories based on

where infection is acquired

community acquired

nosocomial pneumonia =

pneumonia =

pneumonia acquired in a hospital or

pneumonia in a patent

institutional setting

living in the community

microorganism must overcome multiple pulmonary defense mechanisms

within immune competent host to establish infection within lungs
induding:
mucociliary transport
cough refIex
lower airway immune cells and components such as alveolar macrophages, neutrophils, complement, and antibodies

microorganism is able to
replicate and overwhelm host
defenses = pneumonia

intra-alveolar exudates

develop

causes signs and symptoms of:

pleurisy
inflammation develops and
spreads around the

chest pain
, effusions

alveoli into pleura and

empyema

interstjtium

fever/chills

cough
hemoptysis

on physical exam:

chest x-ray displays

1obar or interstitial pattems depending ,

consolidatIon

crackles
wheeze

upon infecting agent

pleural rub

impaired oxygenation
leads to shoMness

of breath and o
respiratory rate
V/Q mismatch

and intrapulmonary shunting

complications can include:

abscess

empyema

acute respiratory distress syndrome (see map)

Genetic Disorders

0
causes single

mutation

changes glutamine

of chromosome11 - basepair - intoa valine residue

substitution on the surface of hemogIobin (Hb)

beta globin

ofthymine

gene

for adenine
defective Hb behavior =

hemogIobinopathy
precipitating factors

if Hb SS

if Hb SA

(homozygous)

(heterozygous)

infection

dehydration

= sickle cell anemia = sickle cell trait

temperature changes-

acidosis

\ deoxygenation

asymptomatic

cause HbS molecules

carriers

to aggregate and
polymerize

molecules form needle-shape

fibers inside RBC =

sickle shape

initially sickling is

but repeated sickling becomes irreversible

reversible with - and causes membrane damage

inflexible and fragile

r RDC membrane forms

oxygenation
intravascular

RBCs are trapped

hemolysis

in spleen sinusoids =

congested =

spIenic sequestration

spIenomegaly

microvascular

"sticky" due to

phagocytosis

occlusions

o adhesion

of sickle RBCs

molecules

spleen becomes

eventually

occlude and infarct

hemolytic ane mia ,

scarring shrinks

sickle cells - spleen =

autospIenectomy

spIenic tissue

causes

more hypoxia

obili =

hyperbilirubinemia

8 immune

function of spleen leads

hypoxia encourages

vicIous cycle

more sickling

of hypoxia and sickling

to O susceptibility

cholelithiasis with

to encapsulated organisms

pigmented stones

S. pneumoniae

(see map)

H influenza

can lead to
bone marrow

vaso-occlusive crisis
expansion =

(aka painful crisis)

can turn into

0 RBC

sepsis or meningitis (see map)=

production

leads to infarction

most common

in wide variety of tissues

producing clinical manifestations

2 reticulocyte

o need for

count

folate decreases

marrow

brain: stroke

expansIon:

kidney: hyposthenuria, renal papillary necrosis

lung: cor pulmonale and acute chest syndrome

megaloblastic

retina: hemorrhage, neovascularization, detachment

anemia=

o MCV

sickle cell patients

.n

serum 1evels

bone: infarction, pain, aseptic necrosis, salmonelIa osteomyelitis

cause of death among pediatric

handfoot syndrome
prominent cheekbones
crew-cut skull

0
multiple autosomal recessive

genetic mutations possible

but most common type is deIta F508

disrupts production

of cystic fibrosis transmembrane

conductance regulator (CFTR) protein
normally found on epithelial cells
throughout body

2 main abnormalities result

dysregulation of

absent cAMP regulated chloride

other ion channels

channel

delayed puberty secondary

, genitourinary - both - to chronic lung disease and

resulting signs and symptoms are organ specific

maInutrition
airways

0 sodium absorption
and

males

females

obstruction in utero

infertiltiy due to:

of Wo1ffian derivatives

sweat glands

5 chloride secretion

congenital absence
causes 8 sodium

8 periciliary

and water content of mucus

1iquid

gastrointestinal tract

and adheres to ainvay '

surface

mucus can become

panc. -intestines

8 sodium, bicarbonate

8 chloride, bicarbonate

and water secretion causes

and water causes desiccation of

retention of pancreatic enzymes

intraIuminal contents

of vas deferens leads

reabsorb NaCI

to azoospermia and

from sweat

infertility

makes conception difficult

fallopian and uterine wall abnormalities

hypertonic sweat

positive sweat chloride test

8 biliary
secretions

leads to:

shows chloride concentration > 70 meq/L

"saIty baby"
hypotonic dehydration

S. aureus

R aeruginosa

leads to:

destruction of pancreatic a

intestinal obstruction

cells followed by p cells

meconium ileus

rectal prolapse

chronic infections and obstructions

destroy lung parenchyma

glands are unable to

hepatobiliary

infected with:

Burkholderia cepacia

abnormal menstrual cycle

thick cervical mucus which

leads to

chronic cholecystitis

chronic hypochloremic, hyponatremic

metabolic alkalosis in infants (see map)

cholelithiasis

biliary cirrhosis

leads to pancreatic insufficiency:

malabsorption / maInutrition

diabetes mellitus
leads to:

chronic hypoxia evidenced by digital clubbing

vitamin deficiencies (especially fat soluble vitamins)

greasy, foul smelling stools

bronchiectasis

pulmonary hypertension
0,i

pneumothorax

cor pulmonale (see map)

average life expectancy is

respiratory failure (most common cause of death in CF patients)

40 years of age

2 possible abnormalities
related to uric acid

metabolism thought to lead

degradation of purinc:

to gout

hypoxanthine -- purine
nucIeosides

xanthine ,

punne
nucIeotides

unc acid

causes include:

malignancy -

chronic renal insufficiency

overproduction

underexcretion

of uric acid

of uric acid

LeschNyhan

monosodium urate

supersaturaton

hyperuricemia = - of urate in > 6.8 mg/dL

crystallizes ,

extracellular

microtophi

and soft tissues

spaces

asymptomatic

asymptomatic

out within joints

Mauma

negative

hyperuncemia - low temperature

birefringent

alcohol

crystals

overeating

fasting
acute flare
occurs when

crystals are

phagocytized

causes release

IL-1

of inflammatory .

IL-6

mediators

pain
fever

'

leukocytosIs

IL-8

activates mast cells

and endothelium

flare eventually
resolves

by itself
synovitis
podagra

mono or oligoarthritis

but if uric acid

1evel remains

high then deposition

of crystals continues =
intercritical segments

followed by
more acute flares

if untreated crystals impair

uncontrolled hyperuricemia

renal function

renal tubular

goUty
nephropathy

nephropathy

\ nephrolithiasis

leads to advanced (chronic) gout

(see map)
chronic arthritis

interosseous tophi
and

joint space narrowing

--

----------T'.,----*------1----.

Hemostasis Disorders

in response to
injury "within" blood
vessels:

damaged vessel endothelium

damaged platelets

intrinsic

pathway

begins by the creation

of a complex on vascular
subendothelium between:

factor X11 (aka Hageman factor)

this complex

high molecular weight kininogen (HMWK)

activates

prekallikrein

factor X11 to XIIa

factor XIIa activates:

factor X1 to XIa

; deficiency of :

factor XIa activates

, factorIX =

factor IX to IXa

hemophilia B
1Xa becomes a

par't of a new complex

induding:

1Xa

x-linked recessive

deficiency of factor VIll

VIlla
X

hemophilia A

this complex
activates XtoXa

Xa initiates the

common pathway
by forming a complex
between:

Xa

both forms are clinically indistinguishable

variations in degree of

Va

deficiency determines

calcium

dinical severity

phospholipid

this complex
cleaves

prothrombin into thrombin

thrombin -

amplifies

the coagulation

intrinsic pathway

of coagulation is affected

maIn role ls

cascade by

to convet

activating factors:

fibrinogen to
fibrin

V
vIll
X1
X111

both hemophilias share common labs:

9 aPTT

fIbrin is cross-linked

normal PT (measures the extrinsic pathway)

by factor X1IIa

normal bleeding time

stimulates

normal platelet count

platelet aggregation
and granule secretion

inability to clot effectively produces

must do factor-

specific assay to

distinguish Hemophilia A from

Hemophilia B

clinical symptoms:

bruising

bleeding into soft tissues and muscIes

hemarthrosis

massive bleeding with trauma or surgery

no petechiae

(see hemostasis map)

permanent dot is
formed as fibrin
combines with

platelet
aggregates

DISSEMINATED INTRAVASCULAR COAGULATION

etiologies are disorders associated with

proinflammatory cytokines

inflammatory activalion:

trigger release

huma , of tissue factor and

sepsis (see map)

other thrombogenic

pancreatitis (see map)

substances

obstetrical complications
malignancy .myeloid and
1ymphoid 1eukemia maps)
transfusion reactions

transplant rejection

activates primarily
extrinsic coagulation
cascade (see coagulation cascade map)

antithrombin 1evels

are 4 by
consumption by continuously
activated coagulation cascade
degraded by activated
neutrophils

impaired synthesis by liver

extravascular leakage

excessive formation
of thrombin

activated protein C 1evels

are 5 by
consumption by continuously

activated coagulation cascade

impaired synthesis by liver

exacerbated by
high thrombin 1evels lead

defective

to excessive formation of fibrin

anticoagulation

at all 1evels of thrombin -

regulation

mechanIsms

extravascular leakage

high TNF alpha downregulates

thrombomodulin (and thereby
protein C activation)
low levels of protein S

thrombotic phase =

exacerbated by

0 levels of

fibrin deposition widespread

defective

plasminogen activator

but unevenly within:

fibnno1ysis

inhibitortype 1 (PAl-1)

brain

mechanisms

hear

C--

tissue factor pathway

inhibitor levels are 8

1ungs
kidneys

prevents conversion of

adrenals

plasminogen to plasmin

spleen
1iver

consumes platelets
G in secondary fibrino1ysis

and clotting factors

occlude small
and midsize
arteries

through thrombi within the

red blood cells are

fragmented as they pass

microcirculation

8 labs in:
8in platelets =

fibrin degradation products

thrombocytopenia

D-dimer 1evels

attempts to counteract

hypercoagulable state by inhibiting

causes infarction of

platelet aggregation

multiple sites within body

fibrin polymerization

elevated PT and aPlT

o fibrinogen
see schistocytes on

causes a

blood smear

microangiopathic
hemolytic anemia

hypoxia and tissue injury

bleeding

multiple organ dysfunction syndrome (MODS)

or multiple organ failure (MOF)

normal hernostasis

initiated with injury

to vascular endothelium

Von Willebrand disease = '

quantitative or qualitative
deficiency of VWF

thrombogenic substances within

(multiple variants)

subendothelial extra cellular matrix (ECM)

including Von Willebrand factor (VWF)

defective platelet adhesion:

are exposed to blood flow

. 0aPTT
obleeding time
normal platelet count

fibrin bridges form

GplbIX platelet receptor adheres to injured

between platelets via

GplIb/lIIa platelet receptors

8 ristocetin co-factor aggregation

endothelium via VWF embedded within ECM

platelets secrete granuIes containing

clinical signs and symptoms:

Von Willebrand factor

Bernard-Soulier Syndrome =
deficiency of Gplb-IX

thromboxane A2

spontaneous mucosal bleeding

ADP

menorrhagia

excessive bleeding from wounds / surgery

platelet receptor

9 aPTT
defective platelet adhesion:
0 bleeding time

thrombocytopenia
large platelets

1eads to
activates the intrinsic

. platelet aggregation

Glanzmann's Thrombasthenia =

formation of a hemostatic plug

pathway of the coagulation

platelet recruitment

cascade (see map)

deficiency or dysfunction of
GplIb/lIIa platelet receptor
defective platelet aggregation:

9 bleeding time (BT)

this complex

1Xa

VWF forms complex

activates

VilIa + VWF 1

with factor VIlIa to prevent

X to Xa

its degradation within

plasma

rn

ultimately leads
to the formation of
fibrin clots

injury "within' blood

vessels activates intrinsic coagulation cascade:
damaged vessel endothelium
damaged platelets

creation of a complex on vascular

subendothelium occurs between:

factor X11 (aka Hageman factor)

this complex

high molecular weight kininogen (HMWK)

activates

prekallikrein

factorX11toXIIa -----....----

antithrombin 111 deficiency

.,

unable to inhibit clotting

factor XIIa -.-- ,

factors:

activates:

XIIa

factor X1 to XIa

XIa
1Xa
Xa

factor XIa activates

results in o

factor IX to IXa

1evels of thrombin

i
IXa becomes a P

9 conversion

part of a new complex

of fibrinogen to fibrin

induding:
prothrombin mutation 20210

IXa this complex

VIlIa activates
X XtoXa

prevents activated
protein C from

unknown mechanism

1 Xa initiates the

fufilling its actions

leads to o

common pathway

including:

1evels of prothrombin

: by forming a complex

protein S deficiency

between:

Va and VIll

fibrino1ysis

leads to o 1evels
of thrombin and

Xa
Va

.'' calcium
factor V Leiden mutation .-

phospholipid

- inactivation of factors

-0

this complex ;

hypercoagulable state

cleaves 0

30

leads to

prothrombin into thrombin

hypercoagulable state
X)

(most common)

APC works in conjundion

thrombin
factor V resists inactivation

thrombin

this complex

(factor lIa) - binds - activates protein C

to activated protein C

thrombomodulin

by activated protein C

*4

with protein S
- to inhibit factors:
Va
VIlIa

-0

3.
n

0
3>

factor V enables factor X

8 thrombin formation

hyperhomocysteinemia

to continue converting prothrombin

and increases fibrino1ysis

to thrombin

C
r.

CO
r-

leads to hypercoagulable state

homocysteine downregulates

protein C deficiency

thrombomodulin
less inhibition of

factor Va ,
factorVIlIa

results in higher 1evels of thrombin 1eading

( r.
; lA

to hypercoagulable state

0
platelet lifecycle begins
in the bone marrow

abnormal bone marrow:

pluripotent hematopoietic

- + aplastic anemia

stem cells tum into myeloid stem cells -------*-------

1eukemia (see myeloid 1eukemia map)

thrombopoietin (TPO) and

other cytokines

ineffective megakaryopoiesis: megaloblastic anemias (folate, B12 deficiencies)

stimulate stem cells to

develop into megakary0cyte

. impaired platelet production due to:

-----

prescription drugs (thiazides, rifampin, phenytoin, etc)

colony forming cells

ETOH

infections (HIV, measIes, ehrlichiosis)

megakaryoblasts

megakaryocytes

1
megakaryocytes break

hypersplenism causes

1/3 are normally sequestered in

up into fragments = - spleen -------

- - more platelets to be stored within

o sequestration

spleen and unavailable for hemostasis

platelets

drug induced immune reaction =

:' heparin induced thrombocytopenia (HIT)

A

immune

antibodies to platelets '

are formed via =

--. autoimmune reaction =

idiopathic thrombocytopenic purpura (1TP)

non-immune

microangiopathic hemolytic anemias:

thrombotic thrombocytopenic purpura (TTP)

hemolytic uremic syndrome

2/3 enterthe
blood circulation

1 disseminated intravascular coagulation (DIC)

causes platelet consumption by activation of
platelets become

senescent after completing 10 day lifespan

abnormally functioning

see o megakaryocyles on
bone marrow biopsy

+ alloimmune

- - post transfusion purpura

platelets = thrombocytopathia
(qualitative)

coagulation cascade (see sepsis/DIC map)

8 lifespan =

4,:t

ultimately phagocytized by

, 4,.

macrophages

massive transfusion

within the spleen

dilutional

8 circulating

to plasma volume

1evels of platelets =

and RBC mass

thrombocytopenia

-1

labs refect

(quantitative

9 bleeding time

leads to primary T. normal aPTT

normal PT

--* clinical

hemostasis defect

- dilutes platelets in relation

,g.
n

manifestations \
\ on physical exam:
petechiae
non palpable purpura

ecchymosis
mucosal bleeding (gums, Gl tract)
intracranial bleed (platelets < 20,000 uL)

-<.
, -1

0
-0 .
rn

'b.

Hematopoietic Disorders

j. j*.:i****' ALPHA THALASSEMIA (

HemogIobin A

agIObin chains are

(adult hemogIobin)

produced under the

genetic mutations result in

is composed of

direction of 4

abnormal a globin chain synthesis

2 a chains

a globin genes

2 B chains
0(
50

40
C

defective hemogIobin

* 30

synthesis causing a hypochromic

anemia = alpha thalassemia

3 20
B
y

1/1

6 12 18 24 30 36 1 6

mutations can afFect between 1 to all

Gestational age

4 a globin genes

12 18 24 30 36 42 48

DiriI:

(in weeks)

Postnatal age
(in weeks)

HemogIobin production timeline

if lout of 4a

globin genes is

symptomatic in utero as a chains needed for HbF

defective or absent
if 2out of 4a

globin genes are

defective or absent
silent carrier

(a thalassemia-2 trait)

if 3out of 4a

globin genes are

a thalassemia minor

defective or absent

(aka a thalassemia-1 trait)

if 4out of 4a

globin genes

hemogIobin H disease

are defective or
absent

mild hypochromic
asymptomatic with

microcybc

moderate to severe

hydrops fetalis

normal CBC

anemia

disease

(aka Barts hemogIobin or

a thalassemia major)

allows unpaired

ineffective

anemia can resemble

B globin chains

erythropoiesis

13 thalassemia

to accumulate

complete absence of
a globin chains

allows deIta globin chains

minor (see map)

some vanants
leads to

B globin chains

some bone

form a tetramer

marrow hyperplasia

= HbH

to accumulate

have bony
deformities

and extramedullary

deIta chaIns

erythropoiesis

form tetramer=
Hb Bads

Hb Barts has high

- affinity for oxygen

HbH precipitates and

forms Heinz bodies

does not release

oxygen to fetal tissues

death in utero due to:

abnormal red blood cells

are sequestered by spleen

hypoxia

hydrops fetalis (edema)

CHF

spIenomegaly

hemolytic
anemia

,4;j't*k*34<4jt0i,, BETA THALASSEMIA

HemogIobin A (adult hemogIobin)

13 globin chains are

defective 13 globin chain

is composed of:

produced

production causes a hypochromic

under the direction of 2

anemia = B thalassemia

2 a chains

2 13 chains

B globin genes
a

50

40

multjple possible

genetic mutations results in

30

abnomial B globin chain synthesis

20

10

mutations can affect

1orboth 13 genes

6
6 12 18 24 30 36 1 6

one

B glObin

GestatIonal age

PosInatal age

(In weeks)

(in weeks)

HemogIobin production limeline

both B globin

gene affected

13 thalassemia minor

13 thalassemia intermedia

(aka 3 thalassemia trait)

B thalassemia major
(aka Cooley's anemia)

single 13 globin gene

one of two affected globin genes is

produces a11 13 globin chains

0nly "mildly mutated

0 1

both p globin genes

while a globin chains

are severely affected by

production continues normally

mutation

0 but not totally

but less than normal amount of B globin

absent B globin

chains available for hemogIobin synthesis

mostsevere form of

chain production

disease requiring
lifeIong transfusions
usually asymptomatic with
mild microcytic anemia

leads to heterogeneous
clinical presentation due to
wide variety of mutations

excess of normal a globin chains

relative to abnormal or absent 13 chains

inadequate 1evels of 13 globin chains for normal hemogIobin

synthesis contributes to the a: B globin chain imbalance

both types of mutation and degree of this imbalance determine dinical phenotype

clinical onset begins at 3 to 6 months

when fetal hemogIobin production stops

and no longer masks abnormality
8 HbA

some a chains

unpaired a chains form inMacellular

production =

cannot find 13 chains

precipitates which accumulate as inclusion bodies

moderate to severe

to pair up with

anemia
inclusion bodies cause

oxidative damage to RBC

8 oxygen

membrane

carrying capacity

deformed red blood

hypoxia stimulates

ineffective

intravascular

erythropoiesis in both

en,thropoiesis

hemolysis - cells are sequestered in

spleen =

bone marrow and

spIenomegaly

extramedullary sites
microcytic

such as 1iver and spleen

hypochromic
bone marrow expansion
causes:

stimulates q

hemolytic

iron absorption

anemia

fractures (especially long bones)

abnormal
blood smear shows

inclusions bodies

target cells

frontal bossing

hemochromatosis

maxillary marrow hyperplasia (ch ipmunk facies)

(see map)

