PATHOLOGY NOTES

DR. GOLJAN

GENERAL PAT

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TABLE OF CONTENTS FOR GENERAL PATHOLOGY NOTES
Prepared by Edward Coljan, M.D.

Pages
General Principles of Lab Medicine Cell Injury
I
I

1-8
9-22
,
1

Inflammation Immunopathology Fluids and Hemodynamics/ Acid-Base

23-41

42-59 60-92
93-117 118-158

Environmental Pathology"

159-186 187-213

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is copyrighted. All rights reserved

GOLJ'AN HIGH YlELD NOTE

FOR USMLE STEP 1©

~otc: This material is copyrighted. All rights reserved. No part of this publicati

n may be reproduced in an~ formor by any means. electronic Of mechanical, including photocopy, recording, or any informauon storage and retrieval s~ stem. \I ithout permission in writing from the publisher (Edward F. Gcljan, M.D ) Abbreviations commonly used: AD = autosomal dominant. AR = autosomal recessive, COD= cause ,)1' death, Dx = diagnosis. Me = most common. Met = most common cause: f;tx = treatment, SiS = signs.and SYlllpjOI!lS, SXR = sex-linked recesslx e
_.)\

High Yield Concepts
General Principles of Lab Medicine
Scnsltivity of a test; "pa it! 'iL)' in dise~!>e"A. TP = patient with the disease

in Genera)

Pathology

D_

., ~.

C.

FN = patient with disease who has a negative rest result formula for sensitivity- TP j TP + FN

.).

.,

use of a test v.... 100 D/II seD.l~iti,..ityith A. best used to sc,reen for di ease a.excludes disease when negative C. includ-es people witb disease when pos itive D, catchwords: ex,cludes and includes interpreurtion of a test with 100% sensitivity when i't returns normal in a patieutA always has a nel.!ative predictive value of l 00% (PV- = Th I TN + FN) B. it must be a TN test result (excludes disease) since there are no FNs; a TN is a true negative or a normal test result in a person without disease

C.
4

e.g., serum A- A has 100% sensiuivlty for SLE: a ne,gau.vesenJm ANA excludes SLE,
of a test with lOO'Yo sensitivity when it returns positive in a patientmay

interpretation

A.
B.

C.

(I) FP = false positive or a positive test result in a normal person (2) note that FPs are not in the formula for sensitivity people with tbe disease are alwavs inCluded e.g., a positive serum ANA result includes all people with SLE: it does IH,)1 confirm SLE since other diseases also have 11 positive ANA (e.g., rheumatoid arthritis, progressive systemic sclerosis) Disease No Disease Positive test Negative test (TP) 100 (F)i) 0
(FP) 10

be: a TP or FP:

(TN) 90

Calculate sensitivity ofthe est: TP / TP t FN = 100 I 100 - 0 = 100% Calculate PV-: TN I- Thl + FN = 90 / 90·+ 0 = 1001l/e
Specificity or a test: l. "negativity in healtb"A. = normal test result in a personwithout disease B. FP = patient without disease who has a positive test result

m

1

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All rights reserved

2.
3.

4.

C. formula for specificity- TN l TN + FP use of a test with 100% specificity- confimlS disease: there are no FP test results, therefore. a positive test must be a TP interpretation of a test with 100% specifieity when it returns positive in a patientA. confirms disease in that patient B. positive predictive value is always 1.,'90% (P0 = IF! TP + FP) C. must be a TP (confirms disease) since there are no FPs D. e.g., anti-Sm for SLE. has 100% specificity (no FPs): all pa.tients with a positive anti-Sm have SLE interpretation of a test with 100% specificity when it returns negative/normal in a patientA. may be a TN or FN: note that the FN rate is not in the formula for specificity B. it d.OesQat exclude SLE C. e.g, auti-Sm is negative in a patient: (1) does not exclude SLE (2) use other tests to confirm SLE if your suspicions are high Disease Positive test Negative test (TP) 90 (FN) 10 No Disease (FP)

0

(TN) 100

Calculate specificity of the test: TN J.TN + FP = 1QO1100+ 0 = 1,@0% Calculate PV'": TP I TP + FP = 90190 + 0 = '100%
(iT'

Calculate the reference interval of the test when given the mean of the test and 1 SD (standard
deviation):

1.
2.

remember to double the 8))-2

SD covers 95%_ofthe normal population

3.

4.

exampleA. mean of the test = 100 m_gldLand] SD:= 5 mg/dl, (2 3D""}O mgldL) B. reference interval = 90-110 mgldL (100 - 1·0= 90 and 100 + 10= 110) for each test, 5% of normal people will. have test results outside the reference intervalA. chance of a FP increases when more than one test is ordered on a patient B. example, 2 tests on a patient increases the- chance of a FP test result on one of those tests to-lO% SD is a marker of the preeision (reproduoibility) of the test- it is not a marker of how accurate tlie test result is

Accuracy: Precision:
'@"

®

good good

@

Accuracy: poor Precision: good

Effect of test sCllBitivitylspecificity ofa test on prevalence: L test with highest .sensitivity (not specificity) increases prevalence of disease (number .of people in a population that have disease)A. it picks up more people with the disease since it is a good screening test B. tests with high specificity confirm disease and help differentiate a TP from a FP but they are poor screening tests

2

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Effect of increasing the upper limit of norma] of a test reference interval (e.g. rluswg a reference interval of 0-4 nglmL to 0-10 nglmL) on sensitivity) specificity, PV+, and PV: 1. increases :specificity and positive predi.ctive valueA. higher values are more likely to representi'I'Ps than FPs B. specificity always increases, which actcniaticalty increases PV 2. decreases sensitivity and negative predictive value (PV)A. B. C. increasing specificity of a test always decreases its sensitivity and PVFN rate increases, since more people with disease are encountered interval increases a normal test result is more likely to be a FN rather than a TN as the reference

Effect of decreasing the upper limit of normal of a test reference interval (e.g., lowering the fasting gluco e level for diagnosing diabetes mellitus [DM] [rom> 140 mgJdL to >126 mg/dL) on sensitivity, specificity, PV and PV: 1. increases sensitivity and negative predictive value (PV) A. dropping the upper limit to a lower value means that more people with a negative test result are likelyto be TNs (rrot have DM) rather than FNs B. senaitivity and PV- always increase when the upper limit of a' test is lowered 2. decreases specificity and positive predictive value (pYlA. fewer people we likely to Have DM, a test result> 126 mg/dL is more likel to be a FP
B. than a IF test result summary schematic

Interval 0 - 4 Sensitivity 100% (no FNs) PV- 100% Specificity decreases

PY'" decreases Interval 0 - 1,0

PVT 100%

Specificity 100% (no FPs)

Sensitivity decreases PV· decreases
Prevalence:

J.

Erevalence (number of people with disease in the population studied) (number of Dewcases over a period of time) x Duration of the diseaseA. B.

... !ncideDce

V=IxD

as duration (D) decreases; prevalence (P) decreases

3

DISEASE COUNTRY

o
~

10

Interval 0 -10 Specificity 100% (no FPs) Sensitivity decreases (more FNs) rv' 100% PV- decreases (more FNs)

...

NORMAL

COUNTRY

+TN

Interval 0 - 4 Sensitivity 100% (no FNs) Specificity deereasesImore PV 100% PV decreases (more FPs)

FPs)

Note: TI1is material is copyrighted. All rights reserved C. as D increases, P increases D. iQ,cidence is a constant in this relationship prevalence calcuJation- 1'P + FN (aU people with diseasej' TP

2. 3.

+ FN + TN + FP (all people with and without disease) example- if treatment for leukemia lengthens the survival period but does not lead 10 its 'cure, prevalence (P) of leukemia increases owin~ to the increase in duration (0): no effect on
incidence (number of new cases of'Ieukemiaj ofa calculation for sensitivity, Disease Positive test Negative test (TP) 60 (FN)20 specificity, PV+, PV-, prevalence:

m

Example

No Disease
(FP) 40 (TN) 80

sensitivity of the test: TP I TP + FN = ,60 I 80 = 75% Specificity of the test: 'IN I TN + FP = 80 /120 = 66% PV-: 1N I TN + FN = 80 1100 <= 80% (80% chance it is a TN and a 20% chance it is a FN) py+: TP ! TP + FP = 60'; 100 = 60% (60% chance it is a TP and 40% obance it is a FP)

Prevalence: TP + FN / TP + FN + 1N + FP = 8.01200 = 40%

NI)rmaJ changes in pregnancy: 1. greater increase in plasma volume than RBe massA. decreases hemoglobin (Hbjand hematocrit (Hct): dilutional effect B. increases glomerular filtration tate (GPR) and creatinine clearance (CCr): due to increased plasma volume C. decreases serum BUN/creatinine/uric acid: dilutional effect + increased clearance 2. increased alkaline phosphataseplacental origin 3. respiratory alkalosisestrogen/progesterone effect on (:NS respiratory center causing increased clearance of CO2 per breath 4. increased T4 and cortisolA. increased synthesis of their binding proteins B. free hormone levels are normal c. no signs of ayperthyrotdism/hypeecortisollsm D. e.g. normal serum TSH and ACTI-I, respectively

Main laboratory
1. 2.

difference in adult male and female: iron studies are all lower in womeD- e.g., serum iron and ferritin lower Hb concentration in women

Children:

1.

increased serum alkaline phosphatase (ALP)~ A 3-5 times higher than adults B. osteoblasts release enzyme when stimulated by vitamin D C. ALP increases bone mineralization
increased serum phosphate- required to drive calcium into bone] slight decrease in hemoglobin concentration when compand to adult levels

2. 3.

Newborn: high hemoglobin (Hb) due to increase in HbFI. left shifts oxygen dissociation curve- (ODe): causes tissue hypo,xia-+ 2. stimulus for erythropoietin (EPO) release-e3. increases RBC production with subsequent increase- in Hb concentration

4

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;J b F :(~"
I'.
It"

l' rJt;'
...;.

c BbF: 1. left shifts oxygen dissociation curve (ODC) 2. protects newborns with sickle cell diseaseA. most of the RBCs at birth contain HbF: inhibits sickling

f." -rI.

~

B.

less HbS:

3.

4. S.

(1) concentration not high eflougb for sickling (2) HbS must be >60% in RBe for spontaneous sickling (3) dactylitis (bone infarctiecsof digits) begins in 6-9 mths protects newborn from severe p-thalassemiaA. HbF contain 20'.arid 2'( chains B. adult HbA will be markedly decreased after a few months since ~-chajn synthesis is decreased: HbA = 20; and 2[3 HbF synthesis is increased with hydroxyureaused to reduce sickle cell crises libF is resistant to alkalllacid denaturationbasis for Kleihauer Betke test in determining amount of fetal blood in maternal circulation after delivery with hemolyzed blood sample secondary to venipuncture:

Analyses increased 1. LDH-

A.

LDHI isoenzyme fraction is primarily increased and is greater than LDH2 isoenzyme fraction. (LDH1ILDH2 flip)

2.