12 18 24 30 36 42 48

bIzarre cells

anisocytosis

60* ANEMIA OF CHRONIC DISEASE

normal

acute phase protein

erythropoiesis initiated when

hepcidin

kidney detects

iron is absorbed by

low oxygen 1evels

Gl tract and

in the blcod

transferred

4 released with
; inflammation

8 serum iron

- 1evels

prevents iron
delivery to

to bone marrow

bone marrow

inflammation
abnormal

causes

1ron

releaseof

homeostasis

cytokines -

e iron uptake

8 transferrin

. by reticuloendothelial - saturation
system (RES)
: ferritin

0 translation of ferritin

within macrophages -

kidney releases

and hepatocytes

erythropoietin
to bone marrow

CO

IL-1 0 EPO

8 production of

1evels

erythropoletIn

(EPO)
inflammatory cytokine
1 TNF-a decreases -

ability of erythroid precursors

erythropoiesIs

response to EPO
tumor invasion

impaired

orinfecIon ofbone

erythropoiesis

marrow 8

numbers of elythroid
progenitor cells

mature red

toxins or cytokines

blood cells

produce a cytotoxic

released into
circulaticn

effect upon erythroid

progenitor cells

<D

5
E

2
red blood cells

last 120 days

toxins or inflammatory
8 RBC
0

lifespan

9- cytokines produce
a direct cytotoxic ellect

upon mature efythrocytes

E

old and dead red

inflammatory cytokines

blood cells are

phagocytosed by
the reticuloendothelial

cause an o

2 in erythrophagocytosis

system

components of
RBC are recycled

reflected in mild

leading to

- anemia of
chronic disease

8 in hemogIobin
and hematocrit

blood smear shows

normocytic
normochromic
R8Cs

lab iron studies show:

low serum iron

normal or low transferrin
normal or o ferritin

low reticulocyte count

normal iron stores in bone marrow
normal or low TIBC

iron storage
1evels

inflammatory cytokine

1evels =
marker for

8 reticulocyte

, count = marker for

5 bone marrow

this lab value

- heIps to rule out

iron deficiency

iron body stores

serve 2 major roles

in the human body:

binding site for oxygen wjthin hemogIobin

electron transfer jn redox reactions

these functions depend

upon iron homeostasis
8 dietary intake

vegetarians

elderly

- iron balance begins

, no physiologic mechanism

ophysiologic requirements:

can only occur

1 of2ways:

for excreting iron

- with intestinal absorption

blood loss
a>

pregnancy

exfoliation of skin and mucosal cells

infants / kids / teens

1ron absorbed by enterocytes

has 1 of 2 fates

8 intestinal absorption: celiac disease

2. most iron is utilized for red

-0

surgical resection
8 stomach acidity ,

blood cell production

1. some iron stored as ferritin

within hepatocytes and macrophages of sent to plasma

the retculoendothelial system (RES)

bound to transfenin

majority of plasma
bound iron is delivered .
to bone marrow

erythropoiesis occurs

iron containing hemogIobin

found within circulating red blood cells (RBC)

blood loss:

once 120 day lifespan of RBC

RES macrophages phagocytize

is over = senescence

senescent RBCs

menstruation

malignancy
hemolytic anemias

recover and recyde

loss of iron prevents recycling from occurring

' Iron

hookworm

hemogIobinuria
hemorrhage
11 TIBC as

8 iron/TIBC ratio

abnormalities with either

lessiron available to fill

(aka transfemn saturation) -

storage or recycling cause

binding sites on transferrin

8 iron stores = 8

iron depletion

i. 1

ferritin

- 8in serum ,ron

9RDW initially as - iron restricted erythropoiesis

large young R8Cs mix

with microcytic /nomlocytic R

8 reticulocyte count
iron deficiency anemia = 0 hemogIobin

clinical presentation:
8 growth and leaming in children

stimulates

erythropoietin

blood smear =

microcytic
hypochromic
0 erythropoietin
1evels attempt to s1jmulate
bone marrow erythroid
progenitor cells to increase
RBC production

8 MCV

fatigue

o MCHC

shortness of breath
weakness

palpitations
angina or MI in patients with
preexisting coronary artery disease
pallor of mucosal membranes
glOSSitiS
angular stomatitis

but production fails because

there is no iron

esophageal webbing
koilonychia

S>'r?z .j VITAMIN B12 DEFICIENCY

normal vitamin B12 (cobalamin) metabolism

begins with ingestion of vitamin B12

diet-related issues which

prevent adequate ingestion of

vitamin B12:

vegetarians / vegans
tapeworm infection

vitamin 812 is removed from

food via pepsin in the stomach

vitamin B12 is unable to be
released from food due to:

hematologic effects due to inability to

defective pepsin secretion

convert homocysteine to methionine:

achlorhydia

pancytopenia
macrocytic anemia

B12 combines with

cobalophilins

pancreatic proteases break

neurologic effects due to

down the B12 cobalophilin

ineffective myelination

complex

dementia

defective exocrine pancreatic function prevents

vitamin B12 from being released from cobalophilin

delirium

* vitaminB12 deficiency-

myelopathy
gait dysfunction
paresthesias

B12 then combines with

intrinsic factor secreted by

gastnc parietal cells

unavailable intrinsic factor due to:

gastrectomy
pemicious anemia (autoimmune destruction of
parietal cells)
B12-intrinsic factor

complexis absorbed by
ileal enterocytes
unavailable intrinsic factor receptors
due to:
ileal resection
ileal disease

B12 then combines

with transcobalamin 11

and is transported into plasma

B12 is delivered

primarily to liver
and bone marrow

high demands for vitamin B12 deplete

normal supplies due to:
ilIness

hyperthyroidism (see map)

malignancy
chronic disease

vitamin B12 supports

DNA synthesis for cell proliferation

pregnancy

other effects:

glossitis

plasma
ironpoot

supplied by

2 routes ofacquisition
tightly controlled
by hepcidin =

1. intestinal

hormone made by

absorption

0 hepcIdin= liver
8 1ron absorption

and release - negative regulator

of intestinal iron absorption

8 in hepcidin=

and iron release by

9 iron absorption

RES macrophages
iron absorbed by

and release

enterocytes
has 1 of 2 fates

sent to plasma

some Iron stored as

bound to transferrin

ferritin within

hepatocytes
and macrophages

most of plasma
ironis delivered
to bone marrow

for erythropoiesis

iron is incorporated
Into new erythrocytes

2. RBC recycling

red blood cells

* by reticuloendothelial

die after 120 days

macrophages

.HFE gene mutation

supplies majorIty
of plasma iron pool

most common cause of

1' hemochromatosis

expanded" plasma iron pool

can be acquired via:
transfusion overload

8 T1BC

o % saturation

as more iron fills binding sites

on transferrin

o serum Iron

of transferrin as excess iron -

leads to --

2' hemochromatosis

must be bound within plasma hemochrmatosis

hemolytic anemias
thalassemias (see map)
chronic liver disease

o ferritin as

excess iron is put into

excess iron is deposited

intracellular storage form

as hemosiderin into tissues

causes organ damage

classic triad of hemachromatosis = cirrhosis, bronzed skin, diabetes mellitus

skin:

0 pigmentation

immune:

causes bronzing

endocrine: jOints:
cardiac:

restrictive cardiomyopathy
arrhythmias
CHF (see map)

hypogonadism arthraigias
liver:

impotence

hepatomegaly amenorrhea

hepatic dysfunction gynecomastia

cirrhosis (see map) diabetes mellitus (see map)

o risk of infection with

listeria, kIebsielIa and
vibno

 ff MYEL0ID 1.YMPHOMA*UKEMIA*d

e
myeloid cell
lineage begins

defect aIong here

with

can lead

pluripotent

to aplastic anemia

, myeloid

stem cell

MP = myeloproliferative

hematopoietic
stem cells

trilineage

myelodysplasias
can progress to

erytiroid

megakaryocytes

essential

myeloid

thrombocytosis

metaplasia

acute megakary0cytic
1eukemia = -

polycythemia

M6AML

monoblast - M4 - myeloblast AML

MOAML

MlAML
M2AML

vera

promonocyte

M7AML

myeloscIerosis

abnormally

9blood volume

large platelets

promyelocyte -

M5AML

M3 AML

andviscosity

splenomegaly
due to

thrombotic
or

t(15;17)

extramedullary

leads to:

hematopoiesis

uIcers

hemorrhagic

contains

pruritus

crisis

can lead to

the most

DIC

auer rods

(see map)

infarctions

myelocyte

organ congestion

DVTs (see map)

HTN (see map)

hypercellular
bone marrow

granu 0cyte
precursors

can go to

"spent phase"

1-

1eukemic

eosinophilic

baso)hilic

neutrophilic

M2 AML:
includes

MP

full range of

myeloid

myelofibrosis

chronic

precursors through

myelogenous

granulocytes

1eukemia

(CML)
auerrods

dry bone tap

Philadelphia
chromosome

(9;22)

bcr-abl

fusion gene

8 LAPscore

can go
to blast
crisis

48;12)

LYMPHOlD LYMPHOMAS AND LEUKElIAS $m

1ymphoid cell
travel to

1ymphoid *-

thymus '

lineage begins
with

CellS

pluripotent
hematopoietic
become double

stem cells

travel to bone

negative

marrow

pre-T ce#

common

T cell

1ymphoid

immunoblast

precursor

helper

pre-B

T cell

1ymphoblast
acute

adult T cell

mycosis

1eukemia

fungoides

* 1ymphoblastic

naive

1eukemia

, B cell

(ALL)

r CD25
markers L CD4
cell

indolent

small

course

1ymphocytic 1eukemia
or

i 1
HTLV-1
provirus found

plaques

chronic

1ymphocytic 1eukemia

amves

most are pre-B cells

at 1ymph

but there are 3 types

pre-B ALL

nodes

develop

T cell ALL

on skin

in tumor

cells
progresses
to tumors

if abnormal cells

if abnormal cells

foundin

found in

1ymph nodes

blood first = called

first = called

CLL

B cell ALL

Ig rearrangement occurs

SLL
tdt +

smudge

reaches blood =

CD19

sezary syndrome

CD20
CD5

Il cell

cells

markers

.mantle - germinal .
cell

marginal -

center .--

zone

SLL - marginal

mantle

4 maJor or
diseases

cell

CLL

1ymphoma

occur at

gIves
rise to
either

zone

1ymphoma

this stage of
associated

B cell development

K11;14)

with MALToma

Non Hodgkin Lymphomas

cell

plasma

memory

cells

B cells

hairy

r CD5
1 CD19

makers L CD20

diffuse

follicular

Burkitts

Hodgkin

multiple

large

1ymphoma

1ymphoma

1ymphoma

myeloma

cell
leukemia

B cell

t(14;18)

1ytic

"starry sky"

small
deaved
cells

characterized by

bone

presence of

lesions

Reed Stemberg cell

t(8;14) use
Ann

malignant cells

spread continuously - Arbor

via 1ymph nodes

staging

4 1
painIess

B symptoms:

enlarged

night sweats
1ymph nodes weight loss

5 WHO subclassifications

nodular

1ymphocytic

mixed

1ymphocyte

1ymphocyte

scIerosis

predominant

cellularity

depleted

rich

TRAP +

Gastrointestinal Disorders

GASTROESOPHAGEAL REFLUX DISEASE

normal lower esophageal sphincter (LES)

anatomy allows for

daily gastroesophageal reflux

without causing injury

but dysfunctional defense

mechanisms can lead to disease

dysfunctional
anti-reflux barrier

exacerbating factors include:

due to i'ther
anatomic abnormality
that interferes with

obesity
caffeine
. most common mechanism

physiologic abnormality

chocolate

that interferes with

esophogastric junction (EGJ)

fatty foods

esophageal function

ex. hiatal hernia

smoking
betablockers
transient

LES hypotension

LES
relaxation

causes: 1

8 in intraluminal pressure in EGJ

can occur

as either

8 length of EGJ high pressure zone

causd by
8 resistance to
renux

o in
causes indude: - strain induced

free reux

proximal
stomach d stension

pregnancy

delayed gastric emptying

LES is

fall in intraesophageal

"blown open"

pH without change in
intraabdominal

by sudden e
in intraabdominal

pressureor

pressure

LES pressure

EGJ is more "compliant, :

. opens at lower pressure
opens wider

acid refluxes ,
into distal

esoplagus .....*
esophageal

refluxate indudes

pH monitoring - gastric acids

may or may not

and pepsin

caused by:
dysfunctional

8 esophageal peristalsis

esophageal

impaired salivary function

acid clearance

be normal

xerostermia

scIeroderma

allows longer

achalasia

exposure to
disrupts bght

refluxate

junctions between
epithelial cells

dysfunctional
'tissue resistance"

allows injury to tissue

acid reaches

intercellular space
and acidifies cell

- cell edema ard - mucosal - to occur during

death

inflammation

exposure to refluxate

cytosol
could lead to

erosive reflux disease:

nonerosive reflux disease (NERD) =

no gross pathology but still has

strictures

metaplasia of normal

dilated intercellular spaces which

erosions

squamous epithelium to

allow the refluxate in

columnar epithelium

microscopic pathology
accounts for presence of GERD symptoms

irritation can lead to

clinical manifestations of GERD

typical:

atypIcal:

heartbum asthma

chest pain cough

dysphagia

belching
sour taste in mouth

0 riskof

Barrett's epithelium = _+

esophagitis

hoarseness

esophageal

adenocarcinoma

unknown etiology
genetics believed to play minor role
infection?

dietary allergy?
autoimmunity?
epithelial cells dysfunctjon?

smoking is protective!

0plasma cells

humoral immune -

actjvation of

response

colonic mucosal

complement

leads to

fixation

* 1gG synthesis

immune system

t
2 types of immune
responses

p- ANCA

attacks colonic

antibody is

epithelium

produced against
unknown antigen

activation of

cellular
-

immune

response

cells,-

neutrophils
and macrophages

amplifies

inflammatory cytokines
are released including:-

inflammatory response

IL-1

of large intestines

TNF-a

can lead to 4

production of albumin =
hypoalbuminemia

IL-6
1eukotrienes
thromboxane

inflammatory cytokines

platelet activating factor

leads to:

nitric oxide

f) cOllagen production

reacti,e oxygen metabolites

edema

d fever and

ischemia

acute phase

response

epithelial cell dysfunction

occurs but it is
' unclear if it is a 1

abnormality or 2
to inflammation (or both)

o epithelial

permeability

bloody diarrhea
which can contain mucus

and can occur

noctumally

tissue damage occursin , formation of pseudopolyps

mucosa and submucosa

hypokalemia

and crypt abscesses

anemia

(see map)

involves colon and rectum only

if damage extends past ileocecal valve

=backwash ileitis

uIcerative

toxic megacolon

dueto damaged neural plexus

extraintestinal

hemorrhagic proctitis

include:

leads to bright red rectal bleeding

fatty liver
pyoderma gangrenosum
significantly

poor anatomical compliance

9 risk

and loss of stool reservoir

colon cancer

lead to tenesmus

predisposing factors:
genetics (NOD2 gene)
infection
NSAlDs

smoking

dysfunctional
intestinal

epithelium

impairs innate
immune system
of Gl tract

results in

allows for frequent , activates antIgen

and inappropriate exposure

to unknown antigen

APC presents

toTcells - TH1 response

presentIng cells -

(APC)

overly aggressive

via MHC class 11

(see map)

CD4 T cells play a

molecule

major role in inflicting

damage to intestinal tissue

activates

inflammatory cytokines are released:

-macrophages

begins vIcIous cycle

IL-1
IL-12

ability of CD4 T cells to

1FN gamma

resist apoptosis prolongs

TNF u

opportunity to do this damage

secretes

cytokines recruit

more

inflammatory cells to

cytokines

intestinal mucosa including:

1eukocytes
stimulates

fibroblasts

THl response

morocytes

furlher

amplified and sustained

In11ammatory response

followed by
, chronic course of

excessIve tIssue Injury

remIssIon and
11ares

leads to a mixed

' TH1/TH2 pattem of

inflammation

leads to clinical

presentation of
Crohn's disease

skip lesions
9 ASCA ,
antibodies

transmural inflammation

can occur anywhere between - leads to serosal

mouth to anus

cobblestoning of

inflammation causIng mucosa

- altered
abdominal pain

extraintestinal

manifestations include:

permeability

seronegative arthritis

fistulas

ankylosing spondylitis
erythema nodosum
aphthous uIcers
uveitis

loss of absorptive
surface

diarrhea

narrowed lumen leading

to string sign on abdominal
x-ray

malabsorption of:
ileocolitis causes

lower right quadrant pain

protein
oxylate causing kidney stone

calcium causing osteoporosis

iron, B12, folate causing anemia
bile salts causing diarrhea

0
risk factors:

alcohol (30%)

unknown mechanism causes

' obstruction

galIstones (35%)

overdistention

9 triglycerides

o permeability

hypercalcemia

of the pancreatic duct

#auma

drugs
pancreas divisum
infection
causes activation of

- trypsin builds up

trypsinogen to ttypsin

and is not removed

within the pancreatic

rapidly enough by normal

acinar cells

pancreatic mechanisms

trypsin activates

release of

other pancreatic enzymes:

more trypsinogen

amylase
and

elastase

1ipase

phospholipase A2

nto serum

carboxypeptidase

_ ' pancreas '

autodigests

could activate
kinin

and complement

fat necrosis

acute

pancreatitis

releases -/

systems (see map)

more

enzymes

i
- can enter

abdominal pain radiates to back

circulation

nausea

but repeated

vomiting
9 macrophages

which can cause

and PMNs

systemic

syndrome
or SIRS

proinflammatory

(see sepsis map)

cytokines released

hypocalcemia

further

pleural effusions
renal failure via ATN (see map)

damages

DIC (see map)

chronic

, - AV shunting - hypovolemia

damage

gut barrier

thrombosis

compromised

edema

pancreas

shock

necrosis or interstitial

enteric bacteria

gain access to
circulation

pancreatitis

Tumers sign

hemorrhagic

calcium precipitates

calcifications

- seen on abdominal x-ray

1S*t
potential

exacerbates

complications:

intraductal obstruction

necrosIs

DIC (see map)

duodenal obstruction

-0

3>

abscess

pseudocyst

Cullen sign

leads to intraductal

(see map)

hemorrhage

more edematous

pancreatitis

and hypocalcemia

-- 8 permeability
ischemia $ 7
injury

ductal protein plugs

irreversible damage =

fever and
ARDS (see map)

via formation of

can lead to

vascular

metabolic dysfunction

inflammatIon

bouts of acute -

pancreatitis

can recover

tachypnea

inflammatory
response

pancreas -

fever

exocrine insufficiency (malabsorption/steatorrhea)

endocrine deficiency (late in disease)

local and

, 9 risk of pancreatic cancer

systemic

pseudocyst formation

j,n*
-30
rn

infection

pancreatitis

0
risk factors:

increased biliary secretion of cholesterol

female

obesity
estrogen
drugs
weight loss
risk factors:

parenteral nutrition
bile in the

oral contraceptive

gall bladder can

pregnancy

become lithogenic via 2 mechanisms

surgery
burns

gall bladder
cholesterol

hypomotility occurs

cholesterol kept in

becomes - solution by bile

supersaturated

acids and lecithin

bile stasis and sludge formation

allows more

composition of

the bile acid pool

time for both

high levels

is key to keeping -+ of deoxycholate

cholesterol in

occur

cholesterol -1

solubon faster nucleation

higher cholesterol

_- most

time

i common

secretion

mixed1 ---1
cholesterol

9 cholester01 - cholesterol
saturation

precipitates out

pigmented:

nucleation - crystals - cholelithiasis - 3 types -

black or brown

form

index > 1
most are

asymptomatic

symptoms arise if stone obstructs

and inflames surrounding
assue

location determines

clinical manifesations - cystic duct

common bile duct

of disease

can lead to:

if stone blocks secretion - intermittent obstruction

of pancreatic enzymes = =

- ifbile stasis occurs -

bacterial superinfection
bacteremia

choledocholithiasis

sepsis (see map)

pancreatitis (see map)

bile backs up into
can be asymptomatic or
look like biliary colic

1iver and injures

ductal tissue

labs show

1eukocytosis

pain

intermittent obstruction

9 bilirubin

Charcot's triad:

impacted stone

jaundice '

can lead to

fever

cholangitis

= biliary colic

2 alkaline phosphatase

pain is:

impacted stone
condition -

= acute

sudden

can progress severe

cholecystitis

steady (not colicky!)

pain

is

due

temporary

to inflammatIon - severe right upper quadrant poorly localized

pain > 6 hrs

right upper quadrant

exacerbated by eating
watch out for perforation

or gangrene \

pain is due to

other symptoms:
nausea

vomiting

1eukocytosIs

bile stasis - from inflammatIon

can grow

fever

bacteria:

Murphy's sign

E. coli
Enterococcus
KIebsjelIa

8. Fragdis

and/ or infection

a functional

spasm of duct

',f{)31,

Liver Disorders
*32

multiple chronic liver diseases:

alcoholic

posthepatIc

progressive damage

biliary

. to liver parenchyma

cardiac

becomes irreversible

metabolic

damage is charactenzed

by both functional

structural

injury = cells impaired

injury = cells destroyed

fibrosis

replaces
hepatocytes

followed by
regenerative
Bads to 2

nodules

major types of
functional

hepatorenal

cirrhosis

abnormalities

syndrome

- metabolic

syntheti*/
function

function

6 steroid clearance

8 gluconeogenesis
8vitamin K dependent

leads to

dotting factors

vasodiIa#on
and renal

estrogen 1evels
0 pressure In the

poMal

vasoConstrIction

liver sinusoids hypertension t

dinical signs:

(See coagulation

8 intravascular

spidernevi

cascade map)

Weeding

systemic

leads to increased

hypoglycemia

2,7, 9,10

9 vascular resistance

impedes blood flow

palmar erythema

lack of valves in

8 abumin

testicular atrophy

the hepatic vein

production

gynecomastia
8 vitamin B12

allows blood to

portosystemic -

storage

shunt

edema formaljon

volume

back up into the

systemic circulation

due to decreased

oncotic pressure

0 metabolization of toxins
macrocytic

(especially ammonia) .-

blood bypasses
liver

anemia

contributes to

development
of ascites

leads to:
confusion

encephalopathy
astenxis

blood backs up
into vessels that
connect to

portal vein

spIenomegaly
vances:

gastroesophageal

ascites =

hemorrhoidal

excess fluid

sequestrabon
of RBCs and

o risk of

platelets

collects in the

peritoneal space
multiple mechanisms

hematemesis
e abdominal

or melena

hemolytic anemia

girth

thrombocytopenia (see map)

thought to be
involved in formation

of ascites including:
primary sodium retention

shifting dullness
on physical

decreased intravascular volume

arteriolar vasodiIation
renal vasoconstriction

exam

2 riskof spontaneous
bacterial peritonitis

exposure to hepatitis B virus (HBV):

neonatal

occupational
blood
sexual conlact

L HBV enters blood stream and reaches liver

HBsAg is bound by
hepatocyte surface receptors

produds of

replication
"immune tolerant

become -

virus enters hepatocyte and

- high HBsAg
C

, detectable

phase" replicates without damaging cell

dunng ...-

(noimmune

incubaRon

response)

phase

completed vinons enter circulation

HBV DNA

and infed other hepatocytes

viremia

vIrIon

"immune

response -+

1aken up by -

phase" antigen presenting

APC degrades virion and

presents to 1ymphocytes

cell (APC)
CD8 T cells become sensitjzed

to HBV antigens present on -

infected hepatocyte cell surface -

antigen nonspecific inflammatory molecules released:

TNF a

releases:

free radicals

cytotoxic T cells destroy

AST

proteases

ALT '
bilirubin

alkaline phosphatase

HBeAg indicates

,,7 high infectivity

clinical signs of
- HBV DNA

inflammation

can be asymptomatic

of liver =

or more commonly symptomatic:

-*a&HBc 1gM

acute hepatitis B

jaundice
fatigue

HBsAg

hepatomegaly

disappears

HBsAg .

use anti-HBc IgM

before anti-HBs -+ to confirm acute

isdetected =

extrahepatic manifestations:

infedion

window period

athraIgias
rashes

polyarteritis nodosa

' and regeneration of - hepatitis D occurs=

glomeruIonephritis (see map)

commonly due to

liver parenchyma increases

risk of chronic liver disease

risk of cirrhosis

and fulminant hepatitis

poor T cell
rarelyprogresses
to fulminant hepatitis

if superinfection with

continual destructjon

membranoproliferative

and hepatocellular carcinoma

acu e hepatitis

response in

followed by

immunocompromIsed host

1 of 3
Immune

outcomes

neonates

elevated

If virus cannot be

transaminases

cleared and replication

then chronic hepatitis

positive antj-HBc total

occurs

HBsAg
HBV DNA

HBeAg
if HBsAg is

totally cleared =
"immune stage"

anti-HBs

also positive with

hepatitis vaccine

provides
anti-HBe
anti-HBc

may or

immunity

"inactive carrier stage"

no injury or inflammation
of hepatocytes but

may not be

patient can suffer

present

from acute flares

exposure to hepatitis C virus (HCV):

1V drug use
blood transfusions

medical procedures

HCV
can be 1 of 6 -

types or clades
wIth numerous

HCV enters circulation

and targets CD81

receptor on

hepatocytes

subtypes / subclades

HCV enters

while on cell
surface HCV
coats itself

hepatocytes vIa

' L0lreceptor-

leads to production

mediated endocytosis \ virus replicates via

- of HCV RNA within 1-2 .

RNA dependent

with LDL

weeks after exposure

RNA polymerase

acute

lack of proofreading
functjon leads to
creation of

F hepatitis
majority of pts are

hepatocyte destruction

"quasispecies"
of HCV within

acule infection

singular infection

asymptomatic but - causes releaseand - elicits 2 types of Immune responses

symptoms may appear

Oin:

which aim to kill virally infected hepatocytes

2 to 25 weeks AST

after infection

ALT

characterizedby - tests positive if

NK

cells

1FN

if HCV RNA is

antiHCV antjbody

adaptive immune response

characterized by:

symptoms include:

--

Innate immune response

measurable in
serum for > 6 months

an infection

CD8 T cells
CD4 T cells

has occurred

jaundice 4 cells
fatigue

(acute or chronic)

nausea

right upper quadrant pain

1eadsto1of 2 clinical outcomes

HCV 'quas species" makes

it difficult for immune system

recovery occurs in 20%

to clear viremia

if Immune response is
strong enough to
clear virus from body
chronic hepatitis C infection occurs in 80%
diagnose with

anti-HCV antibodies

HCV viral

are formed to specific HCV

genotyping

type or clade

due to insufficient immune response

'necroInflammation"

immunity is type/clade specific and

may not be lifelong ( lasts -20 years)

of liver parenchyma
maintained by

1ymphocyte infiltration

leads to both

hepatic and extrahepatic

manifestations of disease --hepatic

extrahepatic

manifestations

manifestations

steatosis

strongly associated with

occur through -

the development of:

infected hepatocytes and

direct viral infeclion

cryogIobinemia

bystander hepatocytes

or deposition of

porphyria cutanea tarda

Immune complexes

membranoproliferative GN

interaction between viral

and host factors leads to

T cells destroy both

activates stellate cells

which in tum activate

(see glomeruIonephritis map)

lichen planus

myofibroblasts
to produce fibrosis

progression of fibrosis to

compensated cirrhosis j

. nsk of developing
hepatocellular carcinoma

is accelerated by:
alcohol

HIV (see map)

coinfection with other types of hepatitis
diabetes (see maps)
obesIty
0age

decompensated
cirrhosis leads to

end-stage liver failure (see map)

,1''ii;731-i,/ /j ALCOHOLIC HEPATITI

Op

risk factors for developing

liver disease concomitant with alcohol use:
Hep C
geneljcs
maInutrition

alcohol is

primarity metabolized
in the liver

alcohol is hepatotoxic

indirectly

directly

1/
4 leadsto

damages

hepatocytes by altering

alcohol is metabolized

oxidative stress

to acetylaIdehyde

-. o inNADH

- 0 free fatty
acid synthesis

11

their membranes

acetylaIdehyde

0 free

inhibits

5 a reactIve

radical formation

fatty liver or
steatosis

causes

vin

gluconeogenesis

metabolite

fat accumulates

- in cells= - hepatomegaly
-

fatty acid oxidation

hypoglycemia

fonns adducts with

proteins in the
hepatocytes

usually reversible if

directly

damages

patient abstains from alcohol

mitochondrial
DNA

alters hepatocyte

1ipid

reacts with and depletes

structure and

peroxidation

glutathione supply

fundion

hepatocytes tum
enhanced by

tamin E deficiency

8 protection

into neoantigens

alcohol alters

against oxidative damage

permeabIlity of

immune response
induces an

reCease gut and allows

TNFux -

and cytotoxins

Kupffer cells activated

by bacterial endotoxins

gram negative bacterial

overgrowth

inflammation =

hepatitis
promotes

lissue damage and

collagen production

hepatocyte
damage and
death via

apoptosis

impaired normal
0 In:

hepatic regeneration .

AST/ALT 2:1

release of

Aver enzymes
activation

fibrosis is initially , can develop into areas of

perisinusoidal

micronodular regeneration

cirrhosis

(see map)

can predispose to

hepatocellular
carcinoma

right upper quadrant pain

constitutional symptoms

alkaline phosphatase
GGT

stellate cells

fibrosis -

- bilirubin

of

jaundice

'33tf*

Renal Disorders 4
%4,3%

4 LM

'::9

HYPERTENSION

2 major
types of
hypertension

primary hypertension ,

risk factors:

(aka idiopathic or essenDal) diabetes mellitus (see map)

>

95%

1ifestyle

age

genetics
smoking
3 main mechanisms

involved in the pathogenesis

secondary hypertension*
inappropriate activation of

endothelial

sympathetic nervous system

dysfunction

inappropriate activation of
renin-angiotensin

aIdosterone system (see map)

3 majOr categories

' i
endocrine etiologies:

releases endothelin

renal etiologies:

other etiologies:

and other mediators

angiotensin 11

pheochromocytoma chronic renal failure preeclampsia

that lead to both

causes vasoconstriction

Cushing's (see map)

(see map)

(see map)

vasoconstriction and

aIdosteronism (see map) renal artery stenosis coarctation of aorta

remodeling of arterioles

thyroid disease (see map)

U cardiac OUtpUt ----_--

o peripheral resistance
* see individual maps for

pathophysiologic process
of different etiologies

cardiac
BP =

total

output >< peripheral

resistance

CNS effects ,

stroke (see map)

blood

pressure

retinopathy

rises

litension

retinal effects

hemorrhages

most commonly an

accelerated atherosderosis

asymptomatic disease
untiI long-term effects

AV nicking

cardiac effects

leading to myocardial infarction (see maps)

unfold

rarely Fresentsas

o aftedoad

malignant hypertension

leading to left ventricular hypertrophy

(akaaccelerated)

and S4 heart sound

renal effects

0 glomerular hydrostatic pressure , chronic renal failure (see map)

- leading to glomerular hyperfiltration

nephroscIerosis

abrupt 8
in glomerular filtration rate (GFR)
occurs due to 1 of 3 causes:

obstruction of

post renal ARF =

urine flow caused by:

problems occur
"downstream"

pre renal ARF =

ureteral stones

from kidneys

'upstream" from

hypovolemia

kidneys

benign prostatic

hypertrophy
neurogenic bladder

hypotension
sepSs

hepatorenal syndrome

hemodynamic abnormality leads

symptoms include

anuria or 11uctuating urine output

compensatory mechanisms

tumor

problems that occur

example causes: -

GFR declines slowly -

urethral strictures

sodIum

diIatation of

alterations in

reabsorption

collecting system

renal hemodynamics

tubular

without damage to
renal parenchyma

pressure

- o BUN / CR ratio > 20

to & renal

intrarenal or intrinsic

perfusion

ARF = problems occur

within the kidney

leads to 3 main

etiology is

compensatory

defned by site

responses 1

of injury

L tubulogIomerular

glomerular (glomeruIonephritis)

feedback

vasopressin (ADH)

myogenic

Is released

reex

interstitial (acute interstitial nephritis)

vascular (vasculitis, renal artery / vein obstruction)

macula densa

tubular (toxins, radiographic dyes)

release renin (see RAAS map)

concentrates

afferent

the urine

arterioles
diIate

most common

leads to release

- is acute tubular

of angiotensin 11

necrosis

8 ability

urine osmolality
> 500 mosm/L

urine 0smoIality

1* to concentrate unne - < 350 mosm/L

efferent

0 sodium

flow to

arterioles

and water - fractional excretion of

kidney \

vasoconstriction reabsorption

o blood

sodium (FENa) < 1

abnormal

tubule cells no longer -

blood flow

reabsorb sodium

FENa>1

effectively
o blood volume
intrarenal

increases
fluid
volume

, retums the GFR

vasoconstriction

to normal

unIess or untiI

BUN/Cr

compensation -GFR falls ,

ratio >

fails 20:1
symptoms seen with
i GFR

metaboli

acidosis

(see map)

1 \ArD#yle
retention of

imbalance

reversible

pre renal

ablood

8ow damages

r disrupts junctions , backleak

of urea and creatinine

between cells and

tubular clIs asement membrane elevted BUN/Cr

but ratio is

GFR

< 20:1

tubule cells no

longer adhere

to one another -7
tubule cells

:C

worsening

azotemia

sIough off and - tubular - includes:

develops

obstruct renal

necrosis

tubule lumen

nitrOgenouS
waste leads to:

fatigue

hyperkalemia

confusion (see rnap)

uremia

(see chronic renal failure map)

urine sediment

tubule cells

can regenerate and

retum the GFR to normal
or near normal

granular and
tubular epithelial casts

CHRONIC RENAL FAlLURE

risk factors:

family history of inhentable kidney disease

hypertension (see map)

chronic injury

diabetes mellitus (see map) -

and irreversible

glomeruIonephritides (see map)

loss of nephrons

autoImmmune disease

oIder age

previous incident of acute renal failure

compensatory and maladaptive response:

9 workload on

remaInIng nephrons hypertrophy of nephron

in order to maintain o glomerular capillary hydraulic pressure (glomerular capillary hypertension)
normal renal function

glomerular hyperperfusion

individual surviving nephrons

long period of asymptomatic

o GFR =

compensation

hyperfiltration
Injures/destroys more
nephrons by altering
tubular structure and
function

glomeruloscelerosis

less nephrons to maintain normal

renal function

compensation fails with

> 50% nephron loss

0 GFR

, azotemia = 2 BUN and Cr

end-stage renal disease =

uremia requinng

transplantion/dIalysis
uremia = syndrome of
multiorgan system
uremic frost

derangement as a
result of kidney failure

pruritis

T neuromuscular disorders
sleep problems

accumulation of - loss of memory

hyperkalemia - 8 K+ secretion.

nitrogenous waste mental impairment

(see map)

products from protein asterixis

loss of renal
metabolic

prevents acids from

acidosis - being excreted in non-anIon gap

form of ammonium

production '

metabolism

peripheral neuropathy

functions

8 ammonia
failure to excrete

includinc
8 infections

due to 1eukocyte

(see map)

suppressIon
can lead to

0rganIc -

anion gap

acids accumulate

by uremIc toxins
pericarditis from

metabolic acidosjs

(see map)

irritation by

uric acid

uremIc toxIns

retention

failure to synthesize / absorb / secrete

Na+ and water

appropriate amounts of

retention

renal products

volume and salt

overoad can lead to

congestive heart failure (see map)

hypertension (see map)

accelerated

atheroscIerosis (see map)

Vit D PO4- retention 8 1,25

hydroxylation

8 Ca

resorption

abnormal hemostasis leads to:

bruising
spontaneous Gl bleed
spontaneous cerebrovascular
hemorThage
prolonged bleeding time
decreased platelet factor 111
abnormal platelet aggregation
and adhesiveness

decreased synthesis of
erythropoietin leads to

2 hyperparathyroidism

normocytic normochromic anemia

(see anemia of chronic disease map)

renal osteodystrophy
osteomalacia (see map)
osteoporosis (see map)

fatigue

GLOMERULONEPHRITIS/NEPHRITIC SYNDROME,:,,=,

3 major etiologies of
glomeruIonephritis -

systemic disease:
post infectious:

primary renal disease:

streptococcal

membranoproliferative GN

(most common)

hepatitis B and C

cryogIobulinemia

mesangial GN

systemic 1upus erythematosis (see map)

idiopathic RPGN

polyarteritis nodosa

Berger

(see maps)

H]V (see map)

Alport

malaria

1gA

Wegenets granulomatosis
hypersensitivity vasculitis

Henoch-Schontein purpura

Goodpasture's syndrome

toxoplasmosis

primary glomeru onephritides

secondary glomerular disease

i
initiates immune
reactIon

1 --

humoral reaction can

cell-mediated

occur 1 of 3 ways

reaction

%11
antibodies attack

circulating

cytotoxic antibody

fixed or planted

antibody-antigen

attacks glomerular

antigen in situ

immune complex

cell components

within glomerulus

deposits within

e 1

sensitized T cells

attack glomerulus

glomerulus

acute inflammation -

(see map)

can lead to 1 of 5

clinical syndromes: -

halImark sign in urinalysis of glomeruIonephritis is dysmorphic RBC and RBC casts

asymptomatic

chronic

hematuria

glomeruIonephritis
acute

glomeruIonephritis
gross or
microscopic

hematuria

rapidly progressing

nephrotic

glomeruIonephritis

syndrome

(aka crescentic GN)

(see map)

insumciency
which can lead to

acute nephritic syndrome:

eg lgAnephropathy

progressive renal

end-stage renal failure

abrupt onset macroscopic hematuria -

(see chronic renal

oliguria

failure map)

acute renal failure

acute nephritis

edema

proteInuna

hypertension
variable proteinuria

azotemia

rapidly o renal function

focal segmental necrosis

1
eg. poststreptococcal GN

can lead to

end-stage renal failure

within days to weeks

3 categories determined by early renal biopsy:

Type 1 (anti-GBM disease) = Goodpasture's syndrome
Type 2 (immune) = postinfectious, SLE (see map)
Type 3 (pauci-immune) = Wegener's granulomatosis

0
common causes of nephrotic syndrome:

damage to glomeruIi
. alters structure and function

minimal change disease (occurs in children)

diabetic nephropathy

of glomerular basement membrane,

focal segmental glomeruloscIerosis

podocytes, and slit diaphragms

membranous glomerulopathy

urinary loss of

membranoproliferative glomeruIonephritis

1gG and concomitant

amyloidosis

, fo susceptibility
to infection (especially peritonitis)

catabolism of complement
components

0 permeability

of glomerular filtration

barrIer 1

urinary loss of
thyroxine binding

0 hypothyroidism
(see map)

globulin and thyroxine (T4)

loss of proteins, hormones,

metals, and vitamins into urine

urinary loss
of transferrin

, anemia

and iron

proteinuria =

urinary loss of

urinary loss of

> 3.0 to 3.5 g/24 hours

antithrombin 111

vitamin D binding protein - loss of 25-hydroxy vitamin D

exacerbates hypercoagulability

osteomalacia

by combining with effects of hypoalbuminemia:

(see map)

hypoalbuminemia

,impaired fibrino1ysis
o platelet aggregatIon

8 intravascular

alters pharmacokinetics

oncotIc pressure

of drug therapy stimulates liver

fluid leaks
can either

out of blood vessels into

stimulates liver

to synthesize

to sythesize more

procoagulants:

1ipids / 1ipoproteins , proteins c and s

interstitium

9 or & serum in an attempt to replace fibrinogen

plasma 1evel of
drug depending on
how it is metabolized

proteins lost in urine

8 in intravascular volume stimulates

hypercoagulability

renin-anglotensIn-aIdosterone system
and sympathetic nervous system

hyperlipidemia

(see map)

(see RAAS map)

can lead to:
accelerated

release of vasopressin

atheroscIerosis

(ADH) causes salt

(see map)

venous thrombosis and pulmonary embolism (see map)

acute renal vein thrombosis

and water retention

restores intravascular
volume

edema

i**: NEPH ROLITHlASIS

urine production
must balance

water conservatjon

excretion of salts

with low solubility

solubility is o by mulitple

factors including:
8 inhibitors (eg nephrocalcin)
8 complexing agents (eg. citrate)
9 transit time

dehydration

imbalance between these 2 things

thIs metastable

leads to supersaturation as amount

eventually urine

physiochemistry

state allows - reachesthe - of urine is now

of substance exceeds its solubility

upper limit of

unstable and new

of preformed

metastability

crystal nucIei form =

crystals still

and can no longer

nucleation

held in solution

hold crystals in

for growth

crystal nucIei grow

on existing surfaces found within

the papillary ducts or collecting ducts

of kidney such as:
epithelial cells

urinary casts
red blood cells

solution =

formation product

crystalsbind each other

= aggregation

4 major substances
can lead to stone

retention can be

formation in the kidneys -

stone retention

caused by

allows for
calcium

ammonium magnesium

uric acid

cystine

0xalate

phosphate stones

stones

stones

stones

radiopaque on x-ray

radiopaque on x-ray

j
urinary tract infections

most common =

70 - 80%

with urease splitting

organisms including:
Proteus
KjebsielIa

can lead to formation of

pure calcium 0xalate

staghom calculi

mixed calcium 0xalate

and phosphate

caused by

9enetic defeci

stones form within

which prevents
causes include:

gout (see map)

papillae and follow

reabsorption

1 of 3 fates

0fcystine

pass through

high purine diet

myeloproliferative disease
obstruction

ureter

1 1
blocks outflow

clinical presentation:

of urine leading

severe pain

to hydronephrosis
causes include:
RTA

sarcoid (see map)

malignancy

thyrotoxicosis (see map)

low urinary citrate

primary hyperparathyroidism (see map)

idiopathic hypercalcuria
hyperoxaluria

high protein diet

functional
abnormalities

nephrolithiasis

radiolucent on x-ray

tumor 1ysis syndrome

2 subtypes:

further growth

caused by chronic

anatomic or

hematuria

frequency
urgency

dysuna

unnary system

without obstructing
or causing pain

.t

Fluid and Electrolyte Disorders

L

...-.B '

total body water

can be divided
. in1O .

intracellular fluid

extracellular fluid

compar[ment (1CF)= 2/3

compartment (ECF) = 1/3

i
ECF is

composed of

interstitial fluid
sodium concentration is

the major osmotIc force -

in the ECF

creates

which contains:

plasma

mostly sodium

osmoIality

plasma

glucose
urea

any fall in plasma [sodium]

-- is normally corrected by

less sodium is

2 mechanisms:

inhibition of

ADH release

hyperlipidemia or
inhibition of

hyperproteinemia

1ipids and proteins

- 0ccupy a larger

thirst

portion of the
plasma volume

leads to

leads to

diuresis of water

8 water intake

measured per unit

isoosmolar hyponatremia

volume in the lab

or pseudohyponatremia

even though 0smoIality

is unchanged
(1ab artIfact)
caused by:

integumentary loss (sweating, burns)

gastrointestinal loss (vomiting, tube drainage,

concentrates

hypovolemic = -

' plasma [Na+] and returns it

sodium loss > water loss

fistula, obstruction, diarThea)

renal loss (diuretics, 0smotic diuresis,
hypoaldosteronism)

to normal range

caused by

corrects water

sodium ratio

3major pathological mechanisms

dilutes body

retention

solutes - hypoosmolar

euvolemic =

including

"pure" water gain

L---+ Can prevent plasma [Na+] - (most from correcting itse]f

primary polydipsia

water

common)

hyponatremia

decreased solute intake

syndrome of inappropriate ADH (see map)

glucocorticoid deficiency

sodium

hypothyroidism (see map)

chronic renal insufficiency (see map)

CO :

if plasma [Na+]
remains low =

hyponatremia < 135 mEq/L

sobody senses low

water gain > sodium gain

intravascular volume

8 plasma

hepatic cirrhosis

nephrotic syndrome

osmoIality causes

(see maps)

water to shift from

cellular swelling occurs

9 plasma osmola1ity

of an effective solute cerebral edema causes

neurologic symptoms

dependsupon
hyponatremia ,

nausea

mannitol

headache

sorbitol

lethargy
coma

independent of
sodium

osmotic

- gradient
that pulls

dilutes [Na+]

hyperosmolar

dilutes [Na+] further

- in the ECF - hyponatremia

water out

causes include:

hyperglycemia

rate of onset of

0 water volume

createsan

0 concentration

otherthan sodium in the ECF

severity of symptoms

stimulates ADH
and thirst

ECF to 1CF

especially in brain

water is extravascular

caused by:
hypervolemic = - heart failure --.

maItose
radiocontrast

of the 1CF
into the ECF
2rn

total body water

can be divided into

extracellular fluid

intracellular fluid

compartment (ECF) = 1/3

compartment (1CF)
.2/3

ECF is composed of

plasma

inters#al nuid
creates

sodium concentration is

the major 0smotic force '

in the ECF

which contains:

plasma

mostly sodium

osmoIality

glucose
urea

any rise in plasma [sodium]

is normally corrected by
2 mechanisms

regulation

regulation

ofurine

of thirst

caused by:

concentration

pure' sodium

via ADH release

overload =

leadsto

leads to

reabsorption of water into circulation

0 intakeof water

via insertion of aquaporins into collecting

excessive sodium bicarbonate administration

, overcorrection of hyponatremia

hypervolemic

hypertonic dialysate (peritoneal and hemodialysis)

hypernatremia

hypertonic enteral or parenteral hyperalimentation

primary aIdosteronism

.
U>

improperly prepared infant formula

ingestion of salt tablets

ducts and tubules

dilutes and

Na+

, returns plasma [Na+]

retention

to normal range

8
C

I3

C.

2 major mechanisms can

corrects water

, prevent plasma [Na+]

sodium ratio

from correcting itself

pure" water

- water

10SS .

lOSS

if plasma [sodium]

(most

remains high =

common)

hypernatremia > 145 mEq/L

pulls water out of

euvolemic
CO

central diabetes insipidus (see map)

hypernatremia

extrarenal causes:

impaired thirst
..

restricted access to water

1CF and into ECF

renal causes:

1 nephrogenic diabetes insipidus (see map)

06>1

.2
SS*

cellular dehydration
water loss > sodium loss =

causes cells to shrink

hypovolemic

hypematremia

affects primarily CNS

renal causes
, diuretics
0smotic diuresis

.I

"rapid adaptation" transports

vascular injury

electrolytes from ECF

extrarenal causes:

leads to:

into cell to restore tonicity

excessive sweating
:Z'

then "slow adaptation" occurs as organic

skin disease (pemphigus vulgaris)

1 --C

osmolytes accumulate intracellularly

diarrhea, NG suctioning,

intracranial bleeding
se1zures
coma

rn

bums

vomiting, third spacing

Ir,/ 1

corrects brain volume

but not high 0smoIality

total body
potassium

can be
divided

Sintake

into

of potassium (rare)

intracellular

extracellular

potassium = 98%

potassium = 2%

majority of this

0nly 0.4% of this

amount is found

amount is found

within muscle

within serum

can be caused by :
abnormal distribution

of potassium
Bess common)

ratio of intracellular to

occurs through fluid shifts 13 2 sympathomimetics

which move K + .

theophylline

from extracellular compartment to hyperinsulinemia

intracellular compartment metabolic alkalosis (see map)

extracellular creates ,

' voItage gradient

across cell membrane

and resting cell membrane

potential

alteration of the ratio

occurs primarily through

'3major mechanisms

8 loss of

loss of extracellular K+

potassium (most common)

nonrenal causes:

excessive sweatIng
severe diarrhea
1axative abuse

hypokalemia

villous adenoma

serum K+ < 3.5 mEq/L

hyperpolarization of
cell membrane

renal loss of

prolongs action potential

potassium accounts

and refractory period

for majority of chronic

hypokalemia cases:
diuretics (most common)

abnormal

osmotic diuresis due to poorly controlled diabetes

cellular function

high doses of penicillin

occurs In 4 major areas

hypomagnesemia
mineralcorbcoid excess (see map)
hyperaIdosteronism

renal tubular acidosis (rare)

skeletal:
weakness

para1ysis

cardiac:

ventricular and atrial dysrhythmias

ECG abnormalities:

rhabdomyolysis

U wave

fasiculations

T wave flattening or jnversion

tetany

prolonged QT interval

gastrointestinal:

renal:

ileus

nephrogenic diabetes insipidus (see map)

iI:

metabolic alkalosis

(see maps)

0
total body
potassium

seen with:

potassium supplement overdose -

0 potassium load

can be

large blood transfusion

pseudohyperkalemia

divided

with hypoperfusion

into

can occur within

blooddraw sample as
hemolysis releases
potassium

seen in conditions of

K+ shifts from

abnormal distribution

insulin deficiency '

intracellular to

of potassium

acidosis

extracellular space

intracellular

extracellular

potassium = 98%

potassium = 2%

majority of this

0nly 0.4% of this

amount is found

amount is found

within muscle

within serum

hyperkalemic periodic paralysis

. ratio of intracellularto ,
extracellular K+ creates

succinylcholine

nonselectIve 13 blockers

voItage gradient

digitalis toxicity

across cell membrane

rhabdomyolysis

and resting cell membrane

tumor 1ysis

potential

caused by
seenwith 8GFRdueto:

impaired excretion of

acute or chronic renal failure (see maps)

potassium (most .

8 real or perceived blood volume

, 3 major mechanisms ,-

alteration of the ratio

occurs primarily through

gain of extracellular K+

common)

hyperkalemia=

serum K+ > 5.5 mEq/L

partjal depolarization of

decreased K+ urinary excretion

cell membrane

can occur with concomitant:

prevents full membrane

excitability

0 Cl reabsorption
seen in:

Gordon's syndrome
cyclosporine

abnormal cell

impaired Na+ reabsorption

function in

due to:

2 major areas

1* hypoaldosteronism
2 hypoaldosteronism due to low renin, NSAlDS, or ACE inhibitors

aIdosterone resistance seen with K+ sparing diuretics or tubulointerstitial diease

cardiac:
skeletal

ventricular fibrillation

asystole

musde cramps
weakness

conduction defects

ECG abnormalities including

peaked T waves

prolonged PR interval
widened QRS
sine wave

para1ysis
paresthesias

decreased deep tendon refexes

e
acid base balance

revolves around concentration of H+

in extracellular and intracellular 11uids

[H+] is highly controlled by 3 systems

buffers in the

lungs=

kjdneys =

extracellular and

"2nd line of defense"

last line of defense"

intracellular fluids =

'1st ne of defense"
mainly HC03 which
accepts H+ and

rids body of

reabsorption of HC03-

excretion of acid

H+ as C02 by converting it

at the proximal

and ammonium (NH+)

from H2C03 via carbonic

tubuleofthe

in order to make new

anhydrase

glomerulus

HC03

becomes H2C03

these controls are represented in the following equation:

H+ + HC03-- H2C03- C02 H20

if either of these components of the equation is disrupted

by o acid load due to

by 8 bicarbonate

4 excretion by kidney

due to losses incurred by

o production or acqui sition

kidneys or Gl tract

o in arterial [H+]

metabolic acidosis

2 types of metabolic acidosis

based on presence or absence of

anion gap

see anion gap vs nonanion gap metabolic acidosis map

leads to 4 physiologic
responses by the body
in an attempt to return the pH to
as close to normal as possible

3 shortterm responses
occur first

-extracellular - HC03- accepts excess H

buffering

and becomes H203 -

H2C03 travels to lungs

C4 gets blown

and is converted to - offin exhalation

C02 andH2O

-respiratory - [H+] stimulates

compensation

centraland

, g in minute ventiIation
(respiratory rate)

peripheral

increases the amount

chemoreceptors

of C02 blown off

intracellular

buffering via:
- proteIns

this process of compensation should be

reflected in the following formula:

phosphate
bone carbonate

expected pC02.(1.5 x actual HC03-) + 8 mm Hg

followed by
long-term response
carried out by kidneys

but ifthe patient's actual HC03- is above or

below the expected pC02 then a mixed acid base
disorder is present

renal excretion

of H+

renal reabsorption

and synthesis of new

HC03-

ANION GAP VS NON-ANIONGAP METABOLIC ACIDOS lS:,1

e
acid base balance

revolves around concentration of H+

in extracellular and intracellular fluids

[H+] is highly controlled by 3 systems

buffers in the

lungs =

kidneys =

extracellular and

"2nd line of defense'

last line of defense"

intracellular 11u'ids =
'1st line of defense'

mainlyHCOF which
accepts H+ and

becomes H2C03

rids body of

reabsorption of HC03

excretion of acid

H+asC02 by convertjng it

at the proximal

and ammonium (NH4+)

from H2C03 via carbonic

tubule of the

in order to make new

anhydrase

glomerulus

HC03-

these controls are represented in the following equation:

H+ + HC03-- H2COs - C02 +

H20

if either of these components of the equation is disrupted ;

by U acid load due to

by 8 bicarbonate

8 excretion by kidney

due to losses ,ncurred by

kidneys or Gl tract

0production or acquisition

2 in arterial [H+]

metaboNc acidosis
2 types of metabolic acidosis
based on presence or absence of
anion gap

- high anion gap

normal anion gap

or normochloremic

or non-anion gap
or hyperchloremic

occurs when an
causes:

occurs when lost bicarbonate

has been replaced by Cl

causes:

acid other than HCl- is

proximal 1ubular acidosis

distal

tubular

added to lhe
acidosis
extracellular fluid

ketoacidosis

lactic acidosis

hyperkalemic renal tubular acidosis renal failure

moderate renal insufficiency salicylate poisoning
carbonic anhydrase defidency

does not change

this acid replaces the methanol poisoning

HC03- while [CIl

the anion gap (AG)

ethylene glycol poisoning

remains normal

AG= [Na+J-([C11 + IHCN)

widens the "gap" between
anions and cations

Cl- O

bicarb 8

catIons

remain the

AG = [Na+] - ([C11 + [HC031 + [other acid])

anion] remains the same

same
T

low cations

high anions

no gap created
gap created

METABOLIC ALKALOSIS

acid base
balance

revolves around

concentration of H+
in extracellular and intracellular flujds

[H+] is highly
controlled by 3

system
buffers in the

lungs =

kidneys =

extracellular and

7nd line of defense"

7astline of defense"

intracellular fluids =
'1st line of defense'

mainly HC03

which accepts
H+ and

rids body of

reabsorption of HC03

excre:ion of acid

H+ as C02 by converting

at the proximal

and ammonium (NH+)

H2C03 via carbonic

1ubule of the

in order to make new

anhydrase

glomerulus

HC03

becomes

H2C03

these controls are represented in the following equation:

H+ + HC03 -

H2C03

C02

H20

i1
if either of these components of the equation is disrupted

vomiting
nasogastric tube 1

by 8 acid load

by o bicarbonate

, acute alkali administration

milk alkali syndrome

diuretics
antacids
excess mineralcorticoids

hypercalcemia

8 in

hypokalemia

arterial [H+]

metabolic alkalosis

clinical signs / symptoms:

other

3 types of metabolic alkalosis

arrhythmia

alkalosis

8 cardiac output
confusion

2 dinical csatveogluomneessbtaatsuesdaunpdonnaur roinwes[tchhelodriifdeef]ewhntiaiclhdidaegsncorsibeess

5 cerebral blood flow

neuromuscular excitability

alkali loading
end-stage renal disease

refeeding with high

chloride resistant

amount of carbohydrates

alkalosis

massive blood transfusion

leads to 2 physiologic

hypercalcemia

responses which attempt to

1V penicillin
urine chloride > 40 mg/L

return the pH as close to

normal as possible = compensation

hypoproteinemia

chloride responsive
alkalosis

alveolar

hypoventiIation

urine [chloride] < 25 mg/L

rapid
renal excretIon

this means the

causes are divided

patient is

into etiologies that occur

volume expanded

with or without

hypertension

of bicarbonate
this means

O PC02

patient is - loss of gastric secretions

8 HC03
the expected pC02
compensatory response=

0.7 [HCO31 +20+/-5

causes:

volume depleted

(NG tube, vomiting)

with hypertension:

without hypertension:

if kidney is unable to

antacids

adrenal adenoma Bartter's syndrome

excrete HC03 alkalosis is

thiazide or loop diuretics

hyperaIdosteronism Gitelman's syndrome

maintained via 1 of 3 mechanisms:

. vIllous adenomas (cause diarrhea)

Cushing's (see map) hypokatemia

chloride depletion
volume (ECF) depletion

K+ depletion

Uddle's syndrome hypomagnesemja

I.3\- ,pII>,0, RESPIRATORY ACIDOSIS ,

acid base
balance

revolves around

concentration of H+
in extracellular and intracellular fluids

[H+]ishighly
controlled by 3

systems
buffers in the

lungs =

kidneys =

extracellular and

"2nd line of defense"

last line of defense"

intracellular fluids =
"1 st line of defense"

mainly HC03
which accepts
H+ and
becomes

H2C03

rids body of

reabsorption of HC03

excre:ion of acid

H+ as C02 by converting

at the proximal

and ammonium (NH4+)

H2C03 via carbonic

tubule of the

in order to make new

anhydrase

glomerulus

HC03

respiratory center

respiratory muscIes or chest wall

, upper airway obstruction

these controls are represented in the following equation:

caused by

H+ + HC03-

H2C03

-4-+ C02 +

H20

abnormality

at any level - gas exchange

ofthe ventiIatory
- process

C02 component of equation is increased by hypovent,lation i :sZZl--_------ mechanical ventiIation

primary

retain C02 =

change

hypercapnia

respiratory
acidosis

O [H+]

8 arterial pH

primarily hemogIobin

' andproteins accept

excess H+

H203 + buffer - Hbuffer + HC03

as buffers accept

H+ from H2C03 = Il

acute compensatory response

o [HC031

renal compensation occurs 3

if hypercapnia persists

2 urinary H+

0 HC03

excretion

retention /

production

8 [H+]

o [HC03]

pH is retumed
closer to normal

chronic compensatory response

S RESPIRATORY ALKAL0515'14

acid base
balance

revolves around

concentration of H+
in extracellular and intracellular fluids

[H+] is highly
controlled by 3
systems

buffers in the

lungs =

kidneys =

extracellular and

7nd line of defense'

last line of defense"

intracellular fluids =
"1 st line of defense'

mainly HC03

which accepts
H+ and
becomes

H203

rids body of

reabsorpljon of HC03

excretion of acid

H+ as C02 by converting

at the proximal

and ammonium (NH4+)

H203 via carbonic

tubule of the

in order to make new

anhydrase

glomerulus

HC03

these controls are represented in the following equation:

H+ + HC03- -

H2C03

C02

H20

C02 component of the equation is decreased by hyperventiIation

primary change

blow off too much

C02= hypocapnia
respiratory
alkalosis

8 [H+]

elevated

arterialpH

, causes H to shift from

intracellular to extracellular

fluid

H+ combines with

HC03 to form H2C03 =

acute compensatory response

8 [HC03]

chronIc compensatory response

H2C03
converts to C02 - .
u PC02

if hypocapnia persists
renal compensation occurs

8 urinary

9HC03

H+ excretion

excretion

O [H+]

8 [HC021

retum pH
closer 10
normal

-' ' ,1

Immune Mediated Disorders

1st exposure to
antigen or allergen
via:

skin

inhalation

Examples of Type 1 HS reactions:

intravenous

allergic rhinitis
asthma

systemic anaphylaxis

antigen

picked up by

maintains

dendritic

cells

- Th2 response \

(antlgen penting cell) c )

T cell

dendritic cell

presents antigen ,

differentiates into Th2 cen

to naive CD4

Th2 secrete cytokines IL 4, 5, 9, 10, 13,

Thelper (ThO) cell and chemokines

In regIonal

1ymph node

Th2 T cells signal B cells

(plasma cells) to class switch

and produce lgE in 2 ways

1 1
binding of T cell CD40 ligand

IL 4 and IL 13

to B cell CD40 receptor

secretion

plasma cells release lgE

nto circulation

Activation Phase

1gE binds to high affinity

1gE bound mast cells

receptors on tissue mast

encounter second exposure

cells and circulating basophils

to that same antigen

= sensitization
stimulates
' Th2 cells

releaseof cytokines:
' IL4

antigen binds lgE

.%-5

on mast cell

iL13

activates lgE producing B cells

maintains Th2 response

Sensitization Phase

IL4

IL 5 activates eosinophils

1gE crosslinks = mast cell activation

i
IL 13:

crossIinking signals

1cell to -

stimulates mucus production

by epithelial cells

synthesize

immediately degranulate

and later degranulate

preformed mediators

secondary mediators

in early phase

in late phase

1eukotrienes and prostagIandins cause:

histamine

leukotrienes -

heparin

prostagIandin D

leads to:

anti-parasitic actions

0 vasodiIation and vascular permeability

smooth muscle contraction
mucus secretion

ILl,3,4,5,6

30

<
-

1 --1

o vascular permeability
mucus secretIon

3.
rn

PAF

TNF alpha

rn

smooth muscle contraction

promotes lgE production

platelet activating factor:

3>
n

attracts more 1eukocytes

amplifies 1ipid mediators

GM CSF . activates neutrophils, eosinophils and platelets

TNF promotes
infammation (see maps)

lf

cytokine production
activation of endothelium

Examples of type2 HS reactions:

penicillin allergy
chronic urbcana

antigen can be
bound to cell surface

transfusion reactions

bound to extracellular matrix

erythroblastosis fetalis

host tissue

antibody
binds antigen

eliminates antigen via

1 of 3 cytotoxic mechanisms

1 non-cytotoxic mechanism

antibody interferes with normal

cellular function

opsonization

and phagocytosis
complement and Fc

ADCC =

antibody coats antigen

antibody dependent
cellular cytotoxicity

receptor mediated

examples:

inflammation

antiacetylcholine receptor antibody in

antibody coats surface

myasthenia gravis (see map)

of antigen

thyroid-stimulating antibodies in
Grave's disease (see hyper[hyroidism map)
activates

augments phagocytosis by NK cells

augments phagocytosis by
macrophages and neutrophils

which recognize and bind

complement
cascade (see map)

the Fc portion of the antibody

which recognize and bind

Fc portion of antibody
release of

C3b and C4b

membrane attack complex (MAC)

coat infected cells

induces 1ysis of antigen / infected cell

cytoplasmic granuIes
engulf antigen

containing perforin and

granzymes

rn

3>

induce cell 1ysis

phagocytosis through
opsonization

0
Z

rn

0
antigen can be
categorized
as 1 of 2 forms

Examples of type-3 HS reactions:

exogenous antigens including:

streptococcal cell wall antigens

endogenous antigens including:

serum sIckness

DNA nucteoproteins in SLE

arthus readion

hepatitis B surface antigen hyper lgA

necrotizing vasculItIs

systemic 1upus erythematosus

rheumatoid arthritis

antibody binds antigen to form immune complex

glomeruIonephntis
takes 1 of 2

initiates acute

r inflammatory - forms depending upon

circulating immune complex

deposits into tissue

reaction

quantjty anstribution

if complexes are in excess and

are formed within circulation then they can be

deposited anywhere:

if complexes
are deposited near

blood vessel walls leading to vasculitis

site of antigen entry

synovial membranes leading to arthritis

glomerular basement membrane leading to glomeruIonephritis

local reaction =

choroid plexus

arthus reaction

systemic reaction =

within 4 to 8 hours

serum sickness

1gG antibody binds

antigen and forms
immune complex

immune complexes

activate complement

C3b coats immune

C3a and C5a released

complexes leading

and binds receptors

to opsonization

/ J..m**

occurs quickly

may take between

if preformed

8 to 12 days if plasma cells

antibodies

need to class switch

aIready exist

from 1gM to 1gG

platelets
are activated

Immune complex

binds Fc receptor on

binds Fc receptor

1eukocytes (neutrophils)

on mast cells

and form
microthombi

(see clotting cascade map)

clinical presentation:
chills
fever

on leukocytes

rash

1eukocyte activation
and migration

mast cell degranulation

release of histamine

and other inflammatory mediators

such as 1eukotrienes and prostagIandins

neutrophils attempt but may not
succeed in

phagocytosing immune complexes =

"frustrated phagocytosis"

-0

..