B. false positive acute myocardial infarction C. LDHI isoenzyme is also ia cardiae muscle potassiumA. pseudohyperkalemia B. K+ is the major intraoellular cation C. ECG will not SllOW a peaked T wave
coming frtlm cbylomtcronacbyJomicrons

Lipid most affected by fasttng: 1. trig.lyceride (TG) component

contain

diet-

derived TG
2. fasting or lack of fasting does nor affect cholesterol (CH) and high-density lipoprotein (lIDL) cODcentrationA. normally CH <3% of the chylomicron fraction B, fasting is unnecessary for an accurate CH or HDL fasting is necessary .for an accurate calculated low-density lipoprotein (LDL)A. LDL = CH - HDL - TO!S B. if TG is falsely increased by chylomicrons from the diet it will falsely lower the

is

j.

..,

calculated LDL
Drugs enhancing the cytochrome system in the liver smooth endoplasmic reticulum (SER): 1. drugs~ A. alcohol B. barbiturates 2. effect on SERA SER hyperplasia B. increased synthesis of y-glutatnyltransferase COOT): enzyme is normally located in SER C. decreases drug levelsowing to increased metabolism of the drug Drugs inllibi in,g cytochrome system in the llver: 1, drugs. A. H2 blockers . iJftWJ.j<1 ) B. proton blockers
5

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Significance of erythrocyte sedimentation rate (ESR) in old age: probably indicates procese1. not an age-related flnding 2. not recommended as a general screen for disease in the elderly

Laboratory test alterations in alcoholics: 1. enhancement of the liver cytochrome P-450 system.A. increased synthesis ofy- glutamyltransferase (GGT) B. excellent enzvme marker for alcoholic liver disease 2. increased production of NADB in its metabolic breakdown causes biochemical reactions involving NAnD to move in its direction resulting in the fcllowingA. lactic acidosis: pyruvate-e- lactate B. fasting hypoglycemia: pyruvateis unavailable for gluconeogenesis C. hypertriglyceridernia: 1 3 bisphosphoglycerate-edihydroxyacetone pncspbate-s glycerol 3-phosphate-4 TO 3, increase ill 'keto act d synthesisA. acetyl CoA,theelld product of alcohol metabolism is used in the following reaction B. acetyl CoA + acetyl CoA--+ C. acetoacetyl CoA~ D. HMG CoA~ acetoacetic acid, increase in NADH converts it into ~ hydroxybutyric acid (a-OHB) 4. Increase in fatty acid synthe~fis- due to the increase, in acetyl Co A 5. hyperuricemia-lactic acid/ketoacids compete withuric acid for excretion in the kidneys 6. increased anion gap metabolic acidosis- lactate + f3~O.HB Laboratory test alteranons in smokers: t. respiratory acidosis- air gets in but cannot get out, so COl is retained 2.. hypoxemia (low PaOl)- see Celt In,Jury notes 3. increased carbon monoxide (CO) levels- CO is present in cigarette smoke 4. secondary poJycytbemia- low P"a02 stimulates erythropoietin release 5. absolute uentrophtllc leukocytosismetabolites JQ smoke mobilize the neutrophil marginating pool in the circulation by decreasing leukocyte adhesion to endothelial cells Plasma/serum turbidity. L doe to an increase in triglyceride (TG)- turbidity does not occur with an increase in cholesterol (eH) in plasma 2. TG is carried by lipoproteinsA. chylomicrons: 85% B. very low-density lipoprotein (VLDL): 55% 3. TGis falsely increased after eating- due to diet-derived chylomicrons 4, cbyiom.icroDs form.a supranate in plasma- contain very little protein: less dense than VLDL 5. VLDL forms an infranate (no supranarej=contains more protein than chylornicrons and does not float on the surface of plasma 6. increased turbidity interferes with measurement of enzymes and serum Na-+- false-ly low enzyme values and sodium (pseudohyponatremia)

6

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Supranate
(chylomicrons

)))1._

Infranate (VLDL)

r:ir

r:JT'

-u

Relation of serum albumin concentration with serum calcium concentration: 1. albumin binds 40% of total calcium in bloodA. 13% of calcium is,bound to other substrates B. 47% calcium is free, ionized calcium: metabolically active calcium 2. low serum albumin decreases calcium bound to albumioA. hypocalcemia B. no tetany Is present, since the ionized levels are norm-al

MLE scena i . 1. calculation of sensitivity, specificity, pyt and PV 2. two tests are ordered on a patient, what is chance for a FP result- answer is -1 0% 3. increase/decrease upper limit of a test
4. 5. effect of sensitivity on prevalence ustngtriple therapy for HIV positive people and effect on prevalenceA. it has extended the t~J1e interval CQuration) before an AIDS-defiqing condition occurs B. prevalence ofHIV positive people has increased effect of pregnancy on serum cO'rtisoJ- answer is that it is increased due to an increase in the binding protein and not the free hormone level

q.

Que ttons used in Board Review: Assuming the use of 2 standard deviations to establish the reference interval of atest reference interval of 10-30 mgJdL, 1 standard deviation would equal..; 'A. 2.5 ,. B. 5.,0 C. 7.5 D. 10.0 E. 20.0 B- mean of the 'test is 20 mg/dl., 2 SO ee 10 rng/dl, therefore I SD = 5rngldL
r;,1j,F'

in a test with a

r:ir

If the prostate specific antigen (PSA) test for prostate cancer is lowered from a reference interval of 0-10 nglmL to 0-4 ng/ml. this will ... A. increase the number of false negatives B. decrease the number of false positives C. increase the test s specificity D. increase the PVB. increase the PY"

D

7

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Study the following schematic involving a control group and disease X

Normal

Disease X

Reference interval
Which of the following correctly describes test results in the space occupied by each oftbe A. B. C. D.

Group D: true positives + false negatives C: group A = all TNs, group B :; TNs + FN~, group C
.r:;jF

lettere-d groups? Group A: true negatives + false negatives Group B: true negatives + false positives Group C: 'true positives + false positives

= FPs + TPs group D = all TPs

A pregnant woman in her first trimester complains of heat intolerance and palpitations. Physical exam reveals an enlarged, non-tender thyroid gland. Her serum T4is. elevated and the TSH is normal. Which of the following applies to this case? A. Thyroid binding globulin is increased B. Free T4 hormone levels are increased C. Estrogen increased the synthesis of thyroid hormone D. Progesterone increased the synthesis of thyroid binding globulin

8

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Cell Injury
Causes of tissue hypoxia (inadequate oxygenation of tissue): ~ ft J) 'I 1. iscbemi;lA. definition- decreased arterial blood flow to tissue B.exam,ple "(l} atherosclerosis in coronary artery; MeC (2) decreased cardiac output 2. hypoxemtaA. definition- low arterial partial pressure of O2 (Pa02) (1) respiratorY acidosis: whenever alveolar PC02 increases alveolar P02 must decrease and Pa02 must decrease (2) ventilation'problems: e.g., atelectasis "" (3) perfusion problems: e.g., pulmonary embolus - -1 (4) d'iffus'ion problems: e.g., interstitial fibrosis in the lungs B. anemia ', t 0: t C. CO poisoning C ... oJ )tIl D. methemoglobinemia v E. left shifted oxygen dissociation curve (ODC) 3. problems with oxidative pathway in mitochondriaA. carbon monoxide (CO) inhibits cytochrome oxidase -; /~).. . • ''1/,A-;rl!l ~u" (_ ~~, B. 'cyanide inhibits cytochrome oxidase Dlh) F \~: ~ ... _uncoup~ed oxida~lve p~osphorylation in ~it()chondria~~tz:n~.. "'1 1# A~f 11:xl. A. mitochondrial poisons (alcohol,sabcyJates) render inner m itoehondriaf membrane ;" r: I permeable to protons ill IJ ~d"''>:''j(,>'"'':1Yf1!iSi B. decreases ATP synthesis V'frI\lJ(I1y~IN f·d< .;} ''<11191 5. arteriovenous shuntingA. AV fistula from trauma: (l} direct communication of arterial system with venous s. stem (2) mierocirculation is bypassed B. spider angiomas: -due to hyperestrinism. C. mosaic bone in Paget's disease or bone
r::ir

J...~V -J--'

oJ

.1·

,1"'O-t If';¥

,1

=

w

Ultimate effect of tissue hypoxia: decrease in ATP production by oxidative phosphorylation mitochondria 1. is normally the electron acceptor at tbe end of the oxidative pathway 2. all proximally located biochemical reactions must cease if Oleis not present 3. no protons come off tbe oxidative pathway-e- no ATP production

in the

o.z

r::g""

Effects of a decrease in ATP in the ceU: 1. cell must utilize anaerobic glycolys.is to generate ATPA. phosphofructokinase: (PFK), the rate limiting reaction in glycolysis, is activated by (1) low citrate (2) increase in adenosine monophosphate.(AMP)

B. C. D.

netgainof2ATP no gain in NADH: (i) NADH is converted into NADT when pyruvate is converted into lactate (2) N.AD+- generated by this reaction is used to produce 2 more ATP
deorease jn intracellular pH from lactate production: (1) denatures cellular enzymes and other proteins (called coa!!:ulation necrosis) (2) produces an increased anion gap metabolic acidosis

9

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2.

3.

impaired Na+1IC"ATPase pumpA. water enters the cell producing cellular swelling B. reversible change if O2 is restored ribosomes falloff rough endoplasmte reticuium- decreased protein synthesis

O2 content formula: J. O2 content-e A. definition: total amount of O2 carried Llfblood B. formula: 1.34 (Hb) x Sa02 + Pa02, where Hb= hemoglobin, 8a02 O2 saturation and PaO:! is the amount of 02clissolved in plasma 2. PaOlA. definition: amount of O2 dissolved in plasma and not O2 attached to l-Ib in RBCs, which is called the oxygen saturation (3a02) B. PaO, is dependent on: (1) percent O2 in inspired air (21 %) (2) atmospherl c pressure: decreases with high elevati on: even though O2 percent is still 21% (3) matched ventilation/perfusion in the lungs (4) diffusion of'O, through the alveolar-capillary interface C. decreased alveolar POl always leads to hypoxemia; (1) must have adequate O2 in the alveoli in order to diffuse into the pulmonary capillaries (2) low alveolar O2 always leads to low arterial POa D. hypoxemia always lead's to less 0, carried bv the Hb in RBes in the blood: (1) decreases Sa01, which is the average percentage of heme' groups in Hb occupied by 01 (2) see discussion below E. POI. at tissue level (1) driving force for diffusion of O2 from the capillaries into the tissue (2) capillary POl must be higher than p~ in tissue for diffusion to occur 3. A. definition: percentage of 02 attached to the 4 heme groups in Hb within the RBes: normal range is 94-96% B. SaOl is dependent on:
=;

me

sso..

(1)

PaG:!.

C.

D.