-1

<

9 vascular permeability
smooth muscle contraction

mucus secretion

superoxide radicals

glomeruIonephritis

leads to:

activates endothelium

leads to release of:

, anhris

1eukocyte chemotaxis

P rn

>

i
,O

15 -1,4

proteolytic enzymes
trn .t
%, 45

tissue injury

HYPERSENSITIVITY REACTION TYPE 4

First contact with intracellular antigen is picked up

by antigen presenting cells (APC)

Examples of type-4 HS reactions:

contact dermatitis

antigen

graft rejections

is processed byAPC

tuberculin test reaction

and presented to naive

Sensitization Phase

T cells within

regional 1ymph node

IL 12 secretion by APC shifts

response to CD4 Thl

pathway

can shift response toward CD4 or CD8

response depending on how APC presents antigen

occasionally antigen is processed

via class I MHC molecule

mostly antigen is processed

- CD8T cells are activated

to that specific antigen

via class 11 MHC molecule

CD8 cells eliminate antigen

via cell-mediated

cytotoxicity (see map)

ThO cells are activated

and differentiate into CD4 Th1

cells specific to that antigen

Effector Phase

Thl cells

2nd exposure

donally expand

to same antigen

Thl cells secrete cytokines:

. 1FN 7
TNF u
IL 8
IL2

IL3
GM-CSF

recruits and activates mainly

macrophages and other

nonspecific inflammatory cells

inflammatory infiltrate
arrives at site of
infectjon 24 hours later =

delayed type hypersensitivity

activated macrophages are

responsible for most of the
effects of the

hypersensitivity reaction by:

0 phagocytosis
0 0xygen radical release
0 nitric oxide release

elimination of intracellular

antigen occurs through

nonspecific destruction of tissue

if hypersensitivity reaction is
unable to eliminate antigen
then continuous

tissue damage can lead

to granulomatous reaction
(e.g. TB granulomas)

enables 0 antigen
presentation

hypersensitivity response is further

amplified by an increase in
class 11 MHC molecule

expression on activated macrophages

0
pluripotent
hematopoietic
stem cells

bone

1ymphoid

x-linked agammagIobulinemia

marrow

stem cell

- -' (aka Bruton's agammagIobulinemia)

common

1ymphoid
precursor

pro-8 _

- 1ymphoblast

defective tyrosine kinase

pre-B

(Bruton's tyrosine kinase or btk)

1ymphoblast

prevents B cells from maturing

low or absent antibody production (all classes)

arrives
naIve

B cell

- at 1ymph - mantle
cell

nodes

recurrent infections by the

end of the first year of life

with:

germinal

H. influenza

center

S. pneumoniae

Staphyloccus

marginal
zone

plasma
cells

memory
B cells

multiple causes
1eads to abnormal
B cell differentiation but

Common Variable

mechanism is controversial: ,

Immunodeficiency +--

absent T cell signaling?

Syndrome

intrinsic B cell differentiation abnormality?

both?

secretes antibodies

i
no antibodies formed

(all classes)

0 risk

later
onsetin of autoimmune disease
mid to late 2Os

*/1 4\\\
1gG

and malignancy

, isolated lgA deficiency

1gA

unknown mechanism

prevents plasma cells

no 1gG response to

from differentiating into

vaccines

1gA secreting B cells

normal 1gG response to

I
C

vaccines

K
0

1gM

hyper-1gM syndrome

3>
r-

defective mucosal

i
caused by absent T cell CD40 ligand ,

majority are
x-linked

that prevents appropriate signaling

barrier leads to

recurrent respiratory

tract infections and

to B cells for isotype switching

sInuSItiS

mostly males

0
rn

no activation of

macrophages

normal or high 1evels of 1gM

cri

absent 1gG, 1gA, 1gE

rn

'Z

cannot eliminate

intracellular microbes

0 tisk

r-1.
-

opportunistic infections

r.

eg R carinii

pluripotent hematopoietic stem cells

1ymphoid
stem cell

bone

DiGeorge syndrome 4

marrow

AD or spontaneous

thymus

22q11 deletion prevents

development of 3rd and 4th

common

1ymphoid - pro-8

pharyngeal pouches

precursor

additional abnormalities

thymic aplasia parathyroids fail to develop

negative

cardiac defects

pre-B

pre-T cell

1ymphoblast

facial defects
abnormal cell-

mediated immunity

low set ears

complete and partial forms

nalve

hypocalcemia

B ce11 ---=

4 severe combined

due to parathyroid
low levels of circulating

1ymphoblast

double

arrives
mantle

at lymph - cell
nodes

immune deficiency

defect (see map)

T cells < 500

germinal

multiple causes:

T cell

immunoblast -

center

x-linked defective IL-7 receptor - affects more males

on the T cell (most common)

poor defense against

adenosine deaminase (ADA) deficiency

fungal and viral infections

marginal
zone

T cel

helper

cytotoxicT

T cell

cells

prevents T cell ,

this in turn affects

from maturing

B cell function

plasma
cells

memory

B cells

severe viral, bacterial, fungal and protozoal

secretes antibodies

opportunistic infections
chronic diarrhea

failure to thrive in infancy lgE

* Ataxiatelangiectasia

1gA

AR mutation ofA gene

accompanied by multiple defects

Wiskott Aldrich syndrome 1gM

8*i

including:

r-

.C

truncal ataxia

telangectasias

other clinical findings

x-linked WASP gene defect

eczema

cause antigen receptor signaling and

thrombocytopenia

cytoskeleton defects

mostly males

affecting all hematopoietic lineages

leads to secondary loss of T cells

immune deficiency probably related

to abnormal thymus development

-< normal 1gG

increased lgAand lgE

K
C

low T cells

antibody production is variable:

L lowIgM
patients succumb to

cerebellar and extrapyramidal symptoms

low lgA 1evels

poor antibody
rn

response to
protein antigens

overwhelming infection with

encapsulated organisms, virus

antibodies cannot form

or R carinii

against polysaccharide antigens

recurrent respiratory infections

stimulates

unknown antigen or

, exaggerated

self antigen
or genetic defect inThl pathway

cell-mediated

THl response (see map)

T cells accumulate at

release ILl which

activates ' site of disease

maintains Thl cell

CD4 Thl cells

proliferation

process

releases other

mediators including:
1FN gamma
IL 12

macrophages

aggregate and tum

recruits and

activates monocytes- into epitheliod and

multinucleated giant
to disease sites

CD4 cells create a rim

activated :

elevated

around the macrophages

macrophages

ACE
1evels

cells
form noncaseating
granuloma

autonomous
conversIon

0 serum
calcium

1, 25(0H)Vit D to

granulomas can

physically distorts

1,25\4t D

, resolve entirely or

surrounding

hypercalcuria with or without hypercalcemia

leave behind

parenchyma

(see map)

fibrosis

large enough quantity

of granulomas can interfere
with organ function

leads to the chronic and

multisystemic signs and

symptoms of sarcoidosis
skin

cardiac

nervous system

1ymph nodes

disturbances
and

arrhythmias

erythema nodosum

1upus pernio

conduction

LV dysfunction
and CHF

plaques

R sided

optic nerve dysfunction

heart failure

uveitis

(see map) T lungs

90% of sarcoid cases have

intrathoracic involvement

painIess
1ymphadenopathy

subcutaneous nodules

CN 7 palsy
encephalitis

cervical

cor pulmonale

granulomas

axillary

distort alveoli,

epitrochlear

bronchi,and blood

inguinal

vessels

pulmonary function tests

abnormal

show restrictive disease with - interstitial lung

chest x-ray shows

8diffusion capacity

disease

bilateral hilar

1ymphadenopathy

due to fibrosis

dyspnea
cough

SYSTEMIC LUPUS ERYTHEMAT0SUS

systemic
autoimmune
disease

environment

caused by

stressors:

interplay genetics
complement assays

- defect wtih -

8 C3

viral infections

drugs

measure

show:

deficiency in early
complement components

lab tests interferes with classical pathway

aC4

sun exposure

between

can invoke

flare ups

(see complemert cascade map)

8 CH50

cell damage

normally followed

defect causes

by apoptosIs but

delay in apoptosis

changes normal

cellular components
into autoantigens

autoantigens linger
on in apoptotic
blebs and bodies

8 access

9 In

to dendritic cells

proinflammatory
cytokines

0 in ESR ,

primary immune

fever

response via TH2 .

weight loss

pathway

malaIse 1ymphadenopathy

(see cell-mediated
immunity map)

. tissue

development of

injury via -

autoantibodies

anRbodies binding to

generates

more autoantigens 4 majortypes

extracellular molecules

immune complexes

which deposit in

autoimmune

subendothelium

hemolyAc anemia

- + coombs test

anti-histones - antinuclear
inflammation resulting

i
seen with drug
induced SLE:

skin

in central

malar rash

clinical features

discoid rash

ANA

photosensitivity

procanimide
alpha-methy1dopa
hydralazine
1sonIazId

d-penicillamine

joints:

sensitive

nonerosIve

but not specific

so look for:

kidney:

anti-phospholipids

anti-dsDNA

polyarthritis
synovitis

1upus nephritis

anti-Smith

classified into

1upus
anti-cardiolipin

anti-coagulant

1
anA-cytoplasmic

kidney failure is

5 types

most common cause

(see nephritic map)

of death in SLE

elements:

acute vasculitis causes focal

neurological symptoms
seizures

but actually a

psychosis

procoagulant =
anti-blood

CNS:

increased aPTT
CVS.

ischemia

anti-RBC

strokes (see map)

1. nonnal

pericarditis

anti-platelets

miscarriages

2. mesangial nephritis

Libman Sacks endocarditis

anti-1ymphocytes

1
can leadto

3. focal proliferative nephritis

4.diffuse proliferative nephritis

hematologic:

5. 1upus membranous nephropathy

hemolytic anemia

(see nephrobc syndrome map)

1eukopenia

tri-lineage

1ymphopenia

cytopentas

thrombocytopenia (see map)

pulmonary

pleuritis
pneumonItis
hemoptysis

Infectious Disorders
R

HUMAN IMMUNODEFICIEt'1CX.VI111$1/

Human Immunodeficiency Virus (HIV)

transmitted via infected body fluids:

semen

vagInal secretions
blood / blood products
in utero

HIV infects host immune cells through

binding its viral envelope glycoprotein 120

to 2 major types of host cell receptors

primary infection

CD4 receptor found on

CCR5 chemokine receptor on macrophages and

immune cells:

CXCR4 on CD4 T cells

dendritic cells

monocytes

microgIia
Th cells (express the most CD4 receptors)

CD4 T cells and macrophages serve

initially infects antigen

, as viral reservoir

presenting cells (APC):

throughout course of infection

dendritic cells

macrophages

APCs then

present HIV angens to CD4 T cells within 1ymph

node

virus is released
into circulation -

viral replication occurs via

, diagnostjc tests:

viremia causing

reverse transcriptase = retrovirus

viral load

acute or primary HIV

ELISA for antibodies

westem blot for confirmation

2 main cytopathologic effects:

can present with flu like

continual activation of cell-mediated

symptoms:

and humoral arms of immune system

virus mutates through course

rash

leading to CD4 memory T cells proliferation

of infection

fever

leads to long-term negative

, consequences for CD4 cells:

o apoptosIs which shortens CD4 1ifespan

reduced regenerative ability of

T cell populations

1ymphadenopathy

tissue destruction

non exudative pharyngitis

headache
mutations enable

myalgias

this proliferation in tum provides virus with

syncytia formation

more cellular targets

CD4 T cell dysfunction

virus to overcome immune

system mechanisms

expanded target population

enables infection to persist =
chronic HIV infection

virus induced cytolysis

' 8 CD4 T cell population

immune function continues

to be compromised
untiI

Acquired Immune Deficiency Syndrome (AIDS) = CD4 count < 200 or the presence of one or more AIDS.defining ilInesses
AIDS defining ilInesses:*
mycobacterium avium or M. Kansasii,

bacterial infections, mumple or recurrent

histoplasmosis, disseminated or extrapulmonary

candidiasis of bronchi, trachea, or lungs

HIV encephalopathy

candidasis of esophagus

HIV wasting syndrome

M.tuberculosis, disseminated or extrampulmonary

carcInoma, invasIve cervical

immunosuppression (severe HIV-related)

M. tuberculosis, pulmonary

coccidiodomycosis, disseminated or extrapulmonary

isosporiasis, chronic intestinal

mycobacterial disease, other

cryptococcosis, extrapulmonary

Kaposi's sarcoma

cryptosporidiosis, chronic intestinal

1ymphoid interstitial pneumonia and/or pulmonary 1ymphoid hyperplasia

cytomegalovirus disease (retinitjs or other)

herpes simplex, with esophagitis, pneumonitis, or
chronic mucocutaneous uIcers
CDC's AIDS surveillance case definItIon conditions.

1ymphoma, Burkitt's
1ymphoma, immunoblastic
1ymphoma, primary in brain

disseminated or extrapulmonary

pneumocystis jiroveci pneumonia

progressive multifocal 1eukoencephalopathy

salmonelIa septicemia, recurrent
toxoplasmosis of brain

.: ,,;512<5232,49','r',,s,.wilf&1POCARDITtj

etiologies:
structural heart disease (congenital / acquired)
intravenous drug use (1VDU)
prosthetic valves
rheumatic heart disease

valve surface of heart is

valve surface is inflammed via

disrupted or injured causing

integrins and cytokines

endothelium to be exposed

(seen with 1VDU)

platelet and thrombin deposition

leads to fibrin formation ,

vegetation (aka coaguIum) forms

on the valve

bacteria enter circulation via:

mucosa membranes

vegetation becomes nidus

skin

for Infection via bacteremia (usually transient) nfections

Staphy/ococcus aureus (most common) -

bacterial infection activates inflammatory response

Streptococcus sanguis, bovis, mutans, mitis 4

these organisms are responsible for > 80% of

infective endocarditis

Enterococcus

HACEK organIsms (Haemoph#us, Actinobaci#us,

vegetation increases in

Cardiobacterium, EikenelIa, Kingella)

size as platelets and

fibrin are deposited

nonspecific signs and symptoms:

fever (most common)
chills

bacteria are protected and able to

malaise

proliferate within growing vegetation

nausea

night sweats
arthraIgias
myalgias
weight loss

vegetation can embolize

to different location

infection leads to

activates both

bacteria resist host immune

clinical manifestations of - humoral and cellular - defenses and are able to

infective endocarditis

immune responses

immune complex deposition

can lead to

disseminate

(seemaps)
glomeruIonephritis
4 broad classifications of endocarditis:

immune complex vasculitis

native valve infections

prosthetic valve infections

infection from 1VDU
nosocomial infections

damage cardiac
structures:

valve destruction

new or chargIng murmur

heart failure

pericardilis
prosthetic valve endocarditis

Janeway lesions

complications of infective

, cutaneous findings - Roth spots

0sIer's nodes

endocarditis

septic joints

persistent bacteremia -

sepsis (see map)

right sided infective endocarditis leads to pulmonary emboli

common with 1VDU)
, septjc emboli

1eft sided infective endocarditis leads to emboli of brain,

spleen, kidney, gastrointestinal tract, extremities

0
bacteria colonize

bacteremia

nasopharynx

bactena cross

epithelial lining via:

membrane bound vacuoles

spaces between apical tight junctions

at this point polysaccharide capsule protects bacteria

bacteria access
labs show:

, from host defense

- bloodstream

mechanisms including

positive blood cultures

neutrophil phagocytosis

positive gram stain

classic complement cascade (see map)

arrive at choroid

plexus epithelial cells

bacterial meningitis lumbar puncture shows

reach CSF via:

CSF with:

bacteria multiply unhindered

+ because CSF lacks effective

direct infection of epithelial cells

migrate through or between cerebral capillary cells

' PMN leukocytosis

o glucose concentration

immune defenses

o protein concentration
9 opening pressure

1ysis of releases of cell wall components into

subarachnoid space:

1ipopolysacchande
techoic acid

peptidoglycans

leads to inflammatory
response

inflammatory cytokines

. TNF alpha

and chemokines released

ILl

by
mIcrogIia
astrocytes

o adhesion and migration

monocytes

of leukocytes = 1eukocytosis in CSF

microvascular endothelial cells

CSF leukocytes
0 CSF protein
meningeal inflammation

neutrophil

o permeability

degranulation

of cerebral

leads to cytotoxic

vasculature

edema

2 permeability

production of excitatory

of the blood brain bamer

amino acids, reactive oxygen radicals,

(BBB)

NO, peroxynitrite

serum proteins
leads to neuronal -

leak into CSF

vasogenic edema

cell death

1eukocytes
accumulate

inflammation causes

most clinical manifestations of

obstructs CSF flow

meningitis

while reducing ability

of the arachnoid vilIi
to reabsorb CSF

signs and symptoms can present

acutely or chronically

0lher symptoms:

classic meningitis
triad.
headache
fever

nuchal rigidity

mental status changes

(1ethargy to coma)
nausea

vomilIng

photophobia
se1zures

other symptoms specific to

o intracranial pressure causes

interstitial

obstructive and communicating

clinical signs and symptoms of meningitis:

altered cerebral

edema

hydrocephalus

blood flow

altered 1evel of consciousness

papilledema

diIated poody reactive pupils

abnormal head CT ,

sixth nerve palsy

causes other

decerebrate posture

complications

Cushing's refiex (bradycardia, irregular

inIcuding

respiratory rate, hypertension)

vasculius
thrombosis

type of bacteria (e.g petechiae)

ischemia
coma and/or

cerebral hemiation

infarction

't 'ii',4it*URINARy iI80*lINFECTION-

0
most urinary tract infections (UTl)
are ascending infections beginning
with bacterial colonization of the distal urethra

UTIs are divided

epidemiologically by
where the infection is

acquired
nosocomial acquired UTIs

community acquired UTls:

candida

Proteus

mirabilis

E. coli (most common)

coagulase negative staphylococci

other gram negatives such as other gram positives (S epidem#dis, S. aureus, E. faecahs)
KIebsielIa, Enterobacter, Serratia, Pseudomonas

bacteria ascend up the urinary tract with heIp of difierent predisposing factors:

mechanical factors including:

infectious / viruIence factors:

fimbriae (pili) enable bacteria to adhere to urethra and bladder wall

capsule preventing phagocytosis

membrane damaging toxins such as hemolysin

prevention of urine flow or bladder emptying
by conditions like pregnancy, BPH, renal calcuIi,
tumors, strictures, loss of neuro control,
vesicoureteral reflux

activities or conditions which enable bacteria to reach bladder

such as short urethra, sexual intercourse (for females), and catheterization

L bacteria can continue to ascend

into urethra causing urethritis
lower urinary tract infection:
dysuria
urgency

4 frequency
diagnostic tests:

, suprapubic pain
bacteria can continue to ascend into the bladder

urinalysis

asymptomatic

nitrite dip stick test

causing acute uncomplicated bacterial cystitis .

1eukocyte esterase dip stjck test

or complicated bacterial cystitis

urine culture

upper urinary tract infection:

. 4 lower urinary tract symptoms
' fever

flank pain
bacteria can contjnue to ascend to ,

CVA tendemess

prostate and kidney causing '

acute prostalitis

pyelonephritis and prostatitis

, prostatitis

chronic prostatiUs

8
:

nonbacterial prostatitis
(aka chronic peIvic pain syndrome)
rarely caused by hematogenous
spread associated with:
S. typhi
S.aureus
M. tubercu/osis

2 acute types:
pyelonephritis - acute uncomplicated pyelonephritis -

or acute complicated pyelonephritis

chronic pyelonephritis

3 causes

vesicoureteral reflux

obstruction

idiopathic

bacteria can continue to

invade bloodstream

and cause urosepsis

St{%2t,tiSEPSU;*DROM&i .9,
infection with:

bacterial membrane components

' bind CD14 receptor on monocytes

bacteria (most common)

fungi
virus

to11 1ike receptor sends

signal to cell to produce

proInflammtory cytokines

including: TNF-a

activates both classic

and alternative

complement pathways

IL 1

(see map)

promotes

induces inflammatory

extrinsic

cascade

coagulation

:
0

cascade (see map)

amplify one another
and initiate

thrombin systemic spillovef

lissue factor

- of in11ammatory mediators

however current theory

accompanied by

. Injures and

suggests pathophysiology

abnormal 8 in

activates endothelium

maylater shift to anti-inflammatory

fibrino1ysis

immunosuppressive state

hypercoagulable

leads to clinical state that can

state

be called either:

upregulation of thrombin receptors

2 proadhesive properties

9 thrombin
and fibrin 1evels

attracts more platelets, monocytes, neutrophils

systemic inflammatory

sepsis = SIRS due to infection

response syndrome (SIRS)

ft vasodilation

0 permeability

includes 2 of 4 clinical signs:

hyperthermia or hypotherniia
local or diffuse

tachycardia

microthrombi form

hypovolemia 1eads

tachypnea

blood is shunted

to poor tissue perfusion = - away from Gl tract

1eukocytosis or 1eukopenia

distributive shock

and toward kidneys

and CNS

depletes

depletes

dotting

platelets =

factors

thrombocytopenia

clinical state can progress to

severe sepsis =

sepsis associated with 4

hemorrhage

severe organ dysfunction

secondary organ dysfunction

due to "cell hibemation" ,

or "cell stunning"

CNS: altered mental stalus, confusion,

can progress further to

septic shock =

lethargy, septic encephalopathy

subset of severe sepsis

with low mean arterial blood

heart: initially hyperdynamic state =

pressure despite adequate fluid

high cardiac output, decreased vascular resistance,

resuscitation

ventricular diIation, low ejection fraction

can progress further to

lungs hyperventiIation, respiratory alkalosis,

refractory septic shock =

hypoxemia, acute respiratory distress syndrome (see map)

persistently low mean arterial blood

pressure despite vasopressor therapy
and adequate fluid resuscitation

Gl: ileus

can progress further to

liver. cholestatic jaundice,

disseminated

elevated bilirubin,

, intravascular

elevated alkaline phosphatase,

coagulation (DIC)

elevated aminotransferases

(see map)

kidneys: azotemia, 01iguna, proteinuria,

renal failure

can progress further to

multiple organ dysfunction syndrome

(MODS)

endocrine: altered pituitary

funcbon

Mycobactedum

primary infection begins with

tuberculosis (TB):

first exposure to aerosolized

in distal bronchioles and

droplets from another person

alveoli

0
aerobic

'

bacilIi inhaled and trapped

alveolar macrophages
ingest bacilIi

with active TB infection

intracellular

aka acid fast bacilli (AFB)

bacilIi replicate
intracellularly and
cause macrophages

to lyse
new bacilIi are released into

circulation = 1ymphhematogenous spread

macrophages

bacilIi ingested by circulating macrophages

present bacilIi antigen ,

initiates Th1 response

(see cell-mediated immunity map)

which then seed extrapulmonary sites

to mainly CD4 T cells

within regional 1ymph nodes

via MHC class lt proteins

cell-mediated
immune reaction leads

1 of 2 clinical outcomes can occur at this point

to 3 major effects

delayed type

/ activates macropha A

hypersensitivity reaction
or hypersensitivity reaction
type 4 (see map)

and augments their

bactericidal actions via

release of 1FN gamma

1
latent TB

leads to development

infection

of granulomas via release of

-7
clinical signs and symptoms:

TNF alpha by activated macrophages

severe

primary progressive or

, disease

miliary TB can develop if

can lead to

patient lacks immunity:

death

usually asymptomatic

HIV/AlDSpatients
CXR shows calcified

elderly

granulomas and fibrosis

TNF alpha causes monocytes

positive PPD

to differentiate into epithelioid cells

causes + PPD reaction

substance abusers

recent infection (within 2 years)

not contagIous

diabetes mellitus (see map)

immunosuppressive treatment

epithelioid cells form caseating granulomas

in order to contain bacilIi

consequent immune suppression

and limit spread

allows latent TB to reactivate =

1eukemia (see map)

renal failure (see map)

reactivated or secondary TB
some bacilIi can

some granulomas

survive within granuloma

heal via fibrosis

by disrupting nitric oxide

and calcification

3 major categories of TB disease

small millet seed sized

production and inhibiting

pulmonary disease

phagolysosome fusion

extrapulmonary disease

or post primary

miliary (or disseminated) TB

granulomas found

..

throughout the body

(most common)

1ymph nodes (most common) can form scrofula

if TB is reactivated

pleura
usually develops in genitourinary
apical 1obes due to skeletal (Pott's disease)
high oxygen concentration gastrointestinal

granuloma grows, 1iquifies

and drains = cavitation

bacilIi are released

into circulation and airways

cough

clinical signs and symptoms:

hemolysis CXR can be normal or show lower and

fever

middle lobe infiltrates with

TB infection is now contagious

weight loss

ipsilateral hilar 1ymphadenopathy (ghon complex)

via AFB positive sputum

anorexia

positive acid fast stain of sputum

night sweats positive sputum culture

n
C

0i

"- :: 3,

4js* *ij'
;A,e-* ,1

Endocrine Disorders

it452..I& DIABETES M E LLITI1UiL,

etiologies:
possible environmental trigger (virUs) - autoimmune attack of
gene1jc predisposition

pancreatic beta cells occurs vIa

humoral

mostly cell-mediated

immune

immune response

response

(see map)

(see map)

isIet cell

CD8 T cells

antibodies

i
8 beta cells

i
8 insulin

- cannot transfer

production

glucose into cells

1
, can present clinically as a - diabetes mellitus type 2 (see map)

hyperglycemia

chronic condition

1
can present clinically
as an acute condition

increased growth failure

r protein - weight loss

8 insulin

catabolism

o risk

o triglycerides

9 fatty acid

0 glucagon -

and

oxidation

of pancreatits

(see map)

VLDL

1 1

polyphagia

ketones:

o hepatic

acetoacetate

gluconeogenesis

beta hydroxybutyrate -

and

aceton; __*

glycogeno1ysis

acetone =

ketones /

fruity breath

ketonuria

vomiting

anion gap

metabolic acidosis -

(see map)

leads to excess

serum glucose which

, diabetic ketoacidosis =

exacerbates aIready

high glucose

existing hyperglycemia

low pH
high serum ketones

exceeds
renal threshold

lOSs Of: ,
0smotic diuresis

-.H20
K+

1 .Na+
glycosuria

O In

plasma osmoIality

polyuria

hypovo/emj

hypotension

dehydration

1
stimulates
thirst

optic disk swelling

blurry vision

loss of intracellular
fluid in brain can lead
to coma

polydipsia

8 bicarbonate

. #41**81,tY' DIABETES MItLITUS TYPE 2.'

. -:*3:mi8a,2 ,s -*S' t

0
mumple contributing factors:
genetics

lifestyle
obesity

initiating mechanism leading to insulin

resistance is unknown but could include:

post-insulin receptor (signaling) defect

elevated 1evels of free fatty acids

glucose dependent tissues

(skeletal muscle, liver,
adipocytes) are unable
to take up glucose

sends signals
peripheral
insulin

excess hepatic

to liver to increase

gluconeogenesis and -- glucose output

resistance

glycogenolysis
stimulates more
insulin release

glucose tolerance
is initially normal because

eventually

beta cells compensate by

beta cell

ilIness

g insulin production =

exhaustion

infection

hyperinsulinemia

occurs

of insulin receptors

glucose - 0smoIality approx -+

> 600 mg/dL

hyperosmolar

coma

>330 mg/dL

onset

insulin

leads to downregulation

plasma

acute

emergent -+

impaired

secretion

no ketones!

a glucose
uptake

hyperglycemia of

diabetes type 2

responsIble
for symptoms
and

labs:

fasting glucose > 126 mg/dL

elevated HbAlc

- onset determines

chronIc clinical presentation

complications
of diabetes

chronic

complications

insidious
onset

1ossof

microvascular

H20

excess serum

macrovascular

glucose exceeds
retinopathy:

- 0smotic diuresis

renal threshold

mIcroaneurysms

neovascularIzatIon

glycosuria

blindness

exudates

I K+
Na+

dehydration

polyuria

nephropathy:

e TG --1

glomeruloscIerosis
microalbuminuria

neuropathy:

proteinuria

gastroparesIs

chronic renal failure (see map)

orthostatic hypotension

9 LDL

stimulates

1-dyslipidemia

0 HDL_

thirst

i
polydipsia

stocking glove paresthesias

accelerated
atherosderosis

(see map)
MI (see map)
stroke (see map)

peripheral vascular disease

hypothalamus

but dysfunctional

T3 and T4
inhibit

continued

hypothalamus

8 in

ignores negative

TRH

feedback

releases

hypothalamic
release

TRH

normally o

which

of TRH

in T3 and T4 shuts

stimulates

down TRH production

anterior

pituitary

abnormality
at the 1evel

tertiary

of the

e in TRH rippIes -

. hyperthyroidism - down hormonal - ft in TSH -

hypothalamus

(rare)

causes excess

O in

-1

T3 and T4

axIs

release of TRH

anterior pituitary

T3 and T4
inhibit

continued

pRuibry
release
ofTSH

increase In
rele3ses

but dysfunctional
+-anterior pituitary

TSH

ignores negative

TSH

feedback

which
stimulates

thyroid

normally O

glends

in T3 and T4 shuts
down TSH and TRH

abnormality at the
1evel of the

anterior pituitary

production

o in TSH
secondary

e in

rippIes
--- hyperthyroidism: - down - 2 TSH - T3 and T4
pituitary adenoma

causes excess

increased metabolic rate leads to:

hormonal

release of TSH

increasedbone tumover and osteoporosis (see map)

axis

increased protein catabolism causing weightIoss, myopathy,

causes clinical

thyroid

- manifestations of -

glands

thyrotoxicosis
abnormality at the

causes excess

* hyperthyroidism: -

production of

Grave's disease

autoImmune type 2

antibodies

(see map)

localized deposition of

on thyroid

glycosaminoglycans
if uncontrolled

other causes:
toxic adenoma

toxic multinodular goiter

and T4

cardiac output and risk of high output failure and atrial fibrillation

hypersensitivity reaction - to TSH receptor

T3 and T4

releases T3

increased cardiac beta receptors causing increased heart rate,

production of

primary

1evel of the thyroid

proximal muscle weakness, and increased appetite

increased body temperature causing diaphoresis and vasodiIation

excessIve release of

or untreated

binds and

pretibial

overstimulates -0in

myxedema

TSH receptor

medical emergency

(non-pitting)

T3 and T4

indicated by:
TSH accumulates

blocks TSH - and signals anterior -8 TSH

De Quervain's thyroiditis

from binding

struma ovarii

1ts receptor

factitious thyrotoxicosis

exopthalmos

thyroid storm =

preformed thyroid hormone

thyroiditis (granu1omatous and 1ymphocytic)

leads to

pituitary to reduce
production of TSH via
negative feedback

tachycardia
fever
diarrhea

:I

5-- -

pX
5-<

10

nausea

agitation
delirium

hypothalamus

T3 and T4
inhbU

reteases

hypothalamic

TRH

release

which

ofTRH

stimulates
anterior

pituitary

abnormality
at the leve
of the
.

hypothalamus

tertiary hypothyroidism .[ in TRH rippIes

due
to:
down hormonal - 0 in TSH - less T4
trauma

causes o

axIs

tumor

release of TRH

anterior pituitary

t
T3 and T4
inhibit

pituitary
release

releases

8 LDL receptors=

of TSH

TSH

hyperlipidemia

which

4 812=

stimulates

signs due to

thyroid

8 in T4:

gl:nds
abnormality at the
secondary

rippIes

---+ hypothyroidism due to: - down

Sheehan's syndrome

causes 8

release of TSH

normocytic anemia

T4

hormonal

pituitary tumor

o prolactin:

axis

galactorrhea

hypopituitarism

1.

thyroid

menstrual irregularities
.*6

causes clinIcal

abnormality at the
1evel of the thyroid
causes decreased
release of
T3 and T4

manifestations of

primary
_ * hypothyroidism
due to:

Hashimoto's thyroiditis
(most common)

1
other causes:

drugs (including lithium

and amiodarone)

auto1mmune process =

post-ablative

leads to

hypothyroidism

both B and (primarily) T cells- apoptotic destruction

attack thyroid

1
chronic 1ymphocytic

>%%f*

of thyroid cells

4*t*

thyroid can no longer

bind iodide

if untreated

clinical (overt)

or severe

hypothyroidism

1 \

infiltrate initially causes

thyroid to become
enlarged and rubbery

myxedema

slow onset as

as T4 slowly

destroyed=

decreases

but eventually

subclinical

TSH

causes gland

hypothyroidism

increases

to become small and fibrotic =

signs secondary to

coma:

fo11jcular cells are

iodine deficiency

hypothermia
decreased

respiratory rate

signs secondary to

8 metabolic rate:

accumulation of

constipation

polysaccharides in tissue:

fatigue

periorbital edema

weight gain

pericardial effusions

cold intolerance

coma

dementia

ascites

hair loss

myxedema (non-pitting edema)

hung up reflexes

do not appear untiI

hoarseness

0heart rate

90% of follicular cells

cardiomyopathy

0 cardiac output

destroyed

neuropathy

atrophic thyroiditis
dinical symptoms

infertility

0 T4

glands

and T4

anemia

1 \8 erythOpolels=

8 in TSH

1evel of the

anterior pituitary

releases T3

- mE1crocytic

psychosis

*tf
f A-

.I

t.--1
,I

f;/

;0

..

0
chief cells within the

parathyroid glands
synthesize
parathyroid hormone (PTH)

if parathryoid

acute or severe symptoms of hypercalcemia:

1hyperparathyroidism(seemap)

nausea

glands

vomiting

autonomously
abnormality at the

produce

1evel of the

0 PTH

- hypercalcemia =

parathyroid glands

o serum

causing

if problem

hypercalcemia

elsewhere in the

confusion

depend on how quickly

coma

hypercalcemia develops

serum calcium

1there is overIap

body causes

calcium and

phosphate

parathyroid

inhibits PTH

hyperplasia

synthesis

elevated

clinical manifestations

' 8 serum

chronic symptoms of hypercalcemia:

- 2 hyperparathyroidism (see map)

nephrolithiasis (see map)

and o PTH

calcium and

osteopenia/osteoporosis (see map)

production

pathological bone fractures

/phosphate

osteosderosis

, promotes PTH synthesis

neuropsychiatric

polyuria
polydipsia

PTH enters

constipation

circulation
and binds

PTH receptors

direct invasion

malignancy:

primarily on

lung (squamous cell) cancer hypercalcemia-' and resorption

kidneys and

renal cell carcinoma r results from

bone to adjust

breast cancer

serum calcium
abnormal bone

1evels as

multiple myeloma (see map) mechanisms -% release of PTHrP

.' 1ymphoma (see map)

resorption

needed

leading to

which behaves

leukemia (see map)

just like PTH

hypercalcemia
abnormality at the

6P

causing o calcium

kidney failure

causing hypercalcemia

resorption and

hyperthyroidism

bone

1evel of the kidneys

of calcium

1of2

5 renal

ncreases

aluminum intoxication

calcium excretion

bone tumover

normally stimulates

F0

osteocIastic

normally 3 effects on kidney's

activity

role in calcium homeostasis

but PTH 1evels

increased

are norma

PhosPhate

increased

g calcium

0 phosphate

reabsorption

excretion and

G phosphate
reabsorption

resorption

resorption

activates vitamin D

of calcium

via hydroxylation

phosphate is
excreted in unne

activated vitamin D

in turn plays a role in

-, vitamin D intoxication

calcium homeostasis

abnormality at the
1evel oftheGItract
causing hypercalcemia

milk alkali

syndrome

abnormality

via 3 ways

with vitamin D

metabolism or
1evels

o calcium

normally indirectly o absorption of calcium

in small intestine via activaiton of vitamin D

(net effect is
o mineralization)

absorption of
calcium

'

.-<
-0

vitamin D:

and bone
mineralizatIon

- - + disease which

k n intestinal

g activation of

reabsorption

gas:rointesintal system

granulomatous

abnormal increases

o calcium
reabsorption
in kidneys

tuberculosis (see map)

o calcium

reabsorption in
small intestine

sarcoidosis (see map)

E rI

'ni
. rn*

calcium homeostasis maintained by

interplay between
serum 1evels of calcium

parathyroid glands via

PTH secretion

absent PTH

hypoparathyroidism
hypomagnesemia
surgical resection

high serum calcium

plasma calcium comes

causes

in 3 fonns

abnormality at the 1evel

6 PTH secretion

serum abnormalities

of the parathryoid glands

can affect calcium 1evels

hypoalbuminemia

can cause hypocalcemia by

free calcium -+

bound to

diffuse

albumin

complexes

(most common cause of

45%

exerls tight control over

preventing appropriate

PTH secretion by

PTH secretIon or function

functional
PTH is ineffective

classification of

chronic renal failure (see map)

hypocalcemia

vit D deficiencies or resistance

based on status

parathyroid glands

(see osteomalacia map)

of PTH

45%

pseudohypoparathyroidism

hypocalcemia)

most important

form because it

causes pseudohypocalcemia =

is biologically

serum calcium appears low because there is

active

low serum calcium

normally causes

PTH is "overwhelmed" by

0 PTH secretion

another pathological process:

i binding to albumin

hyperphosphatemia

tumor 1ysis
acute renal failure (see map)

hypocalcemia =

calcium correction formula

rhabdomyolysis

< 8.5 mg/dL

will distinguish real

from pseudohypocalcemia

PTH normally attempts to correct serum

calcium 1evels via its action upon:

gastrointestinal
system

f----------signs and symptoms of hypocal cemia:

neuromuscular: <
paresthesias
tetany

pancreatitis
--- malabsorption of calcium or vit D

hepatic insufficiency

PTH indirectly
causes Increased

respiratory

Gl calcium absorption by

laryngospasm

activating vit D in the kidney

bronchospasm

%*f

stridor

Chvostek's sign

Trousseau's sign <

abnormality atthe
1evel of the Gl tract

PTH does 3 things

kidneys - to the kidney to

seizures

ectodermal

, muscle cramping

brittle nails

parkinsonIsm

dry skin

psychosis

enamel hypoplasia

abnormality at the

o serum calcium 1evels

1evel of the kidneys

- chronic renal failure (see map)

acute renal failure (see map)
nephrotic syndrome (see map)
PTH resistance

hyperphosphatemia
I

cardiac

prolonged QT
T wave changes
congestive heart failure
systemic:

phosphorus

calcium

excretion

reabsorption

ocular:
cataracts

bone

abnormality at
the level of the

skeletal system

activates vit D

00>
in

osteoblastic metastasis

; 3>

PTH resistance

confusIon

weakness

PTH causes calcium

mental status changes

resorption from bone

, ItY

chief cells within the

primary hyperparathyroidism

parathyroid glands

caused by:

synthesize

parathyroid adenoma is (most common)

parathyroid hormone (PTH)

parathyroid carcinoma
parathyroid hyperplasia
if parathyroid glands
autonomously produce
more PTH

labs show:

MEN 1: cancer or hyperplasia of parathyroid, pituitary gland,

pancreatic islet cells and other rare neuroendocrine tumors . high serum calcium
MEN 2B: cancer or hyperplasia of parathyroid, medullary thryoid cancer, high PTH
and pheochromocytoma low-normal or low phosphorus
familial hypocalciuric hypercalcemia

abnormality at the 1evel of the

parathyroid glands can
cause o PTH secretion
if problem occurs elsewhere in

the body causing low calcium

nonnally o serum

leading to

calcium
and phosphate 7
inhibits synthesis

parathyroid hyperplasia
and o PTH secretion

of PTH

normally 8 serum

secondary hyperparathyroidism

calcium and phosphate

.4 causedby

promotes synthesis of

chronic renal failure (most common)

' PTH

long-term overstimulation of

PTH gland can lead to the

aluminum toxicity

vitamin D deficiency (see map) -

tertiary hyperparathyroidism

osteomalacia
disease state
overrides -

malabsorption syndromes

abnormally o PTH enters circulation

parathyroidgIands

skeletal resistance to PTH

primarily on kidneys and bone

mechanisms

become

hyperplastic and

clinical presentation
can differ from

labs show:

hypercalcemia

high PTH

. variable phosphorus

lithium

and binds PTH receptors

these feedback

labs show:

development of - , high calcium

autonomously
produce PTH

low or normal calcium pnmary hyperparathyroidism

/'

depending on

high PTH
variable phosphorus

underlying abnormality

often asymptomatic and discovered on routine chemistry screen

but when primary hyperparathyroidism is symptomatic the clinical presentation is characterized by "moans, groans, stones, and bones"
bones

bone:
stones

0 bone turnover

osteitis fibrosa cystica

I

osteoporosis (see map)

kidneys:

o risk of fracture
'

r.