(2) valence of heme iron: must be ferrous (+2) to bind 02, (3) if oxidized to ferric (+3), it cannot bind O2 and is called methemol!!obin measurement of SaOi (f) measured non-invasively with a pulse oximeter (2) ealeulated from measured Pa,02 P) directly measured in arterial blood decreased Sa:Ch correlates with cyan.0sis of skin/mucous membranes: SaOl <80%

produces visible cyanosis
Respiratory acidosis: I. increase PaC01 2. low O2 contentA. decreased Pa02 B. decreased Sa02

Note: This material

is copyrighted, All rights re-served

Anemia: 1. decreased O2., cootentA. decreased Hb concentration B. normal Pa0zlSaO"i normal O2 exchange in the lungs so these parameters

remein oormal

2. 3.

decreased Hb coucentratlouA. B. most important component fa} carrying O2 determines the amount of 0, delivered to tissue

iron deficiencyis MCC of anemia

Carbon monoxide (CO) poisoning: 1. decreased O2 contentA. normal PaOl B. decreased Sa02: CO has a higher affinity for heme 2. additional causes of tissue hypox_iaA. left shifts the O2 dissociation curve (ODC) B. inhibits cytochrome oxidase 3. causes CO poisoning~ A. car exhaust ~. )~r.4i./£+'(l cJ../~:.h B. space beaters (tISML.E C. smoke inhalation in fires D. wood stoves 4. R;t (trea:tment)- 100% 01

011

Hb than O2

5.

8/8A. headache first symptom B. cherry red color of carboxyhemoglobin masks cyanosis long term effect= necrosis of globus pallidus leading to Parkinson-like findings methemoglobin (metHb) is heme with iron +3- heme cannot bind O2

6. 1.

Methemoglobinemia:

2.

O2 content decreased-

3. 4.

A. normal PaOl ~ B. decreased SaO,: decreased.even thoughPeO, is nomlaJ· -"r .J t,,), ... <I;"; cause- Iieme OXIidized by muo I su ltd ized bv ni '1,3compaUD Sr 8/8;:{t.~-Itdl"'r' t<~ I rlll.....(~,(l.6PD~J,r.~ . A. cyanotic B. blood is chocolate colored fremIncreased decxyhemoglobin

r

4/. .dlVf<£,.I')~e:tJi,t;lo'·.. ,

e."

r,

5.

RxA.
B.

N methylene blue is gold standard for Rx: activates a methemoglobin
that is not normally operative ascorbic acid: reducing agent that is used as ancillary therapy

reductase system

Factors altering the oxygen dissociation curve (ODe): 1. left shifted ODCA. increased affinity for O~: does not releaseO, into blood B. examples: (1) J.2,3 bisphosphoglycerate (BPG)

(2)
(3) (4) (5) (6)

CO
metHb HbF hypothermia alkalosis

11

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2.

right shifted ODCA. B. dectaased affmity.fo(02;: examples: readilyreleases O2 into blood

(1)
(2) (3) 1. C.0

i2,3 BPG
fever acidosis /-..... ,. ) <
~ ;1"., ).

Cytochrome o~dasc lnhtbitor :
2. 3.
!fl"" ~.

I_,t.f';,

(' 1;- ty,_J.h
(.

lU

-r ~ ;:
t'

i

'I

r.(.

I~

cyanide clinical effects of inhibitioDA blocks oxidative pathway in the mitochondria

..;

/l d~.J
as an

even though 0:. may be presen

B.
C.

electron acceptor protons from the electron transfer system are no longer entering the intermembranous
space

protons are not entering the proton pores in the inner mitochondria! membrane: no. ATP
is produced

Causes of tissue hypoxia with a normal O2 content: 1. iscbemia- MCC 2. cyanide poisoning 3. uncoupling of oxidative phosphorylationA. uncoupling is where the inner mitochondrial

membrane

1S

rendered

permeable

to

B.

protons, protons are drained 'off without forming A TP examples of drugs that uncouple include:
(1) (2)

4.

alcohol salicylates (important 'in Reye syndrome) (3) dinitrophenol possible outcome of uncoupling- hyperthermia A. loss of protons into the mitochondria without forming ATP increases the rate of chemical reactions B. reactions increase production ofNADH and NADPH to provide additional protons to the electron transport chain '

First bistoiog.ic sign of tissue bypoxia: cellular swelling1. due to -red u etitm in A. TP and im paired N a +tK.:' ATPase pump 2. sodium and water enter the cell Causes of irreversible cell injury due to tissue hypoxia: 1. disruption of the ceU membraneA. lipid peroxidation by free radicals: reversed by ~tamin E ~ B. activation of pbospholipase by calcium C. complement activation with damage to cell membrane 2. damage to mitochondria. Role of ealcium in irreversible cell Injury: 1. enters the cytosol 2. activates enzymes in following locattousA. cell membrane phospholipase: enhances lipid peroxidatien B. activates enzymes in the nucleus: produces nuclear pyknosis 3. enters mitoehondriaproduces electron dense deposits and destroys mitochondria L contributes to coagulatton necrosis - intracellular buildup of lactic acid also leads to coagu lation necrosis

12

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Free radicals:

2.

1.

exam pleaA. B. C.

deflnttion-

unpaired electrons in outer orbit

OH'

superoxide: O2- generated FR inactivated· by supemxide dismu.tase (SOD)

..

.

D.

peroxide I'. (I) inactivated by catalase and glutathione caSH I y nHt'! (2) GSH is synthesized in the hexose monopllOsphate shunt 'drugs/chemica Is: (1) (2) (3) acetaminophen (inactivated by GSH) CC!4 converted i.nto,Ce1]· oxidized low densityljpoprotein (LDL, greater atberogenicity marl native LDL)

3.

ira!] Increases the synthesis ofDH FRs via the F~nton reaction- FRs are the mechanism of
damage in

iron overload dise-ases:e.g., hem.ochromato§.i.s.

~

d- ~

Exampl~s of FR injury: L normal aging processA. wear and tear theory B. lipofuscin accumulates in cells damaged by FRs: (1) indigestible lipid from lipid peroxidation (2) gives tissue a brown appearance 2. O~-dependeDt myelopero:ridase (MFO) s)'stem-

(.-we~ ~

"j2.~.4.

3.

A. most lethal bactericidal system present in neutrophilshnonocytes: see Inflammation notes B. NADPH oxidasein cell membrane converts molecular O2 into superoxide FR O2 toxicity-. "1_ /I 1':'1 I 4' ~~. (;I I' ,oJ " r A. su,peroxide FR damage B. A.
iOD~_ng

4.

e.g. retrolental fibroplasia: leads to blindness in newborns radiatioD-

5.

'*

B.
A.

generates hydroxyl (OR') FRs in tissue from r-adiolysis of water in cells danlages DNA witft potential for ca~cel':'"e.g .• s gf acetaminophen toxicity- 1'r"\A-;~\ ~<'-I-acetaminophen is con verted-by the (~epatocyte sulfhydryl groups in hepatocyte cell membranes: due to drugs __!c ty Icysteine theraEj' (Mucornysr) e (1) replenishes GSH (2) GSH »eutralizes the drug FRs pOisollingdry cleaning industry CCI4 converted by cytochrome

!VIce of

fulminan

.8.
6.

N-

eel.
A B.

Apo.pt.osis:

system into. CC13 FR-> liver cell necrosis

1. 2.

B.
3.

definition- mdividual cell necfQsis microscopic appearanceA. deeply eosinophilic staining cytoplasm-

pyknotic nucleus

C. no inflammatory infiltrate D. cells "drop out" normal functions of a:popto,sis-

A.

involution of strbctures: cell/organ atrophy in old age/thymus/gravid

uterus

13

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B.

C.

4.

apoptosis £ene: programmed cell death embryogenesis; (I) loss of Mallerian structures in male fetus and Wolffian structures in female fetus (2) creates lumens for bowel pathologic roles ofapop osisA. CouncBman (acidophilic) bodies in vilal hepatitis B. psammoma bodies: apoptosis of neoplastic oe!!swith subsequent dystrophic ealcification C. cancer (1) inactivation.of apoptosis g~ne, in 's ce~ l.e~.dsto B cell follicular lymphoma (2) see Neoplasm notesl 1'1. [I 1-' ,r ) • AI
V{

Types of cell n~crosis:. 1, coagulation necrosra;~ ;~e~~::do~::a~~~~nn

F___"".J

IIAito,:. A).rl_~ &,zk:_ tlCc,l.,;..iu (Jic

2. 3.

4.

5.

6.

7.

(1) heart (2) kidneys~~e..l~~"" !lq;,~&lku (3) liver (least likely to infarct due to port~~ vela/hepatic artery blood supply) (4) spleen C. hemQIThagic 'tvpes of infarction:-;t~._Q q U?h.t;,,6;\J tk f~~ &A'l (1r/f~p-£<{:?4:' (l) small bowel ~J (2) lungs (3) testicles r f'I!tI,~ I D. dry 'gangrene (1) predominantly coagulation necrosis without evidence of infection (2) example: diabetic foot eNS j,ofarcts-liquefactive not ooagulative necrosis liquefactive necrosis• I I rn{f'1 J< f:' ,., q:J A. neutrophil destruction ofti!sYL __ 114, ..... ' ,), :/' ~ -re (1) absoe~s-- '-;'1, l (Iv:tMZ,".I"~ (2) wet gangrene (infection superlmposed 0D dry gangrene) B. brain infarct/infection caseous necrosisA. cheese-like material noted ~11 gros~ exam ~f tissu~: represents lipid. mate~jal in.. . f+o htdD granulomas from macrophage destruction oftyplcaUatvplcal TB and s stem1C fun"l (c.OCCI./.,)o/J..1 I / B. other types of granulomas are non-caseatina: b)~ (1) Crahn's disease /!' -,/.-t'Jf1:{&-C (2). sarcoidos~s >~ (f£.-;t!iJI enzymatic fat necresis-:1:~-CA ,0 f\- li;1i\ It .; IJI7 ( 1/11,1 A. key finding in aCllte pancrea~ (tn ~ _";;-j (UJI~ B. release of amylase and Iipa!felFom damaged pancreas ( ~~ /t(j,p.)~ fibrinoid necrosisiJ A. necrosis of immunolozic injury with protein material appearing like fibrin B. examples: (l)smalf vessel vasculitis (Henoch-Schonlein) (2) rheumatic heart disease vegetations on mitral valve (3) immunocomplex types of glomerulonephritis (systemic lupus erythematosus) gummatous necrosisA. tertiary syphilis B, rubbery masses that are very destructive in tissue

:;~~~k:~;;l.vt~.~ /ttA ~q~'~~ ~,~
aual
LA

11artAf..t1i·dt.~tI.fJf.'pCee~:J) I
,jI)-.w~1

i~~Jd4/~

rk4

Q'~U

j

I ....

~"4f)(/(~

..::ii:ii..:,

,.,.,u;)

14

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I
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I' ~ )/1 ,j~ ~ Ilf I H

",t.,&A."u
AJ. ;.)<'" '~~'
(j

'>
-d-~

j

~ ~;;d\k~~ft:ttf.,
p fo~~, r.1r
(/l.!}!-I ~

Fatty liver:

frtUI/(r;, ~~'

r

VI} ~
-t5fI~
:I.

4<&~'
'rf

:be carbohydrate back~one of TG . _. '. .' , increased acetyl eoA u:' al~q~ol metal:olrsnl 1"Sused ~o increase fatrv acid (F f}) sy:n;%eSls.,. 4\ .J~., .ltoH'~ ,;rJ4JJ"/I',.c. alcohol decreases j3-mudabon ofFAs In mitochondria ~DlI ~_f. !.••~ 'O./;/~ . -,..7 "4t!~".1( I ...t,,,,,,, kwashiorkor- latty liver due to decrease d syn thesi 0 f apo I' . >1'.' ,. ,,'JVfIi f!Ilih-/ d/, , V(~... ".:.; eSlS Jpopro~ I s necessary to 'coat ve • '12.te"") ,. . tr~.EJ low density lipoprotein (VLDL)
{J

/l,,!tid

tiJq

,.

/

alcohol MCCA. increased NADH in the metabolism of alcohol causes a build-up of di1wd.roxyacetone 9 ...... H:> phosphate (DHAP), art intermediate ill glycolysis; DEAP produces' glycerol 3-pnospllate, B.

-ZOrJ:?- ~

(M ~~

M 4N~ S

~O~ j1trt-:~7q:'lJYlc
(~.l

f...{~)

-Ip

A'I

~nd~"'.l

~

i..

3f.~ COpo.isoning

f\Cb.e,

J ij{.~A~.. - drugs(/ rl
iJ ..... ..._.

. __)hod, s
A.

r~ \

6,

B. Reye's syndrome

tetracycline amiodarone

Increased melanin pigment: 1. nevus- benign melanocytic neoplasm 2, malignant melanoma- malignancy of melanocytes 3, increased ACTHA. B. ACTH has melanocyte stimulating hormone activity causes of increased ACTH: (1) functioning pitu itary adenoma

(2)

ectopic synthesis in small cell earcincmaef

lung and medullary carcinoma of

4.

thyroid (3) Addison's disease with hypocortisolism (4) adrenogenital syndrome with enzyme deficiencies leading to hypocortisolism African-AmericansA. African-Americans have the same number of melanocytes as whites B. melanosornes are larger and more numerous than in whites C. .dendriric processes in melanoeytes are more abundant than in whites: more transfer of melanin to keratinocytes albinismA. AR disease B. absence of tyrosinase C. melanocytes present in the epidermis: devoid of rnelanosomes

Absence of melanin pigment:
1.

2.

vitiligoA. autoimmune destruction of'melanocytes

3

B. patch): areas of skin depigmentation pbenylketonuria (PKU)A. AR disease B. deficient mhenytaJanine hydroxylase:
(1) (2) (3)

(4)

- AVfJ',ht/ R..ef.tdol{f,'urJ normally c?nv~rts phenylalanine i,ntotyrosine-:: frlf~J20~f.ll~1 phenylalanine increasesand tyros me decreases _ ';,Wttv tyrosine is the key amino acid substrate for melanin synthesis Y PKU children have blond hair

'.Ad5p'~1innQte.

cdJ

(Jlo~

J
q{~ ,\I "J.,I \'

,;l.,., ,·te

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Melanin

1.

2. 3.

look-alikes: anthracotic pigme,ntA. coal dust B. inhaled as i!U1 environmental pollutant (1 ) phagocytized by alveolar macrophages (2) called dust cells .. C. "black lung' disea e: disabling lung disease alcaptcnur'ia+ see Genetics melanosis coliA. black bowel syndrome B. deposition of black anthracene pigment in macrophages large bo .... sign of laxative abuse -el:

within the lamina propria of

4.

hematinA. B. black pigment derived from acid effect on hemoglobin (Hb). black color of melena

Increased iron: 1. iron overloaclA. hemochromatosis: AR disease B. hemosiderosis: acquired excess 2, anemia of chronic disease (ACD)- increased iron in macrephages that is unavailable for Hb synthesis 3. stasis dermatitisA. deep vein thrombosis in the calf with hemorrhage of vessels around ankles B. hemosiderin deposits in subcutaneous tissue give tissue a rusty colored appearance 4. sideroblastie 8ne.miaA. defectln .heme synthesis ill mitochondria B. iron accumulation producing ringed sideroblasts 5. Prussian blue- stain for iron Decreased iron: iron deflciency anemiaGI loss of blood is MCC Genetics Glycogen excess states: glyccgeaoses-esee

Glycogen depletion: fasting/starvation state (US-:Ml'JL)1. g]ycogeDoly~.is _ 2. eleetron'micrcscopy E:M) oil' DSMLE sho~ea hepatocyt~with b ack granules fn fed s"ta_teand another EM with a lack of the bla(li( g;1'a:D ules in fasting t-a te

(glycogen)

Excess glycosaminoglycans: 1. myxomatous degeneration+ pathogenesis of mitral valve prolapse 2. mucopclysacchartdoaes-lysosomal storage diseases (e.g., Hurler's disease)
3. pretibial royxedemanon-pitting edema Doted in Hashimoto's thyroiditis and Graves disease Hemoglobin-derived pigments: I. bilirubinA. unconjugated type (1) lipid soluble (2) e.g., extravascular hemolytic anemia B. conjugated type (1) water soluble (2) obstructive jaundice

16

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2.

3.

hemosiderinA. storage product of iron B. consists of packets of ferritin C. small circulating fraction of ferritin represents macrophage iron stores: serum fen'1.tin is the best screening :test for iron disorders hematin hemosiderin: first sign of'iro~1deficiency anemia

Decreased

Dystrophic calcification: 1_ deflnitionA. calcium deposition in damaged tissue B. normal serum caleium/phosphate 2. examples= A. atherosclerotic plaques B. enzymatic fat necrosis: visible on plain fiim, C. damage-d cardiac valves ("'" :;p! I ,·q<;f' "'f {.r [-If' - -} ilfell rr D. psammoma bodies (1 serous- cysradenooarciuorna of ovary (2) pap ill ary adenocarcinoma of thyroid (3) meningioma (4) mesothelioma B. periventricular calcification in congenital cytomegalovirus infections
Jj

A---;.,

:_-Ir-;t ~,~ ~

Metastatic calcification: 1. defiuitiooA. increased serum calcium and/or phosphate B. deposition of calcium in normal tissue

2.

examplesA. nephrocaJcinosis
B.

in primary hyperparathyroidism: calcification -of tubular basement membranes calcification of basal ganglia in primary hypoparathyroidism: high phosphorous levels-in hypoparathyroidism drives calcium into the brain tissue

Genetic example of a microtubule dysfunction: Chediak-Higashi syndrome 1. AR disease ~ j111(;f1'Y4ldi it ir I'JYIII,:r1r>>(;~ ~ 2. defect .in microtubul~ p~lyroerization _ CoJc;~;c;Il~-7 a.dllUj t('fJ!J ~ -kettr~D'f1f t*.'1.Ve,,1s I'IIC.o"UII([J,,_" 3. defective ph agocytoSJs: increased suscepti bility to infections 4. iant red inclusions in peripheral blood leukocytes: represent giant lysosomes filled with enzymes tbat have never been released Genetic example of a membrane defect: congenital spherocytosis

1.
2.

AD disease
defect in spectrin in the cell m.embrane A. results in RBCs with too little membrane B. spherocytes develop in peripheral blood extravascular hemolysis of spberocytes by splenic macrophages

3.

Examples ofintermedia'te filament defects: 1. Mallory bodiesA. ubigulnated(marked for destruction by ubiquitin) keratin intermediate filaments B. microscopic feature of alCoholic hepatitis 2. Lewy body- ubiquinated neurofilaments from degenerated substantia nigra, neurons m Parkinson's disease,

17

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3.

neurofibrillary disease

tangles-

ubiquinated

neurofilaments

in the brain

In

old age! Alzheimer's

Labile cells: I. contain stem cells- > 1.5% of cells are in the cell c-ycle at anyone time

2.

exam

A. bone marrow stem cells .6. skin: stratum basalis C. intestine: base of the glands 3.. clinical significance- most affected by radiation and S phase chemotherapy high rate of mitotic activity of labile eells

ples-

drugs due to the

Stable cells:
1. cells usually in Go (resting) phase-A. must be stimLlia'ted to,'enter the 01 phase (1) hormones (estrogen) (2) growth factors (epidermal derived growth factor) (3) loss of perenchymal tissue (removal of Liver tissue) B. <1.5% of the cells arein the cell cycle at anyone tune examplesA. most parenchymal cells in organs: (1) liver (2) endothelial cells B. smooth muscle: not striated or cardiac cells c. astrocytes/other neuroglial tells clinical significance- capacity to undergo hypertrophyandror hyperplasia

2.

3.

Permanent cells: 1. cells cannot enter the cell cycle- permanently differentiated 2. examplesA. skeletal/cardiac muscle: can only hypertrophy B. neurons Cell cycle: ~ 1. inactive edk (cyclin-dependent kinase) i activated by' cyclin D (see diagram)A. cyclin 0 is synthesized in the G1 phase of the cell cycle: key phase of the cycle B. G1 phase is the most variable phase 2'. Rb uppressor gene on chromesome 13 produces the unphosphorylated Rb proteinA. Rb protein prevents the cell from moving from theG, phase into the S phase: S phase functions include chromosome replication and organelle replication B. phesphorylation of the Rb protein by the active, cyclin D/cdk complex: allows the cell to pass inte the S phase and finish the cycle which includes the Gill phase (mitotic spindle synthesized) and the"M,phase (mitosis) C. inactivation of the Rb supp.res'sor gene: (1) loss of-the inhibitory effect of the Rb protein on the cell (2) cells constantly enter the S phase once they are phosphorylated 3, p53 suppressor gene functions in cell cycleA. located on chromosome t 7 B. produces aprcteiu product that inhibits the active cycJin D/cdk complex (1) prevents phosphorylation of the Rb protein (2) keeps cell in the G: phase (3) allows cell to repair any defects il,.DNA ("stuardiall of the cell")

]8

r

p53 suppressor

gene inhibits (allows DNA repair in cell or cell undergoes ~ve cyclin Dzcdk complex.c.; __

apoptosis)

cyclinDdegraded

inactive cdk

inacttve cdk

cyolinD
eyclin D synthesized
~
!

+

I

-

fIJ'::'fV'oic
J?;,<t/~

or <Lr-

pJ

"'S~ IV (1

hormone factors

growth]

!

Go (resting phase) inactive cdk
-it

cdk == cycltn-dependeirt kinase .. Rb (hypophosphorylated form) inhibits cell from going from Gl to S phase * Rb phosphorylated form allows cell to go from G1 to S phase

Inactive cdk is activated by cyclin D, which is synthesized in the G1 phase of the cell cycle. The :Rb sUllPre or geDe 00 chromOl1 JJ.le. 3 produces the Rb protein which inhibits a cell from moving from the Gl phase into the S phase of the cell cycle. When the Rb protein is phosphorylated by the active eyelin D/edk complex, the cell passes into the S phase and finishes the cycle. The p53 s~presso.l' gene located on chr mosome 17 produces a product that inhibits the active cyelin D/edk complex hence preventing the pbosphorylaticn of the Rb protein and keeping the cell in the 01 phase. Inactivation of the Rb suppressor gene results in the loss of the fubibitory effect of the Rb protein in keeping the cell from entering the S phase. Furthermore, Inactivation of the p53 suppressor gene allows the active cyclin Dzcdk complex to continually phosphorylate the Rb protein, which allows the cell to complete cell division. Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell growth and the potential for cancer.