0 calcium reabsorption

moansand groans

oriskof nephrolithiasis

Kl

nephrocalcinosis

chronic renal failure (see map)

hypophosphatemia
psychiatric:

gastrointestinal system:

neuromuscular

confusion acute pancreatitis , proximal muscle weakness

fatigue

gastric uIcers peripheral sensory neuropathy

depression constipation motor neuropathy

nausea

dyspepsia

--4,

ZI'

hyperchloremic metabolic alkalosis (see map)

C X' .

hypercalcemia (see map)

bO,
,' 0

hypothalamus

releases CRH (aka corticotropin)

acute onset

to stimulate anterior pituitary

due to:

8 androgen 1evels

Sheehan's syndrome

abnormality at the 1evel of

cause:

pituitary apoplexy

the hypothalamus

0 axillary and pubic hair

clinical presentation
chronic onset
2 adrenal

pituitary

insumciency

r . amenorrhea

adrenal insumiciency

due to:
anterior

, small testicIes

--*- unique to secondary

0 1ibido

prepubertal growth deficit or

prolonged steroid use (most common)

delayed puberty

pituitary tumor

dry, itchy skin

metastatic tumor

pituitary surgery or radiation

sarcoidosis (see map)

abnormality at the 1evel of

0 ACTH

hypothalamic tumors

the pituitary gland

releases ACTH to

8 glucocorticoid 1evels lead to

cortisol 1evels will rise in

stimulate adrenal cortex

common signs and symptoms including:

response to ACTH stimulation test

fatigue
weakness

dizziness

normal aIdosterone 1evels

weight loss

but hyponatremia can slj11

anorexia

adrenal gland

occur due to abnormal

nausea

vasopressin release

vomiting
neurogenic stress

mood changes

can ovemde

hypoglycemia

feedback inhibition

hyponatremia
chronic onset

mild normocytic anemia

and stimulate

due to:

cortisol release
cortisolinhibits

further release of
CRH and
ACTH via

autoimmune adrenalitjs

0 mineralcorticoid

tuberculosis

1evels cause:

metastatic carcInoma (breast, lung, kidney)

salt craving

opportunistic infections assocIated

hyperkalemia (see map)

systemic fungal infection

abnormality at the 1evel of

the adrenal gland

1 adrenal insufficiency
--

or

Addison's disease

acute
-

3>

hyponatremia (see map)

1 *s*55\me'&*\

feedback inhibItIon

0
3.

postural hypotension

clinical

presentation /
onset

r-

cortisol 1evels

unique to

will not rise

due to:

Addison's

o ACTH

meningococcal septicemia

disease

1evels

Cf
..
-rl

, in response to

ACTH stimulation
rn

(Waterhouse-Friderichsen syndrome) -

test

coagulation disorder or warfarin/heparin use

cause o stimulation of

anti-phospholipid syndrome

n.

melanocyte receptors resulting in

releases cortisol

hyperpigmentation of skin creases,

scars, and mucosa

acute onset leads to

adrenal or Addisonian crisis

cortisol plays an
important role in:
carbohydrate, protein, and 1ipid metabolism
synthesis of catecholamines
wound healing
vascular tone and permeability

can be precipitated by
medical emergency characterized by:

infection, trauma, or surgery

severe hypotension or hypovolemic shock

E.
0%
Z4

. U:j
.5 Of

unresponsive to fluid resuscitation or pressors

acute abdominal pain
vomIting

3>3
i/'

rn 1

fever

hypoglycemic seizures (in children)

0
hypothalamus

hypothalamic abnormality

causing hypersecretion of CRH

releases corticotropin
releasing hormone (CRH)
to stimulate anterior pituitary
ectopic CRH
(produced outside of

cardiovascular.

the HPA axis)

hypertension
o ACTH levels

anterior

musculoskeletal

pituitary

osteoporosis
o growth in children

high-dose dexamethasone
supression test does
pituitary adenoma

musde wasting
proximal muscle weakness

suppress corbsol

(aka Cushing's disease)

skin:

thin (cigarette) skin

releases adrenocorticotropic

easy bruisability

hormone (ACTH)

cortisol binds

to stimulate adrenal cortex

ectopic production

of ACTH (and/or CRH) by nonpituitary tumor

(outside of the HPA axis):
small cell carcinoma of lung

hypercortisolism =
Cushing's syndrome

throughout body
leading to

multisystemic effects

bronchial carcinoid

pancreatic cancer
thymoma

adrenal gland

violacious stria

glucocorticoid receptors

low-doSe dexamethasone

metabolic:

truncal obesity
moon facies

buffalo hump
9 triglycerides and cholesterol
glucose intolerance / hyperglycemia
metabolic hypokalemic alkalosis (see map)

supression test does not

suppress cortisol

reproductive

menstrual irregularity / amenorrhea

adrenal neoplasms produce
excess cortisol

, ACTH levels via

adenoma

cortisol inhibits

feedback inhibition

carcinoma

further release of
I

CRHand

8 testosterone

,impolence

loss of body hair

other.

exogenous glucocorticoid administration

eye: cataracts, glaucoma

psychiatric: lethargy, depression, psychosis

(outside the HPA axis)

immune system: fungal infections,

ACTH via

feedback inhibition

o cortisol production decreases

reactivated TB, poor wound healing

suppresses HPAaxis
releases cortisol

cortisol production

in circadian pattern

causing atrophic

rr,

adrenals

cortisol plays an
important role in:

carbohydrate, protein, and 1ipid metabolism

synthesis of catecholamines
wound healing

vascular tone and permeability

cortisol is ultimately
metabolized by the kidneys
and secreted into the urine
0

rn

0 24 hour urine free cortisol 1evel

is the best screening test for Cushing's syndrome

0
hypothalamus synthesizes
arginine vasopressin (AVP) aka
antidiuretic homione (ADH)

in response to either:

Oblood osmoIality
large intravascular volume deficit

ADH is transported to ;
posterior pituitary

abnormality at the

1evel of the hypothalamus

and/or pituitary gland causing
lack ofADH synthesis
or secretion

-- central diabetes insipidus

caused by
surgical removal
trauma
tumor

congenital abnormality
Sheehan's syndrome

low levels of ADH

urine concentrates

nonnally in response to

desmopressin (DDAVP)
because kidney function is
hypotonic (dilute) polyuria

normal

accompanied by:

posterior pituitary
secretes ADH into

low urine 0smoIality

circulation and elicits

low specific gravity

low urine sodium

2 major physiologicresponses

high plasma 0smoIality

more important

high plasma sodium

of 2 responses
nephrogenic diabetes insipidus

abnormality at the
1evel of the kidney prevents
normal response to DDAVP

oblood pressure

both forms of diabetes insipidus result

in the body's inability to:

pregnancy

muscle to vasoconstrict =

genetic defects in ADH receptor

downregulation of aquaporin channels
due to hypercalcemia or hypokalemia (see maps)

'

1. ADH causes smooth

caused by:

2.ADH q water
reabsorption by kidneys
by stimulating insertion of

concentrate unne
conserve water

,:f: U

sickle cell

t"41

drugs (lithium, amphotericin b,

ef*

demeclocycline, colchicine)

aquaporins into collecting tubules

and ducts

normal or elevated

polydipsia due to

a positive "water deprivation test"

activation of thirst

demonstrates patient's inability to

in response to

concentrate urine despite

o serum osmoIality

dehydrated state

levels ofADH

restores water homeostasis

within the body

results in
concentrated urine

urine will not concentrate

in response to DDAVP

because kidneys are not

f urine osmoIality
and urine specific gravity
u11jmate goal is to restore

re%

functioning normally

however, if patient is unable to drink then

clinical state can progress to:

C.
rr
-1

dehydration

prerenal azotemia (see acute renal failure map)

hypematremia (see map)
hyperchloremia

Z1
-0 *

5,j

perfusion when the body is confronted with

volume deficits

0
closely associated with

normal water , antidiuretic hormone (ADH)

homeostasis

or arginine vasopressin (AVP)

ADH synthesized in the hypothalamus

transported and stored within , ADH is normally released into circulation

the posterior pituitary

in response to 2 physiologic stimuli:

Syndrome of Inappropriate ADH Secretion (SlADH) can be caused by

9 ADH

lung disease: pneumonia, lung tumors, tuberculosis

release which occurs independently

-+ drugs: cyclophosphamide, phenothiazines, antidepressants

of normal physiologic stimuli

hypothalamic abnormalities: head injury, brain tumor, meningitis

and normal PoSm

carcinomas: 1ung small cancer of lung, duodenum, pancreas

o ADH

leads to exaggerated

physiologic effects

1. when 0smoreceptors within the anterior

2. when baroreceptors locat

hypothalamus indicate

atrium and carotids indicate

u plasma osmoIality (Posm)

hypovolemia

stimulates thirst to q

released ADH restores fluid balance by

water intake

acting upon receptors within

highly o water reabsorption

highly concentrated urine =

and oral intake =

urine osmoIality > 300 mOsm/kg

hypervolemia

kidney collecting tubules

expanded circulating volume

water dilutes

stimulates

serum electrolytes

-0
-0

atrial naturetic peptide (ANP)

0 synthesis and

and insertion of aquaporin

-0

water channels in tubules ,

dilutes

dilutes

dilutes

1eads to naturesis which causes

bicarbonate

potassium

sodium

urinary sodium and water loss

3>
rn

o water reabsorption

exacerbates

concentrates

urine

o H+ secretion

but K+ shifts out

by kidneys

of cells while

3>
Z

hyponatremia

H+ shifts into
C

cells

0 plasma volume

8 plasma osmoIality

1
negative feedback causes reduction of ADH release

, normalizing serum

K+ and pH

hypoosmolar hyponatremia (see map)

0

develops when

sodium is < 135 mEq/L

symptoms of hyponatremia

no or little edema

include:

because most of water

confusIon

gain is intracellular

nausea
seizures

frI

4.

-*. : t..
.**c., ..

Rheumatologic and Bone Disorders

*&bS

unknown etiology:

genetic susceptibility (HLA-DR4)?

infectious?

autoimmunity?

unknown antigen activates

CD4+ Thl cells

CD4+ cells in tum activate:

B cells differentiate into

monocytes

plasma cells

macrophages
activates B cells

which produce

synovial fibroblasts

antibodies including:

polyclonal immune globulin

rheumatoid factor

release matrix metalloproteinases (MMPs)

secrete inflammatory

which destroy cartilage matrix -

cylokines including:

0 anglogenesis

' in the synovium

IL 1 and TNF-ot

rheumatoid factor ( RF) =

immune complexes

1gM antigIobulin formed

formed

cytokines suppress

against Fc portion of human 1gG

MMP inhibitors leading to

endothelial cells activated

o cartiIage destruction

and recruit inflammatory cells

actIvates complement cascade

RF is present in 70% of

(see map)

patients with RA
but also other diseases

osteocIasts activated

complement o

such as SLE (see map)

forming: bony erosion,

inflammation and

subchondral cysts,

acute phase reactants

osteoporosis

such as C-reactive protein

chronic inflammation

(see map)
leads to erosion of both

vasculitis of small and

cartilage and bone

medium arteries -

with accompanying

thickening of synovium

systemic manifestations
rheumatoid nodules -

include

synovium intially becomes hyperplastic

and then hypertrophies

systemic symptoms:

into a pannus composed of

low grade fever

inflammatory cells,

weight loss

pleural disease:

FeIty's syndrome =

with joint effusions

spIenomegaly and

commonly involving:

pancytopenia

WriSt

interstitial fibrosis

ankIes

pulmonary nodules

elbow

pneumonitis / pleuritis

granulation tissue, and fibroblasts

symmetric arthritis

malaise

joints are red

swollen, warm, and

painful

pannus invades and destroys

cartilage via secretion of
proteolytic enzymes

pannus eventually grows over

can "bridge" to the bone

a bony ankylosis
'C

3>

knees

cervical spine

tendons, ligaments, and

joint space are destroyed

usually affects smaIll joints of
hands and feet first

joint deformities:

metacarpophalangeal (MCP)
proximal interphalangeal (PIP)

pannus ossifies and forms

arlicular cartilage and -+

swan neck

x-ray shows:

pain is characterized by:

boutonniere

bony erosions

worse with movement

uInar deviation

osteopenia

morning stiffness > 1 hour

hyperextension

narrow joint space

2 main components of
articular cartilage
found within joints

proteoglycans =

collagen=

provides cartilage with stiffness

provides cartilage with tensile

to resist damage from high

strength to resist

loads

shearing forces

together these components contribute

to the 2 mechanical functions of carbIage

enables joints to

disperses weight

glide over one another

over joints so that bones

smoothly to create fluid

do not break under concentrated load

movement

osteoarthritis (0A) = synovial joint failure occurs with loss of cartilage

due to:

primary or idiopathic OA (most common)

secondary 0Adue to the congenital, endocnne, metabolic, or trauma-based etiologies

biochemical abnormalities

mechanical abnormalities

IL 1 and TNF alpha

exacerbates

* activity of

g stress placed upon joints assoiciated with:

one

matrix metalloproteinases (MMPs)

relative to decreased inhibition

8 levels of

age

another

repetjtive use

inhibitors of matrix

genetics

degrada8on such as

trauma

tissue inhibitor metalloproteinase (TIMP)

f degradation of

plasminogen activator inhibitor (PAl-1)

proteoglycan matrix

negatively influences the biochemical properties of cartilage

, disrupts cartilage metabolism

so that cartilage catabolism >
cartilage repair and synthesis

disease process is most obvious

within load bearing joints

cartilage initially thickens

in response to damage but
eventually thins, fissures,and

loss of cartilage eventually

, affects other tissues of

the synovial joint

uIcerates

followed by remodeling
- and hypertrophy of bone =
compensated osteoarthritis (0A)

clinical picture of OA is
bony abnormalities

defined by joint pain that is

aggravated by use
relieved with rest

altered joint structure

aflects joint function '

result including:
osteophytes or spurs

moming stiffness that lasts < 20 minutes

scIerosis

symptoms

4 rangeof motion

eburnation

are not

crepitus

note:

systemic

involved joinS include

hands: DIP joints have Heberden's nodes, PIP joints have Bouchard's nodes, "squared' thumb base
spIne: joints show osteophytes on x-ray
knees

risk factors:

genetics

, imbalance occurs

alcohol

during bone

smoking

remodeling between

low calcium diet

low vit D diet

low physical activity

female

osteoblasts lay down

bone formation

bone resorption or turnover

, collagen type 1 and other

low baseline bone density

proteins

as a young person

osteocIasts break down - these become new sites for

followed by a much

bony matrix and form

slower remineralization phase

lacunae

but as rate of bone turnover

exceeds bone formation

more bone enters

slow mineralization

phase (lasts several months)

trabecular structural

continuity is disturbed

which means more bone

is in a weakened state

causing irreversible
weakening of bone

asymptomatic but
decreased bone mass -

can be detected via a

DEXA scan T score < - 2.5

increased risk

of fragIlity fractures:
vertebral compression fracture (most common)
wrist (ColIes fracture)

osteoporosis

hip fracture

2 types

primary
, osteoporosis:
menopause

secondary
osteoporosis:

hyperparathyroidism (see map)

medications induding steroids,
heparin, antiepileptics
immobilization

glucocorticoid excess
(see Cushing's map)
hyperthyroidism (see map)
hypogonadism

multiple factors involved:

decreased calcium and

phosphate absorpljon / intake

decreased estrogen
1evels after menopause

N2 0STE0MALACIAAND,,j,CKETS /

abnormal
bone

7-dehydrocholesterol

mineralIzatIon

(in epidermis)
little or no exposure to sunlight _

caused by 1 of

dark skin pigmentation

2 major deficiencies
some cases

caused by
phosphate

Vit D3

' poor diet

deficiency

poor maternal nutrition -

* is absorbed
by intestine

celiac sprue

pancreatic insumciency
deranged
phosphorus
homeostasis due to:

caused mainly by

chronic antacid use

vitamin

x-linked hypophosphatemia

deficiency

caused by
D

, liver disease

multiple mechanisms
including:

transported to

liver

Fanconi syndrome

25 hyd

renal tubular acidosis

25(0H) Vit D

leads to

calcidiol

8 caldum absorption
from intestines

CO

renal disease

hypocalcemIa

stimulates PTH secretion =

causes o serum

1 alpha-hydroxylase deficiency -

alkaline phosphatase due

(hereditary vitamin D

to o bone tumover

dependent rickets Type l)

2 hyperparathyroidism

transported to

kidneys

1 alpha-

(see map)

hydro
calcitriol receptor deficiency or defect

causes

(hereditary vitamin D

hypophosphatemia

dependent rickets Type 11)

through urinary
excretion

affects bone

"blunts" hypocalcemio

mineralization

temporafily by

even if serum calcium

ls normal

8 calcium

9 calcium

osteoid laid down

excretion

by osteoblasts is

from kidneys

resorption from
bone

2 calcium

activates

absorption

a 1 hydroxylase

from gut

in the kidney

not adequately
mineralized

9 activaton
but eventually
hypocalcemia

excess unmineralized

can develop '

bone matrix

in children

of vit D to calcitriol

in adults

Interferes with

deranges

growth plate =

bone remodeling =

rickets

osteomalacia

, weakens bone
structure

bone pain
excess epiphyseal
cartilage causes loss of structural rigidity =
rachitic process

waddling gait
grossskeletal
deformities result
craniotabes

rachitic rosary
frontal bossing
pigeon breast
lumbar lordosis

bowing of legs

muscle weakness

pseudofractures

1,25(0H)2 Vit D =
* calcitriol

(active form)

Neurologic Disorders

etiology has genetic basis

associations with:

- trisomy 21
traumatic head injury
high cholesterol
high homocysteine 1evels (controversial)

inherited mutations occur

in early developing
A1zheimer's disease:

more commonly sporadic mutations

APP gene

(aka susceptibility genes) occur

presenilin 1 gene

in late developing A1zheimer's disease:

presenilin 2 gene

apolipoprotein E gene

amyloidogenic mutations
interfere with normal processing

, APP isa transmembrane

of amyloid precursor protein (APP)

glycoprotein with uncertain

functions which could include:

cell substrate adhesion

leads to cleavage of

synaptogenesis

APP by beta and gamma secretases

synaptic plasticity

into 13 amyloid

promotion of neuronal cell survival

leads to 11 amyloid deposition and senile (or neuritic) plaque formation

mild =

short-term memory loss

plaques consist of B amyloid core

neuronal cytoskeletal

surrounded by dystrophic neurons, reactive

abnomIalities result

1.2rt**

depression
poor judgement

astrocytes, and microgIia

mood and personality changes

development of

plaques affect 2 major components of the central nervous system

neurofibrillary tangles =

moderate =

hyperphosphorylated
causes loss of
cerebral vasculature

brain parenchyma including: - cholinergic

causing amyloid angiopathy

hippocampus

worsening memory loss

microtubule associated Tau protein

clinical categories

. t.Jt
4.

neuropsychiatric symptoms

visual hallucinations

activity

entorhinal cortex

microtubule dysfunction leads to

association areas of neocortex

neuronal degeneration and loss

faIse beliefs

abnormal sleep pattems

basal forebrain
blood vessels become
friable and are at o

risk of hemorrhage

severe =

cortical atrophy accompanied

progressive loss of cognitive function

A-13 plaques are neurotoxic via

by widening of sulci and- causing most common form of dementia in elderly =

mechanisms of:

ventricular enlargement

A1zheimer's disease

motor signs including loss of

ability to speak, eat, etc

rn

motor rigidity

cognitive decline

oxidative stress

K
,

LA '

inflammatory mediator release through activation of microgIia

disruption of neuronal calcium homeostasis

diagnosis made by:

physical exam

rn;

patients most commonly die of

cognitive testing

infection, concomitant ilIness or

ruling out other diagnoses

lack of ability to eat/swallow

, rn

mulitple and unknown

etiologies

sporadic (most common)

familial (for example alpha synucIein, parkin, DJ-1 mutations)

secondary forms: environmental, drugs (typical antipsychotics), MPTP insecticide exposure, head injury

3 major mechanisms which may interconnect different etiologies

to common endpoint of dopaminergic neuronal loss

may in tum ,

mitochondrial

dysfunctio

exacerbat

oxidative

ubiquitin proteosome

and nitrosative stress

system dysfunction

abnormalities related

alpha synucIein - tothe mitochondrial-

damages:

prevents breakdown

protein aggregation

11pids

of cytotoxic proteins

complex lead to

proteins
DNA

o reactive oxygen

species (ROS)

8 ATP

ormation

e
while surviving
neurons contain

1ewy bodies =

death of

dopaminergic
neurons

eosinophilic
intracytoplasmic
prote1naceous
inclusIons

mainly affects dopaminergic

. neurons found within the

8 in dopamine 1evels
affects the cortico-basal ganglia loop via 2 pathways

substantia nigra pars compacta

..1
L excitation

5 inhibition

of the direct pathway

of the indirect pathway

no promotion of movement

unchecked inhibition of

via the thalamic nucIei

movement via thalamic nucIei

results in a net effect of

inhibition of cortical motor pathways =

hypokinetic movement disorder

motor symptoms:
bradykinesia

asymmetric resting tremor (pill rolling) \

cogwheel rigidity

dyskinesia
shuffling gait
postural instability

non-motor symptoms:
slow cognitive abilities

masked facies dementia

hypophonia depression or anxiety

micrographia psychosis

urinary and bowel dysfunction sleep disorder

.- 1. ..*.