Note: This material is copyrighted. All rights reserved (4) cells incapable of repair undergo apoptosis ,inacti:vatiotl of the p53 suppressor gene:' (1)acrive cyelin D/cdk complex contint:lalJy phosphorylates Rb proteins (2) cells continually mitose important conceptA. inactivation of either the Rb or p53stlppressor gene (1 ) unrestricted cellgrowth ~ (2) potential for cancer B. see Neoplasia notes for additional discussion

C.

4.

Examples of growth alterations: (~ -~ ~-1't(Jj~ ) 1. atrophyA. decrease in cell/tissue mass, B. organ less weight C. capsular surface wrinkled D. less mitochondria than normal cell E. increased lipofuscin in cells agenesis2. A anlage (primordial tissue) is absent B. e.g., renal agenesis aplasia- anlage present but never develops 3. hypoplasia4. A, anlage develops incompletely B. tissue present is histologically normal bypertrophy~ increased cell size (~t!1AQ ,Z;;k"10'>1£ 5. hyperplasia6. A. increase 'in number of cells B. common in hormone excess staies C. can progress to dysplaSIa and Cltllcer if left unregulated metaplasia- replacement of one adult cell type by another adult cell type 7. dyspLasia8. A. atypical hyperplasia with p-otential for evolving into cancer B. premaJignMtgro'Wth alteration

r

~\....:J)

Examples of atrophy: 1. muse le in a cast- disuse of muscle Ieads to atrophy 2. thyroid gland in someone taking excess thyroid hormone- decrease in TSH from increase in T~ causes atrophy of thyroid renal artery atherosc1erosis3. A. potential for secondary hypertension B. stimulation of renin-anglotensirt-aldosterone system compression atrophy ofrenal cortex by hydrenephrosis 4. muscle atrqphy in lower motor neuron disease 5. 6. marasmusA. tissue atrophy due to total calorie deprivation B. broomstick extremities 7. carotid artery atberosclerosisA. cerebral atrophy B. site for atherosclerotic stroke 8. atrophy of pancreatic ducts and islet cells in cystic fibrosis (US ,A. thick ductal secretions obstruct the lumen leading to glandular atrophy and fibrosis

19

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Clinical examples of predominantly bypertropb 1. left ventricnlar hypertrophyA. causes due to increased afterload: (1) esse.ntial hyp.ertension /' ~'C.AI'''': c , {2) aortic stenosis ~ rj I , -) n'\ '1'''-' r B. causes due to volume overload t I' "') C. alvular insufficiencies: ~.g., mitral or aortic valve jnsuffid{ncy 2. skeletal muscle in weight training 3. removal of kidney and hypertrophy of remaining kidney (USMLIll

I"~'~ ,.. .

1

I

FA,

('

C

r::rr 1,b 'Ii

t~,!~lfJ~/8
-J~ \

Cllnicnl examples of predominantly hyperplasia: 1. hormone excess,j t nl=.3 A. unopposed estrogen: endometrial hyperp las ia/can cer B. increased ACiH (e.g., pituitary adenomaj.adrenal cortical hyperplasia C. increased dihydrotestosterone + estrogen: prostate hyperplasia D. prolactin-induced lactation: ( 1) normal finding in postpartum state 2) prolactlnoma is benign neoplasm producing excess prolactin E. gynecomastia; excess estnogendevelcps male breast tissue F. acromegaly: excess growth hormone/insulin-like growth factor due to a pituitary adenoma secreting growth hormone G. RBe hyperplasia; erythropoietin stimulation by hypoxia H. secondary hyperparathyroidism: parathyroid gland hyperplasia due to hypocalcemia gUO! hyperplasiaphenytoin therapy 2. persistent injury to tissue-e.g., regenerative nodules in cirrhosis due to chronic injury psoriasis- hyperplasia of squamous epithelium '~.k!'Of p. ~ "~ t14.1~ 4. Increased goblet cells in bronchial epithelium in smokers- example of metaplasia if goblet S. cells are found in terminal bronchioles

i

Clinical examples of equal hyperplasia/hypertrephy: 1. uterine smooth muscle hyperplasia/hypertrophy2. iodine deficiency- goiter

pregnancy

Clinical examples of squamous metaplasia: 1. transformation zone of cervix Inhuman papilloma virus (IiPV) infectionsA. mucous secreting columnar cells normally undergo squamous metaplasia to replace exocervical epithelium B. may progress to squamous dysplasia/eancer if l-I?V ,is present 2. bladder transitional epithelium in schistosotnlastaA. Schistosoma hematobium eggs in submucosal venous plexus cause mucosal squamous metaplasia B,. may progress to dysplasia/cancer 3. true vocal cords/bronchia! epithelium in smol<ersA. epithelium is normally ciliated columnar epithelium B. carcinogens ill cigarette smoke/alcohol irritate mucosa: may progress to dysplasia/cancer 4. cornea in vitamin A deficiencyA. cornea is normally cuboidal epithelium B. in vitamin A deficiency, it undergoes squamous metaplasia: vitamin A normal) prevents squamous metaplasia

20

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Clinical examples of glandular metaplasia: 1. mucous secreting cells/goblet cells in the distal esophagus in add injury (gastroesophageal reflux disease)A. normally squamous epithelium in distal esophagus B. acid injury due to gastric reflux causes glandular metaplasia: called Barrett's esol2harws C. adenocarcinoma of esophagus due to a.arrett'pesophagus has replaced squamous cell carcinoma as the Me cancer of theesopliagus 2. goblet eells/Paneth cells in pylorus/antrum in chronic atrophic ga trttis due to

Helicobacter pyloriA. B.

cytokines

goblet/Paneth cells are normally present in the small intestine released by H pylori damage stomach mucosa metaplasia: precursor elf stomach adeno<:arcinmma

and produce

intestinal

1.

2. 3.

4. 5. 6. 7. 8. 9.

MLE,scena:rios : cyanosis not relieved by oxygen in a patient com lnghome from a cam ping hi p in the Rocky Mouotai'nsA. methemo!!lobinemia B. water in the mountains has nitrites that-oxidize iron to ferric condition antioxidant that prevents lipid peroxidarion of cell membranesvitamin E USMLE pictures of coagulation necrosisA. acute myocardial infarction B. hemorrhagic infarct of small bowel incarcerated ill inguinal hernia sac In a weight lifter glycogen depletion- electron micrograph: present in fed stale and absent in fasting state wbat happens to the other kidney if one is damaged or removed- undergoes compensatory

hypertrophy
dysplasia- precursor to cancer fatty cbange in the iivel'- alcohol 'MCC first sign of tissue hypoxia in tissue- swelling due toinactivation

of the NarK
00

ATPase

pump
picture of adrenal cortex and asks what part is atrophied in a patten A. fasciculata and reticularis; are atrophied due to suppression corticosteroids B. glomerulose is normal: (1) where aldosterone is located (2) glomerulosa is stimulated 'by ATII [lot ACTH growth aIteratioos- see previous examples eozyme markers of cell deathA. transaminases: hepatitis B. creatine kinase: muscle C. CKrvm: cardiac muscle D. amylase/lipase: acute pancreatitis E. lactate dehydrogenase: (1) malignant Iyrnphoma (2) disseminated cancer (3) intravascular hemolysis (4) 1/2 flip in myocardial infarction eNS infarct- liquefactive not coagulative necrosis apoptosis- see previous discussion free rad.icals- see previous discussion antioxid1lllts- see previous discussion cortico~teJ-oidsof ACTI-I by the

10. 11.

12. 13.

14.
1S.

21

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Question used durin
Qj"

Board Review:

Hyperplasia is primarily operati e in Which of the following growth alterations? A. Appearance of the affected kidney in renovascular hypertension B. Thickened bladder wall In a patient with urethralcbstruction C. Barrett's esophagus in a patient with gastroesophageal reflux D. Enlarged left atrium in a patient with severe mitral stenosis E. Galactorrhea in a woman with a prolactinoma Which ofthe following disorders is an example of coagulation necrosis? A. Lobar pneumonia in an alcoholic B. Hepatic abscess in a patient with amebiasis

e.

D. E.

Pseudomembranous colitis in a patient on ampicillin Diminished brain mass in a patient with Alzheimer'S disease Embolus to the superior mesenteric vein leading to bowel infarction


r::Jr

ill which of the following diseases would you expect a low arterial POl and a low oxygen saturation (SaOl)? A. Carbon monoxide poisoning B. Iron deficiency anemia C. Decreased cardiac output D. Respiratory acidosis

E.

Cyanide poisoning

Which of the following disorders is an example of metaplasia? A. increased goblet cells in the main stem bronchus ofa smoker B. Squamous epithelium in the mainstern bronchus of a smoker C. Proliferative endometrial glands in a woman on unopposed estrogen D. Hyperkeratosis of the skinin a patient with psoriasis E. Multinucleated giant cells il),~ granuloma, B

22'

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Inflammation/Repair
Latin terms for acute inflammation: J. calor-

A.
2.

heat

3.

4.

5.

B. histamine-dependem vasodilatation. ruborA. redness B. histamine-dependent vasodilatation tumorA. tissue swelling B. histamine-dependent increase in vessel permeability in venules do]otA. pain B. due to orostaglandin E, and bradykinin funetio laesaA. loss of 'function B. sum total of the effects of acute inflammation

Sequence of vascular events in acute inflammation: 1. vasodilatationA. his·tamine-dependent
B. increases blood flow/hydrostatic pressure

2.

increased vessel permeabilityA. B. C. D. histamine-dependent histamine receptors on endothelial cells in venules stimulated tocontract basement membrane transudate initially moves into the interstitium lymphatics take up excess fluid leaving a bare

Sequence of cellular events iu acute-inflammation: 1. neutrophil ma'rginatioD, A. neutrophile pushed to periphery of the vessel B. due to adhesion mqlecuJe'syntbesis in neutrophile/endothelial cells 2, neutropbil adhesion to endothelial cells (pavernenting)A. adhesion molecules are CDII/CDN, complexes of glycoprotein and 131 and 132lntegrio.s B. endothelial oell-derived adhesion molecules: (1) leukocyte adhesion molecules (ELAM) (2) intercellular adhesion molecules (ICAM) (3) chemical mediators involved for synthesis of endothelial-derived adhesion molecules are interleukin (IL)-l and tumor necrosis factor C. neutropWl adhesion !BOleClllesyn:thesis: C5a and LTB~ mediated 3. emigration of neutrophilsA. neutrophils emit collagenase and destroy type IV collagen in bare basement membrane .8. protein/cell rich fluid accumulates in interstitium (called exudate) 4. directed chemotaxisA. receptor-mediated B. chemical mediators: (1) C5a (2 LTB4 (3) bacterial products

23

No e: This material is copyrighted. All rights reserved

5.

6.

pbagocytosiBA. reeeptor-mediated epsenizatien of bacteria by }gO and C3 b enhances neutrophil/ monocyte/macrophage phagocytosis, all of which have Fe receptors for IgG and C3b: (1) primary opsonizing agents IgG/C3b (2) nonspecific opsonizing agents: C-reactive protein, fibrinogen, fibronectin B. bacteria internalized by Ieukoeytes into vacuoles (phagasomes) which become filled with lysosomal enzymes (ohagolysosomes) bacteriocidal mechanisms in leukocytesA. neuttophllsand monocytes have three systems: (1) Oj-dependent myeleperoxidase (MPO) system (most patent system) (2) Os-dependent free radicals (3) lysosomal enzymes B. rnacrephages only have the latter two systems

respiratory burst mechanism in neutrophlls/monucyrea1. part of the Os-dependent myeloperoxidase (MFO) bacterincidal system 2. NADPH oxldaseA. enzyme located in the membrane of neutrophiis and monocytes B. uses N ADPH derived from the hexose monophosphate shunt as a cofactor C. converts molecular oxygen into superoxide 'free radicals: energy given off in this reaction is called the respiratory burst 3. superoxide FRsA. Located in the- phagolysosornes B. converted b superoxide disrnutase into peroxide 4. myeJoperoxidase (MPO)- combines peroxide with chloride anions to form bleach, which .destroys bacteria 5.-* NBT (nitroblue tetraznliurn test) dye testA.~ evaluates the integrity of the respiratory burst B. neutrophils convert a colorless dye into a colored dye if the respiratory burst system 1:S intact "I L 1 LJ & 1." -J... 1] .
• . .:#" . . ~~

Chron rc gr. an u 10m atOllS. disease of childhood.

2.

1.

3.

4.

SXR disease-- mJc,r~blcldal defect >IE' :i) Sf~h ItIfl~~,(.'I) A¥'~)IJI(S 6) E: (01; absent NADl'H oxidase." _I I A. absent respiratory burst: negative NBTdye test ?;S,llIIOlld" !,)C4fld.Jq4/6J&I~ B. no peroxide is produced in ph ago lysosome C. MFO and' ell loride anions. are present in' phago lysosomes patients cannot kill catalase positive S. aureusA. S. aureus releases peroxide, which is all the leukocyte needs to synthesize bleach B. catalase is released by the bacteria, which neutralizes the peroxide leukocytes can kill catalase negative streptococci- peroxide released by streptococci is used by MFO to make bleach and kiU the bacteria
of chemical mediators in acute inflammation:

•.

••

.>if

.~"

0iflll(q5e w /A(!. ,eR,q ~ TCf'1:) I
j •

:

~ }Cr~II'IfIf((

/I

fnItlVlOllI"

.'

i/ fSN<I~~IJJ"_"

,\ fl.l

~..r

<'"\ AI.. o J. ::y,,,vN<\Q/1

Summary

1.

bistamineA.

B.

C.

D. E.

overall mostimportant mediator released/synthesized by basophils/masr cells vasodilator/increases esse! permeability important in anaphylactic shock prod uces the- "wheal' and' fl are reaction"

24

tf&9.'~
()J

~P
.

.:
ffI

~.~

y

:~

~I

()

rn

F

Note: This material is copyrighted. All rights reserved

2.

serotoninA . released/synthesized by basophils/mast cell sip latelets B. synthesized from tryptophan C. functions: (1) vasodilator (can also be a vasoconstrictorylncreases (2) neurotransmitter (3') synthesized from tryptophan ~ D. important in carcinoid syndrome:

vessel permeabillty

(1)

flushing

3,

(2) increases collagen synthesis (3) diarrhea (4) metabolized in the liver into 5-hydroxyindoleacetic acid C3a1CSaA. anaphylatcxins B. directly stimulate histamine release from basophils/mast cells C. important in tissue swelling and shock

5.

6.

7.

A. opsonizing agent B. neUltophilslmonocytes!macrophages have receptors for C3b CSaA. adhesion molecule synthesis on neutrophils B. chemotactic agent C. 'anaphylatoxin bradykininA, vasodilarer/increeses vessel permeability B. bronchoconstrictor C. pain (dolor) of acute inflammation D, . cough and angioedema with ACE inhibj1or~ .1 prostagl~DdiDS in gener~-. . (R._(1tI·ew !.m+114,! A. derived from arachidonic acid (called eicosancids): (1) released from phosJ;holipid.s in cell membranes by activation of phospholipase A! (2) synthesized from linoleic acid B, most prostagl andins are vasod iIatorsl increase vesse I permea b iIity PGH~productsA. thromboxane A2 (TXA!): (1) POR) is converted by platelet-derived thrornboxru1e s-vnthaSe into TXAl (2) product of arachidonic acid metabolism (3) platelet aggregator (4) vasoconstrictor! bronchoconstrictor D (5) TXB2 is end-product of its metabolism: no biologic function

C3b-

8.

me)

B.

prostacyclin (PGI'2)l (I) PGl'h is convert-ed by en dothel iaI cell-derived prostacyclln 'synthase inro PGl) (2) prostacyc1in synthase is not inhibited to any significant degree by aspirin and NSAlDs (3 ) inhibits pla:telet aggregation
(4) vasodilator makes skin hypersensitive to pain vasodilator in kidneys (blocked by NSAIDs but not acetaminophen) increases renal blood flow (counteracted by angiotensin II)

C.

PGE.:
(1) (2) (3)

25

.Note: This material is copyrighted. All rights res-erved (4) decreases renal reebsorptionof sodium increases gastric mucosa'! blood flow (important

(5)
(6) (7) (8)

in generation

of the mucosa]

barrier)
activates csteoclastsIimportant in producing hypercalcemia, in malignancy) important in fever production (ll...-1 stimulates its synthesis in the anterior hypothalamus) : inhihits platelet aggregation/Il.vl and IL-2/1eukocyte aggregation

D. E. LTB4A. B. ~

PGF1c._:
constricts uterine muscles (cause of primary dysmenorrhea) vasoconstricts/bronohoeonstricts PGD2: vasodilator/increased vessel permeability (1) (2)

9.

derived from arachidonic acid adhesion molecule synthesis on neutrophils _chemotactic agent

l6.~--=A.

11.

12.

13.

derived from arachidonic acid B. J?,roQchocoostrictor/v4s0constrictors C. important in asth~ nitric oxide--A. endothelial cell-derived B. vasodilator/increase vessel-permeability C. important in shock eudothelinA. potent vasoconstrictor in endothelial tens B. important in shock lnterleukfn (IL)-lA. fever: stimulatesprostaglandin E2 synthesis in anterior hypothalamus B. B cell stimulation to synthesize immunoglobulins C. activates osteoclasts: (1) called osteoclast activating factor (2) inhibited by estrogen in women and testosterone in men (3) release from osteoblasts is stimulated by parathormone (4) present in plasma cells (cause of lytic bone lesions in multiple myeloma) D. increases adhesion molecule synthesis by endothelial cells E. increases liver synthesis of acute phase reactants: (1) coagulation factors (fibrinogen, V VIII) (2) Csreactive protein

14.

Hageman factor XllA. B.

C.
D. 1. 2. 3. 4.

activates intrinsic coagulation system activates plasminogen in fibrinolytic system activates kinin system: produces bradykinin .irnportant ill the pathogenesis of disseminated intravascular coagulation

Essential fatty acids (FAs):
linoleic acid (see be-low)- C18:2w6 a-linolenic (see below)- C18:3ro3 both are required in the diet- cannot be synthesized in' the body functions-A. synthesis ef biologically active F As

26

Note: This material is copyrighted. Ali rights reserved
B. synthesis of eloosanoids- e.g, araehidonic precursor of eicosaaoids.which include: . (1) prostaglan dills acid (polyunsaturated C:20 FA)
is

the

(2~
(3) 1,

leukotrienes
thromboxanes

Importance of linoleic acid:

'"

2.

precursor of 0) ...6 FAs~ A. linoleicacid produces arachidonic acid (C20) B, arachidonic acid is the precursor for (0-6 FAs (eicosaneids) eicosanolds derived from 00-6-

A. 3.

POE I and E,

4.

B. thromboxane Aland sourcesA. com oil B. safflower oil C. cottonseed oil O. soybean oil notcardioprotective

A2

Importance of linolenic acid: 1. precursor of (1)-3FAs-

A. B. C.

PGE~
POll

TX.A.3 (1)
(2)

2.

sources-A. fish oils:

eicosapentaenoic acid (C20;5Q)3, precursor of w-3 FAs)
docosahexaenoic acid (C22:6ro3)

B.
C. D.

soybean oil canola oil: best oil
walnuts

E.
3.

wheat germ

eardioprotecriveA. greatest effect on lowering triglycerides {not cholesterol) B. inhibit platelet aggregation: e.g., via the action ofPGh C. produce anti-inflammatory prostaglandins D. protect myocardium: less damage to myocardial tissue in infarctions acid metabolism: cyclooxygenase-

Enzymes involved in arachidonic
1.

A.
B.

inhibited by aspirin and other NSAIDs
prcduoed

2.

prostaglandins and thromboxanes Iipoxygeo.ase-1e:ukotrienes produced

y-Interferon: 1. produced by 2. functions-

CD"l T helper cells.and NK cells

A.
B.

C.
D.

activates macrcphages to kill microbial pathogens antiviral activity induces class 1 and II antigens increases production ofIL-2 and IL-12 by CD4-T helper cells

27

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Interleukin (IL)-2: 1. produced by CD'I T helper eells 2. fUDctionsA. primarily a Teell gro ..... factor rth B. promotes BcelllNK cell proliferation
qr

IL-3: 1.. 2.

~.

.

produced by T cells and thymic epithelial cells functionA. stimulates pluripotectial stem cell marrow B. increases hematopoiesis

(jJ"

n-s.
1.

TI..-4: 1. produced by activated T cells functions2. A. main ly promotes growth of B cells B. switch ofIgM synthesis in B cells to 19E synthesis in type 'I hypersensitivity produced by T cells and mast cells

reactions

2.

functionsA. promotes growth of eosinophils
B. promotes IgE synthesis

rJr

IL-6:
1. 2. produced by T'cells, macrophages, endothelial cells fibroblasts epithelial cells functlonsprimarily stimulates synthesis of acute phase reactants in the liver in acute inflammation

r:jJ"'

n-iz :
1. 2.

produced by macrophages functionsA. promotes growth ofeDa T cells B. promotes differentiation of CD4 T helper cells into TH 1 and T H2 classes ( 1) important in granuloma formation (2) important in production of memory T cells C. promotes production of "I-interferon D. enhances NK activity

W'

Gr.anulocyte colony stimulating factor (G-CSF): 1. produced by fibroblasts 2. fnnction-stimulates neutrophil development in tine bone marrow

rJr

Granulocyte/macrophage
1. 2. produced

colony stimulating factor (GM-CSF): by macrophages and T cells functi.on- stimulates neutrophil and monocyte development in the bone marrow adhesion molecule synthesis:

@"

Factors increaSing and decreasing
l.

increase syntbesisA. CSa B. LTB4 C. endotoxins: causes severe peripheral blood neutropenia D. 11-1 E. tumor necrosis factor (TNF).