. ::,i.,3.2 HUNTINGTON'S DISEASE'..

genetic mutation
of chromosome 4
occurs in autosomal
dominant fashion

leads to development of CAG - repeats > 40

trinucIeotide repeats
which code for glutamine

i higher # of repeats =
earlier onset of disease

overexpression of glutamine
occurs within mutant

huntingtin protein

1
exact function of

huntingtin protein
is unknown but is

could directly

fragments aggregate into

proteolytic processing

neuronal cell death

and bind ubiquitin

polyglutamine tracts

neuronal degeneration

or indirecty lead to - and death occurs

produces fragments of - intranudear inclusions

via apoptosis

associated with:
vesicle membranes
microtubules

role of aggregates is

probably interferes

endocytosIs

controversial:

with normal neuronal

intracellular trafficking

cytotoxic?

cell function

membrane recycling

neuroprotective?

mainly affects the

striatum causing atrophy of putamen and caudate

(caudate is first) .
damaged striatal neurons

exert less inhibitjon

1st affects the

later affects the

striatum decreases

upon the external

indirect pathway

direct pathway

inhibition of

globus pallidus (GP)

internal globus pallidus (1GP)

GP increases

1GP is able to exert more

inhibition of the

inhibition of thalamus

subthalamic nucIei

subthalamic nucIei

less stimulation of

decrease excitation of

motor cortex

intemal globus pallidus (1GP)

1GP exerts less

slowing down of

inhibition of thalamus

motor movements =

athetosis

overslimulation

of the motor cortex = hyperkinetic

movement disorder characterized by
irregular jerky movements or
chorea

, other signs and symptoms include:

clumsiness

slow saccadic eye movements

memory problems
concentration problems
depression
paranoia
hallucinations
dementia

ultimately fatal due to

aspiration pneumonia or
suffocation secondary to dysphagia

0
normal neuromuscular

transmission begins with

an action potential traveling
down the motor neuron

action potential reaches

the nerve terminal

this leads to activation of calcium

channels

/ synaptic vesicle is
recycled

synaptic vesicIes containing

o calcium causes

acetylcholine (ACh) to be released

into synaptic cleft
T cell process

unknown initiating event ------- . produces ACh recptor antibodies which reduce
normal neurolransmission = myasthenia gravis

1
associated risk factors Include
autoimmune disease

3 mechanisms -

thymus abnormalities (tumor, hyperplasia)

most significant

genetic link

mechanism

during normal
ACh binds ACh

receptors (ACh R)
located on muscle plasma
followed by rapid decline in

membrane

amountofACh
released with each

directly alters function

activates

of receptor by blocking

promote

ACh binding and ACh R

endocytosis of ACh

ACh deactivation by

ACh R channel opens

acetylcholinesterase (AChE)

and allows sodium into

within the synaptic cleft

musde

post synaptic
accelerates the

surface leading to

degradation of

decreased number

ACh R

ofACh R

8 neuromuscular transmission to
skeletal muscle

generates action potential

' reactivations ofACh receptors

exacerbates

voItage-gated sodium
channels open and allow
more sodium in

, muscle fatigue caused by disease

1
muscle weakness and

myasthenic fatigue

i
of myasthenia gravis

to muscle contraction

diagnosed via

4'7*

5* 3

' positive edrophonium test

extraocular muscIes

diplopia
ptosis

fatigue with repetitive use =

clinical presentation

action potential leads

(see map)

destroys

- impulse is reduced =

rising sodium 1evel

this prevents multiple

complement

activation

presynaptic rundown

ACh levels via:

ACh diffusion

neurotransmission

facial weakness

chewing problems

'snarting' expression upon smiling

' nasal speech
swallowing dimculties

generalized weakness
proximal limb weakness
normal deep tendonreflexes
respiratory muscle weakness

4-1

S3

unknown etiology
(possibly an environmental insult)

i
occurs in a genetically susceptible
individual leading to immune

system dysregulation = autoimmune disease

1
anatomical starting point of
disease process is controversial

i
does it begin as a primary abnormality of

does it begin as a

peripheral immune response?

primary CNS abnormality?

i
1eading to dysregulated

leading to CNS

peripheral immune response

injury

t
in turn leading to
more CNS injury
ultimately CNS injury occurs and causes

clinical presentation of multiple scIerosis (MS)

3 components characterize

heterogeneous pathophysiology

dif erent components may be inter elated or oc uring independently of one another

demyelination and plaque formation

1
occurs primarily in white
matter of brain

diagnosed by MRI which shows:

gadolinium leaking into brain parenchyma via

axonal injury
prevents propagation

of action potentials down

inflammatory response

inflammatory demyelination

abnormally permeable BBB

the axon

multifocal lesions in brain, brainstem, and

spinal cord

causes transection of

consisting mainly of

axon

T cell response
axon forms ovoids
T cells activated

via Thl pathway

amyloid precursor protein

by unknown antigen

accumulates

wallerian degeneration
this immune response is

requires less costimulatory signals

abnormally permeable

develops T cell memory pools

and invade CNS

1
T cells reactivated

by unknown CNS

occurs distal to transection

axonal transport

more reactive

immune cells adhere to

blood brain barrier (BBB)

indicating impaired

0 1FN gamma
8 regulation of CD8 cell activation and

effector functions by CD4 cells

15

, clinical presentation

> YS.

presentation depends

upon which type of

clinical course is followed:

1. relapsing remitting (most common form) = functional stability and

recovery between discrete attacks

remain dinically silent

for neuronal loss

3. primary progressive = steady functional dedine from beginning of

-0

disease onset with no discrete attacks

4. progressive relapsing = steady functional decline with attacks

untiI CNS can

no longer compensate

antgen:

1
symptoms include:

sensory symptoms including tingling, prickling, pain

limb weakness ataxia

rn

n
r-

rrI:

spasticity bladder and bowel dysfunction

molecular mimic?

epitope spread?

N43

2 secondary progressive = steady deterioration that is not related to attacks

most lesions

31
1,:,411".

axonal atrophy

optic neuritis cognitive dysfunction

diplopia

0
multiple mechansims believed to
cause different types of seizures
and epileptic syndromes

abnormalities occur
r level of neuronal circuits

at 2 basic 1evels of

central nervous system

1evel of individual neuron

abnormalities
with neurotransmission:

8 GABA inhibition

hyperexcitability

9 post synaptic excitation

neurons are more 1ikely

2 burst frequency of AP
kindling

to propogate action

-EB

potentials inappropriately

g
2

alters tI way

:
abnormalities

with extracellular

seizure =

neurons communicate with

lasts > 30 minutes =

sustained neuronal discharge

status epilepticus

one another creating

environmenl:
-EB

0 extracellular K+

- 2major components of
epileptogenesis

altered ion channel function

glial cell abnormalities

altered intra- and extracellular ion
concentrations

epilepsy

i
epilepsy syndromes

hypersynchronicity

are divided into 2 major

excitation is more 1ikely to activate

9

if seizure
recurrent seizures =

repetitive, excessive, and - -

categories

and involve neighboring

neurons and circuits

inappropriately
8
abnormalities

with neuronal morphology:

4 extracellular space

mossy fiber sprouting

cIonic seizures

gap junctions

several myocIonic

scIerosis

seizures occunng

gliOSiS

in rapid succession

plasticity

generalized

cortical malformations

partial or focal

seizure activity begins

in both hemispheres

h.*

sudden loss of postural tone

1%1',.'

, tonic seizures

at the same lime

one or more

atonic seizures:

'C*P*

flex at waist and neck

localized foci in one

abduction flexion/extension

hemisphere

of upper extremities

usually occur during sleep

rn

2 subdivisions of parbal seizures

based on 1evel of consciousness

myocIonic seizures

i
simple partial seizures =

brief shock like jerk of muscle or muscle group

complex partial seizures =

conscIousness ls preserved
Jacksonian march

kfA.",

altered consciousness

tonic cIonic or grand mal

poly spike and slow wave discharge on EEG

absence or petit mal

staring with impaired
awareness or responsiveness
no postictal confusion

staring

(most common)

usually children

automatisms such as

tonic phase = stiffening, fall, cry, legs extended

3 Hz spike-wave discharge on EEG

1ip smacking and chewing

postictal confusion

cIonic phase = jerking of extremities

drooling, foaming, biting of tongue / cheek / 1ip
bowel or bladder incontinence

partial seizures can progress to secondarily

postictal confusion or lethargy

generalized seizures

generalized polyspikes on EEG

3>
Z
U

r- 4
rTl
-0

9 INTRACRANIAL HEMQRRHAGE .

bleeding into brain

parenchyma

4 classifications
based on location

risk factors include:

chronic hypertension (see map)

F- hematoma

vascular malformations
brain tumors

subdural

commonly caused by

ruptureof

platelet and coagulation disorders

hematoma

cocaine

middle meningeal --. fracture of temporal bone

cerebral amyloid angiopathy

aMery

rupture

intracranial or

of bridging veins

intraparenchymal

hemorrhage (1CH)
arterial pressure

venous blood

causes hemorrhage

fills potential

F- 2 pes -

space between

to expand rapidly

non-traurnatic

traumatic

forms a crescent dura and subarachnoid

shaped
hematoma

, bleed into
pressure

but hemorrhage

separates dura -

iis contained within

from the skull

crantal sutures

brain parenchyma
two types

hematoma forms
forms

lens-shaped
biconvex
hematoma

lucid inte<val

acute

chronic

subdural

subdural

focal neurological

hematoma

hematoma

deficit via mass effect

due to

blood accumulates

trauma

over weeks to months subarachnoid

(no symptoms)

hemorrhage (SAH)

assoated wth
elderly patients

because atrophic brain

compresses brain tissue =

has space to accommodate

oIder brain atrophies- accumulation of blood

mass effect

can cause

ischemia

vague symptoms result

hematoma or hemorrhage

sudden rupture
of major blood
vessel located between

arachnoid and pia

2types
9 intracranial

bridging veins

pressure

are more vulnerable

of surrounding

to tearing

tissues

non-traurnatic

traumatic

with minimal
brain tissue can

or no history

hemiate

of trauma

most commonly due to

bleed into

eg.cerebral

symptoms indude:

arlefial aneurysm

cerebrospinal

contusions

headache

(berry or saccular)

fluid

cognitive impairment
unsteady gait

focal neurological deficits

spontaneous
rupture leads to

eningeal
2 intracranial

irritation

pressure can lead

to brain hemiation

dinical presentation:

"worst headache of my life"

lethargy
followed by

photophobia

cerebral vasospasm

phonophobia
fever

nuchal rigidity
seizures

Kemig sign

ischemic stroke

Brudzinski sign

(see map)

4 major

mechanisms of ischemic stroke - embolic

from heart =

-- cardiogenic
embolus
atrial septal defect

stenotic

clot can

clot is formed

narrowed cerebral artery

outside of cerebral -

due to:

vasculature

most commonly atheroscIerosis (see map)

from 1 of 2

places

vasculitis
enters cerebrovascular

outside of the heart =

non-cardiogenic embolus:
aIr

circu ation

eventually
thrombotic -

global

.atrial fibrillation

originate

fat

leads to thrombosis

amniotic fluid

ischemia

due to hypoperfusion

clot fonns within

caused by:

, 8 cerebral blood -

a cerebral artery

cardiac arrest

flow for more than

shock

. several seconds =

severe hypotension

cerebral ischemia

hypoxic ischemic

encephalopathy
neurons and glial cells
energy

cells surrounding

F-

deprivation

cannot metabolize glucose

without oxygen

necrotic center= - kills cells can't

at center

schemic

penumbra

make ATP
ischemic damage

of ischemic

further accelerated

focus first

by inability to

membrane

switch to anaerobic

F- ion pumps fail

without intervention
cells become

tIansmembrane

vulnerable to

ion gradient

damage via

iS lOSt

metabolism

inhibits

glutamate
uptake

excessIve

extracellular

glutamate levels

constant stimulation

induces cell

of glutamate receptors= -

apoptosis

excitotoxicity
associated with
calcium and sodium

chronic HTN

enter cells

(see map) which

release more

neurotransmitters

including more glutamate

small vessel

resulting

depolarization - calcium

enters ce11 -1

manifestations

activates death of brain _- ischemic - associated

with
focal ischemia
enzymes:

proteases

phospholipases

cells =

infarction

size of
' vessel affected

stroke

lacunar

1ipohyalinosis or

infarcts

thickening of vessel

within

deep

depend upon
3 factors

location

J lacunar syndromes:

structures

pure motor stroke

pure sensory stroke

incerebral

endonucleases

causes athero-

infarctor /thromboticor

clinical

vasculature
f10wls

affected

quickly restored

posterior circulation

before neuronsdie
anterior circulation

supplied by vertebral arteries

supplied by
symptoms are transient =

carotid arteries

supplies only 1/5 of brain but

transient ischemic

this includes the brainstem

attack (TIA)
supplies
most of brain cortex

stroke territories:

stroke territories:

anterior cerebral artery

posterior cerebral artery

basilar artery

middle cerebral artery

vertebral artery

intemal carotid artery

posterior/infereior cerebellar arteries

 Female Reproductive System Disorders

0
hypothalamic abnormalities:

pituitary abnormalities:

hyper or hypothyroidism

Sheehan's syndrome

stress

prolactinoma

anorexia

exercIse A

hypothalamus ' stimulates anterior pituitary -iM-* FSH:LH > 1

releases pulses of
GnRH

to Telease gonadotropins:
LH

FSH

primary ovarian failure:

Tumer's syndrome

follicular phase of ovarian cycle

stimulates

polycystic ovarian syndrome (see map)

leads to secretion of:

. polyglandular syndrome

granulosa cells <

tosecrete
estradiol

1
estradiol

secondary ovarian failure:

lack of gonadotropin stimulation

progesterone--...*--.

) excessive androgen production:

enters granulosa cells

and is aromatized into

Cushing's syndrome (see map)

estradiol

congenital adrenal hyperplasia

r rising estradiol 1evel

anatomic abnormalities of uterus and outflow tract:

' Ashermann's syndrome

proliferative phase of endometrium

9 LH receptors

expressed on theca cells --

ovulation of

LH surge - dominant follicle

inhibits pituitary gland
via negative feedback causing

--7

within 3 to 6 hours

8 FSH release

i
FSH:LH < 1

secretory phase of endometrium

luteal phase of ovarian cycle =

1 further prepares uterine lining

follicle turns into corpus luteum

for implantation

and secretes mostly progesterone

pituitary secretion of
FSH and LH 8

diSt.

as progesterone rIses

f.-------------- -

if implantation occurs =

pregnancy induced amenorrhea

8 stimulation

of corpus luteum

if no implantation occurs

corpus luteum involutes

FiP

causing C in
progesterone

hypothalamus and anterior ' endometrium degrades

estradiol
LH

untiI o inhibition on

allows for increased release of gonadotropins =

and sIoughs off leading

new cycle begins

to menstruation

. r. -

3.I_ MENO PAU Sfi'2

0
onset of
penmenopause

caused by combination of -*-* 89k ovaries

. leads to a
decrease in

1 .....................

aging endocrine axis

quality of

quantity of follides

follicIes

"disorderly" pulses
of GnRH released

by hypothalamus

i.

anterior pituitary responds

makes ovary

makes less

less responsive

inhjbin

to normallevels

by releasing

of gonadotropins
less negative
feedback on

hypothalamus and
anterior pituitary

stimulates the anterior pituitary

to produce more gonadotropins

disproportIonately

high levels of
FSH compared

to LH

FSH attempts to
compensate for
decreasing
ovarian function

j
initially follicular

ultimately

secretion of estradiol

. 'follicular exhaustion'

remains normal

occurs

1
8 estrogen

produced by ovanes

1
endometrium

does not grow

# of cycles decrease

while duration of cycle increases

eventually

menses stops altogether

menopause= lack of menses for 1 year

menopausal syndrome:

physical changes:

vasomotor instability

alrophy of vaginal epithelium

hot flushes

changes in vaginal pH

night sweats

mood changes

0 in vaginal secretions
0 in vaginal/uterine circulation

sleep disturbances

peIvic relaxation

loss of libido

loss of vaginal tone

o risk for cardiovascular disease

osteoporosis (see map)

<t4,t.: POLYCYSTIC OVANY SYNDROME,

2 frequency

of GnRH pulses
released from

hypottalamus

could be contributing
to abnormal

causes pituitary

GnRH pulses

constantly low or

gland to preferentjally

low-normal 1evels

make more LH than FSH

of FSH

LH:FSH> 2 /'

0LH

classic ratio

(but not always seen)

stimulation of follicIes

theca lutein cells

without maturation

make more androgen

precursors from -

of single ovum

pregnenolone

granulosa cells , less progesterone

prOduced

secrete less estradi01

cholesterS 1
progesterone

necklace sign on

.oligomenorrhea - anovulation/

ultrasound

e
increased risk of developing
DM type 2

amenorrhea

infertility

17-0H progesterone
associated with ,

. associated

insulin resistance/

with

hyperinsulinemia

obesity

(see map)
and

gestational
diabetes

aromalase

0 amounts of
androstenedione

- 8 sex binding
begins

vicious cycle by

converts some

allows for

androstenedione
to estrone

globulin

in granulosa cells

production in liver

further

decreasing
testosterone

binding globulin r

mostly converted to

estrone converIed

testosterone

peripherally to

1eads to

estr.diol

e free testosterone

8 sex binding
hirsutism
acne

4 1ipoprotein

globulin
causes

more circulating

1ipaSe 3ctivity

estradiol

atherogenIc
1ipid profile:
8 HDL

0TG
unopposed and chronic
- exposure of endometrium to
estrogen

9 riskof
endometrial cancer

/* PREECLAMPWA/ECLAMPSIA

0
predisposing factors:

contribute to an abnormal

primigravida

'maternal vascular response"

multifetal pregnancy

to implantation

diabetes mellitus

hypertension
hydabdiform mole

normally implantation

family history of preeclampsia

induces matemal

obesity

uterine vasculature

renal disease

to undergo 2 major

types of change to
support placental
development

morphologIcal
changes

biochemical

changes
8 in

O in

diameter of

muscular and

blood vessels

elastic components
of blood vessels

o vasodiIators and

these changes

8 vasoconstrictors

allow more blood

. if left untreated -

to perIuse ,

intrauterine growth retardation

pIeIaIption / infarction

placenta

i
but unclear mechanism

prevents this from happening

, placental ischemia

adequately

01igohydraminos

, causes the release

of an unknown factor

more 1schemia and

damages

damage to endothelium

vascular endothelium

first placental :

then matemal

vasculature is affected

vasculature is affected

1 1
starts vicious cyde of

system wide endothelial

more hypoperfusion

dysfunction
damage to endothelium

9 vasconstriction

glomerular capillaries

exposes basement

relative to vasodIIation

leak protein

membrane to platelets

systemic HTN

proteinuria > 3 g/24 hrs

platelets aggregate and activate

> 140/90 at 20+ wks

or 2+ protein on urine dipstick

dotting cascade (see map)

hypoperfusion

CNS

11
headaches

kidney

liver

abdominal

visual changes pain

gestaticn

GFR goes

hypercoagulable

down

stroke

microthrombi

abnormal

o BUN, Cr and

1iver enzymes

uric acid

thrombocytopenIa

J <see map&

preeclampsia -

stroke

(see map)
can progress or be

HELLP syndrome*

superimposed onto
HELLP syndrome*
hemolysis
elevated 1iver enzymes
low platelet count

this could be a part of

if left untreated this condition

can progress

to seizures = eclampsia

./..