28

Note: This material is copyrighted. All rights reserved

2.

decrease syntheslsA. catecholamines: B. corticosteroids C. lithium

released by stress

Congenital adhesion molecule (~- integrins) defect - S1\D...E,~: 1. failure of the. umbilical cord to separate In newborns 2. no adhesion of neutrophils to the-endothelial cells 3. no inflammatory cells in the umbilical stump Corticosteroid effects in acute inflammation: 1. block phospholipase Ar decreased synthesis of prostaglandlns and Ieukotrienes 2. decreases leukocyte adhesion synthesis,.... A. marginating pool (normally 50% of the peripheral blood leukocyte pool) is now circulating B. absolute neutrophilic leukocytosis ..,. .}. decrease peripberaJ blood lympbocytesA. lymphopenia B. decreases synthesis of antibodies decreases peripheral bleod eesinophils=eosinopenia 4. stabilizes the basophil/mast cell membrane5. A.prevents release reaction ofpreformed mediators B. important in Rx of asthma N eutrophils: 1. key cell 'inA. acute inflammation B. bmnunocomplex reactions: (1) activation of complement by immunocomplexes increases CSa (2) CSa is chemotactic to neutrophile (3) neutrophils damage the tissue wherever immunoeomplexes are deposited contains receptors for IgG/C3b 2. bone marrow mitotic pool (can-divtdej3. A. myeloblasts

B. 4. A.

progranulocytes
pool (can no longer divide)-

C. myelocytes bone marrow post-mitotic

metamyelocytes

5.

B. band neutrophils C. segmented neutrophil peripheral blood poolsA. marginating pool: (1)- adherent to endothelium (2} -50% of peripheral blood pool (3) >50% in African-Americans (reason for neutropenia in African-Americans) (4) become part of circulating pool when adhesion molecule synthesis is decreased

B.

ciroulating
(1)

pOD]:

measured in CBC

(2)
(3)

-50% in non-African-American.populations decreases jf adhesion molecule synthesis is increased

29

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Monocytes!macropbages: I. key ceU in chronic infiaDlmatio'D 2. 3. receptors A.
monocytes become macrophages-

for IgG/C3b:

important in extravaseular removal

ofRBes, leukocytes, platelets

B.

fixed macrophages: (1) Kupffer cells (2) macro phages in splenia red pulp' (3) macrophages outside sinusoids in the bone marrow wandering:
(1)

alveolar

4.

(2) microglial cells in eNS functiOlls-A. process antigen B. scavenger cells C. D. E. enhance hast immunologic response: secrete eytokines like IL-l, Ii-12, TNF secrete growth factors secrete nitric oxide in endotoxic shock

Lymphocytes: primary inflammatory cell in1. viral infections 2. type IV reactions 3. pertussis infections Plasma cells: 1. derive from activated B lymphocytes funetions-, A. antibody production B. IgM produced on first antigen exposure in acute inflammation: (1) IgM is more potent than 19G in activation of the classical complement hence ensuring complement components for acute inflammatory process (2) IgG is synthesized after 10-14 d (isotype switching) (3) IgG is the main immunogicbulinof chronic inflanunation morpbologyA. B. C. D.

2.

pathway,

3.

well-developed rough endcplasmic reticulum: easily identified on electrorimicroseopy bright blue cytoplasmic staining with Wright-Giemsa cartwheel appearing nuclearchromatin pattern, peripheral nucleus

Natural killer cells: 1. key cell mA. antibody-dependent type II reactions' B. graft versus host reactions C. ki lling of tumor cell szvirally infected cells 2. large granular Iymphocytes- noted in the peripheral blood, particularly in cancer patients Platelets: 1. derived from megakaryocytes A. bud off'of the cytoplasm B, -5000 platelets per megakaryocyte 2. functionsA. platelet aggregation: (J) TXA2 (synthesized)

30

Note: This material is copyrighted. All rights reserved (2) ADP (released from platelet granules) growth factors for wound healing contain von Wiliebrand factor (VWF) for platelet adhesion: adhesion molecule 'of the platelet

B. C.

Endotaelial cells: synthetic functions 1. prostacyclin (PG11) 2. vonWillebrand factor (VWF); platelet adhesion 3, nitric oxide: vasodilator 4. endothelin: vasoconstrictor 5. tissue thromboplastin: activates factor VII in the extrinsic system Mast cells/basopbtls: I, function- main effector cell for type I hypersensitivity reactions 2. activated byA. histarn ine B. specific allergens interacting with 19Eandbodi,es on-their surface C. C3a/C5a (anaphylatoxins) D, temperature changes E. pressure preformed mediators= ~ .•J.u</{ A. histamine B. serotonin C. heparin D. chemotactic factors: eosinophil chemotactic factor 4. late phase reaction- synthesis of the following chemicals: A. prostaglandins B. leukotrienes r crt: 'r I L T \), ) 5. early and late phase release reaction is prevented byA. Chrornelin sodium B. certicosteroids Eo inopbils: 1. functionsA neutralize histamine/leukotrienes B. destruction ef helrninths: -(1) type II (not type I) hypersensitivity reaction (2) eosinophils have Fe receptors for IgE (3) receptors interact with 19E coating the surface of invasive helminths (4) antibody dependent cytotoxicity reaction causes the release of major basic protein-» kilts helminth granules contain crystalline ooateria.l- become Charoot-Leydea crystals in sputum, 2. particularly in asthmatic's chemical mediators3. A. major basic protein: kills invasive helminths B. histaminase C. arylsulfatase: neutralize leukotrienes eosinophilia4. A. type I hypersensitivity reactions: (1) allergic rhinitis (2) bronchial asthma (3) drug allergies

31

Note: This material is copyrighted, AJ] rights reserved

B.

5.

eosinopeniaB.

response to invasive helminthic infections (not the mechanism of killing helminths, excludes pinworms, which are not invasive) J miscellaneous: .J._, (1) Hadgkin'~ .disease 5. , (2) polyarteritis nodosa i.05"'Alo/'Ji..~ -':tIl (3.) Churg-Strauss. .. 'I7~'l/e ~ . (4) lung hyp~re~smophilJa Sj'ndrames iii., ;'jAn Hf/"'~.s (5) bypocortisolism qL

(4)

(7\.

A.corticosteroids

Y~..lf)

Cushing's syndrome

1m
L

0113'Ot

2.

3.

4. S. 6.

7.

8.

cluster designation (CD) Wes for l1SMLE~ CD1A. histiccytes (Langerhans cells) B. dendritic cells C. tlsed jn a histiocytesis X questlen i1Ifi US1\.rL.B CD3A. T cell antigen recognition site B. OKT3 monoclonal antibody is an immunosuppressive agent that blocks this site CD~A. helper T cell marker B. .gp 120 antigens in 1:1IV-1and 2 bind to this molecule CDa- marker for cytotoxic and suppressor T cells CD15 and CD3o- markers for Reed-Sternberg cell in Hodgkin's disease CD21- receptor for EBV on B cells CD4r A. leukocyte marker B. leukocyte common antigen C. ve!}' useful in surgical pathology in separating leukocyte from epithelia! malignancies CDs(I NK cell marker for 02-dependent MPO

Role of fever in inflammation: " 1. right. shifts oxygen diBsodation curve (ODC)- more O;c3vailable system 2. provides ~ hostile environment for baeterial/viral reproduction Types of acute inflammatieu:

1.

suppurativet)71e I,j < 4. --> '. r : tl. ~.. ;u;.p,~ h.('T:J bscess \rI'J~·1fo1f-tM.""1!· ,.1'/ A . e,g., a B. Staphylococcus aureus contains coagulase: cleaves fibrinogen
I ), "" I 1('

'I'

l' ~ J..I; 4~r"'I'
~/h'. I ",

t

r.t/,

.t:,...~

.j

_.'

2.

into fibrin and traps (. 4 '/'l !,,' •\ r ' , I/. I. - r: bacteria/neurroph ils r "Of.J' ~ f II' (.(., ...' cellulitisL '> I I· ~f {I 1 lev ~Ntctr.1'I -' A. commonly (not exclusively) due tostreptoceccus B. bacteria contain hyaluronidase, which allows bacteria to spread through subcutanecus

I'

tissue
3. C. examples include: erysipelas and impetigo pseudomem brano DSA. toxin-induced damage of tissue , (liftotl B. not in asive infection • ., C. examples: (l) diphtheria th"u.. '" tl ~u

"III;£h' (."

lV'

"Me

~1

32

ore: This material lIScopyrighted. All rights reserved (2) Clostridium difficiie in pseudomembranous eolitis

4.
5. 6.

fibrinousA. B. protein-rich fluid that has a "bread and butter" appearance on serosal membranes e.g., pericarditis ~IC~.J. (. ~~rd-i.IJ~ fI(:;;=

setousA.

.

r,»'

,

J

protem-poor fluid R e.g., blister fluid in second degree 'bum,: phlegmonous (catarrhaJ)A. excess mucous secretions B. e.g., common cold

Types of wound healing:

J. 2.

primary Intention- wound edges are apposed secondary iotentionA. wound is left open B. myofibroblasts are important in closing wound
C. takes longer to heal

Sequence in primary intention
.J.

healing of wound:

2.

3.

4.
5. 6.

first dayA. clot develops in wound B. neutrophils infiltrate second d-ayA. squamous cells from basal cell layers of apposing skin margins seal off the wound after 4&hs B. maerophages emigrate into wound third dayA. beginning of granulation tissue formation: (I) angiegenesis due to basic fihroblast growth factor (2) fibroblasts lay down type ITI collagen B. fibronectin is key chemical mediator; (1) derived from macrophages/fibroblasts/endothelia' cells (2' chemotactic to fibroblssts/macrophages (3) opsonizing-agent (4) adhesion agent 4th-6th days- granulation tissue formation peaks 7-IO days- tensile strength 10% of normal

weeks-monthsA. collagenization: ~ (l) type ill collagen replaced by type I to increase tensile strength (2) collagenases important in remodeling (zinc is a cofactor) maximum tensile strengthof -80% after 3 mths

J.JI(i1 #~trl·':>. ~ '1 J
ON
(.<

~J'I 4e

"'~

I

f Ilfflj,hl fC' JJ

'0, 4'.1" .

,~
."

B.
,clr

Sequence of collagensyntbesis: 1. initial synthests in fibroblastsA. formation of polypeptide pro-a. 1and pro-a.2 chains B. hydroxylation of proline and lysine by vitamin C: site for cross-linking outside the fibroblast C. glycosv lat ion of lysine residues with glucose and galactose D. assembly of 3 pro-a. chains- inter and intra. chain xlisulfide bonds at C terminal extensions E. formation of tripLe helix

~y~'
--'>

~.'4 "',_,(;t,,,,_,,"(, ••• ~",

.____-- tU"'-r..··

cl'ro ttt(t·.!)t·~

C.,,,t

%,.J. ,

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2.

F. procollagen molecules translocated to ,Golgi apparatus for packaging.and 'secretion extracellular synthesis of collagen= A. ptocollagen molecule secreted into, extracellular space B. proeollallen peptidases cleave N-terminal and C-tenninal propeptides to release triple

helix
C. D. collagen molecules form fibrils cross-linking of collagen fibrils to increase tensile strength: Jysy1 oxidase (copper is a cofactor) is a cross ..linking enzyme ~ ~"s.::; t." ~ a, I, .. ),.,<18,,.,./.,,,,/ j ,~

I~t"·,j(,-,

Important collagen, types: 1. type JA. highest tensile strength B. tissues: (1) bone (90%) (2) skin (80%) (3) tendons 2. type TI- cartilage 3. typemA. initial type in wound repair B. skin (10%) C. blood vessels 4. type IV- basement membrane 5. type IX- cartilage 6. type x- epiphyseal plate (pieture of bone in YSMl1E) Key factors interferiugwith wound healing:

1.
2,

infectionA most important B, Staphylococcus aureus Me pathogen tissue hypoxia malnutrition zinc deficiency- cofactor in collagenase involved in wound remodeling » vitamin C defictencyA. nc hydroxylation of proline and lysine B. hydroxylation sites.are where cross-bridges attach to fonn strong collagen bundles C. structurally weak collagen in scurvy genetic disordersA. Marfan's: defect in fibrillin B. Ehlers-Danlos: defects in collagen

~.
4.

..

5.

6.

Keloid: 1. hypertrophic soar tissueA. resembles a tumor B, contains type ill collagen 2, :pred1qlO!ition to.squamous eaneee• '. ..,.

*The f'Il(_
;S

C ffQJ.
5.

59"1,'U

(~rr t~R

"~soc'l
j

1~INO~'0~;

1/

1\.IJ111

Characteristics of chrome Inflammatien:
1.

particulariy if due to third degree bums of... "I "J..I:.:NI IJ dllllN i,l ~ oS ,Nil ~
'J

pathogenesisA. pre ious acute inflammation B. de novo: (1) granu tomatoes inflammation (2) autoimmune disease

34

Note: This material is copyrighted. All rights reserved

2.

3. 4.

cell types-A. monocytes/ macrophage", B. lymphocytes C. plasma cells D. fibroblasts E.endothe Iial cells IgG is the predominan immunoglobulin- polyclonal peak in r-globlllin region in a protein electrophoresis compJications of chronic inflammationA. production of serum associated amyloid (SAA) protem' by liver: seeondary/reacrive amyloidosis B. excess fibrous tissue deposition: e.g. fibrosis in liver with formation of regenerative

nodules (cirrhosis)
Recognition ufa granuloma. (IJS:MLE picture): I. histology-A. well-circumscribed B. red C. contain multinucleated giant cells 2. usually a type IV hypersensitivity reactionA cell-mediated immunity B. CD4 T helper cell and macrophage are main cells Formatiou of TB granuloma: 1. pbagocytosis oftJB by alveolar macrophages 2. systemic Iymphobematogenous spread of macruphages with bacteria-: A. rnacrophages begin processirig TB antigen B. no systemic infection 3. macrophage interacts with enol T belper ceD via class n antigen sitesA. macrophage release of .JL-12 B. CD4 T cell differentiates into TAl class cells: (1 ) retain memory of encounter (2) important in PPD reaction and reactivation IB 4. macrophages secrete IL-lA. augments T cell proliferation by causing IL-2 release frOID CD.! T helper cells 'B. produces fever 5. CD4 T helper cells secrete cytokinesA. y~interferon: (1) activates macrophages to kill TB (2~ PPD becomes positive (3) lipid from killed bacteria is responsible for caseous necrosis (4) activated macrophages are called epithelioid eel] B. macrophage inhibitory factor: keeps macrophages together to form discreet granulomas 6. macrophages fuse into multinucleated. giant cells- best marker for granulomas

7.

PPD reactionA. B. C. injection of purified protein derivative (PPD) into skin Langerhans cells (histiocytes of the skin) phagocytose and process the PPD antigen: present antigento previously sensitized T HI CD>!cells reactivated T~'ll CD4 cells locally releasecytokines into tissue leading to redness and induration

rJ:'" j, R r) 5'1.;r'r tl.lfi .q/~/,AJ
j
tJ;J

iIf. A~N b

'Y.(

rf f ed
Pj

_::s; ---"Y

':;1'l/'ll

-)

35

10 ~f>rl
f';',.,.,,r,

N ate: This material is copyrighted. All rights reserved

@"

Fistula versus sinus': J. fistulaA. communication between two hollow structures B. Me fistula is colovesical fistula (colon with bladder) due to dtverticulitis 2. sinu A. tract leading, to skin surface B. oommon with skin abscesses due to S. aureus and Actinomyces infections Liver reaction to iujury: t. stable tissue in Go' phase enters cell cycleA. regeneration of hepatocytes B. persistent injury causes rerrenerative nodules to form 2. scar tissue Iormaticnin alcoholics an acetaldehyd~-protein (normally stores retinoic acid) to synthesize collagen Cardiac muscle reaction to iojury:

complex

stimulates ItO cells scar

permaneat tissue, hence it is replaced by non-contractile

tissue
Kidney reaction to injury: 1. stable tissue enters cell cycleA. renal cortex responds better to injury than medulla: receives 90% of the blood Versus only 10% in the medulla B'. renal tubular cells regenerate only if the basement membrane is intact: (1) reason why nephrotoxic damage is more likely to recover than ischemic damage (2) in ischemic damage there is disruption of the basement membrane 2. thick ascending limbA. most susceptible part of nephron for hypoxia :if B. where the Na+/K'/2cr cotransport pump is located a;;r~NfLe:j

-+

Lung reaction to injury: type II pneurnocyte is key repair cell1. replaces damaged type I pneomocytes 2. syntbellizes surfactantA. lowers surface teasion to keep airways open on expiration B. surfactant is present in lamellar bodies (look like whorled-bodies microscopy) 3. ether names for surfactantA. lecithin B. pbospharidylcholine C. phosphatidyl glycerol Central nervous system reaction totnjury: 1. astrocyte is analogous to the fibroblast 2. eNS response to injury is called glios'isA. gliosis is primarily a proliferation of astrocytes B. protoplasmic processes offer some structural support C. microglial cells (macrophages) are scavenger cells in the repair process PeJlipberal nerve reaction to fuJury (1'J:SMLE): undergoes wallerian degeneration1. distal degeneration of axon and myelin: sheath and proxlmal degeneration nearest internode 2. macrophages/Schwann cells phagocytose axonal/myelin debris 3. muscle undergoes atropby in -15 d 4,. nerve cell body undergoes central cbromatolysis-

on electron

Up to {he

36

Note: This material is copyrighted. All rights reserved A. swells B. Nissl substance disappears centrally C. nucleus peripheralized Scbwann cells proliferate and enlarge in distal stump axonal sprouts develop in proximal stump and extend distally guidance regenerated axon grows 2-3 mm/d axon becomes remyellnated muscle eventually reinnervated

5, 6. 7. 8. 9. Bone L 2. 3. 4.

using Schwann

cells for

healing: hematoma organlzation (precallus) at fracture site conversion of procallus into flbrocertllaatnous callus fibrocartilaginous callus replaced bymature bone- bone remodels along lines of stress factors interfering with bone healingA. not properly aligned B. infection C. not immobilized properly D. inadequate blood supply

CiT

Femoral neck fracture: 1. bleeds into the capsule 2. 3. may compromise

necrosis

.;:m:::.:ed=i.::aI:....:.==:l....:::;:;:..::.:==:;....:=~--I.,;ru:::..LS~ML~=1lD:=..I.- may lead to avascular
are mast dangerous

posterior dislocations

W

Erythrocyte sedimentation rate (ESR): 1. measure of rate of settling ofRBes ill a vertical tube in mm/h 2. RBe and plasma factors are responsible for ~SR-

l2illpoR.~r Aete.e:·/,'s

Ir1
-1'-

j

M ~t.t.,-a

A.

aggregation ofRBCs increases settling:
(1)

agglutination (clumping) ofRBCs is due to increased IgM (e.g, cold agglutinins) or cold reacting globulins called cryoglebulins t~yO,tOh1""{lflJ;1 ~ C~I'1IINJN iN J...A. PIlJJJ ~~ (2) rouleaux (stack of coins) is due to increase in fibrinogen and/or y-globulins B. abnormally soaped RHCs (e.g., sickle cells) do not settle C. too many RECs (e.g., polycythemia) interferes with settling D.anemia enhances settling

3.

ESR IncreasedA. B.

C.

acute/chronic inflammation monoclonal gammopathies: e.g., multiple myeloma best initial screen for temporal arteritis; (1 ) if normal temporal arteritis unJike ly (1) if increased, start corticosteroids

4.

D. anemia lowESRA. sickle cell anemia
B. polycythemia

Lab findings in acute bacterial infections:

l. 2.

absolute neutrophilic leukocytosis left shiftA. > 10% band neutrophils or
B. presence of any neutrophil less mature than a band

37

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3. 4. L. 2.

toxic granulatioD- prominence of azurophilic granules containing rnyeloperoxidase Dahle bodies- dull gray inclusions representing dilated endoplasmic reticulum (transthyretin): Iunction- binds thyroxine/retinoic acid (vitamin A, called ret,illQl-biriding protein) clinicalA. transthyretin is an indicator ~fproteio status: short half-life of 1-2 d B. converted into amyloid in familial senile and cardiac am, loidosis C. retinol-binding protein: 1) most sensitive indicator of }/isceral protein mass 2) 12 h half-life bound to transthyretin and only 3.5 h half-life if free

(MPO)

Prealbumin

Albumin: 1. Il1DctionsA. binding protein fur: (1) cal alum/magnesium (2) drugs (3) unconjugated bilirubin (4) free fatty acids B. 80% of oncotic pressure 2. cJiD.icalA. hypoalbuminemia due to: (1) chronic vee disease: (MeG) (2) malnutrition (3) nephrotic syndrome {4) Glioss (malabsorption), B. when albumins binding capacity is exceeded: (1 ) drugs d isplaced lead ing to drug toxicity (2) unconjugated bilirubin displaced in newborns resulting in kernicterus C_ marker of protein status: long half-life of 20 days limits its usefulness D. marker of severe liver injury

u

Alpha, antitr:yps~n (AAT): .... 1. function- antiprotease: A. serine protease inhibitor B. inhibits elastases released by neutrophils 2. clinicalA. acquired deficiency in cigarette smokers: smoke denatures AAT B. genetic deficiency; (l) AR disease (2) newborn cirrhosis (problem with secretion of AA by hepatocytes) (3) panacinar lower lobe emphysema (decreased synthesis oLA..._J~T) C. marker for hepatocellular carcinoma. Haptoglo bi n: 1. synthesized in liver 2. bind's free hemoglobin (Rb)- so called "suicide" protein 3. low in intravascular hemolysis- macrophages remove/destroy haptoglobin-Hb complex

Transferrin'
1. fUoctionA. synthesized in liver

38

Note: This material is copyrighted. All rights reserved B. binds iron and delivers 'syntl:tesis/storage

it to developing normoblasts

in the bone marrow

for Hb

2.

clinicalA. corresponds with total iron binding capacity (TIDe): (1) law/absent iron stores ill hone marrow (e.g., iron deficiency) result 'in increased liver synthesis of transferrin (increased TIBC) (2) increased iron stores (e.g. ~~ia chronic disease iron overload states result in decreased transferrin synthesis.Idecreased me), excel 1 marker of protein statu s: short hal f-1ife of 'l 0 d ent

B.

Increased iron stores

Higb
Immunoglobulin G:

rmc

X

Decreased iron stores

Low TIBC

1.

functionsA.80% of'total v-globullns B. opsonin

C.
D.

warm-reacting antibodies

2.

transplacental transfer of antibodies protects fetus: any IgO antibodies in newborn are maternal in origin: e.g, HlV antibodies E., . activates the classical complement pathway --':J.. "f -M _'<"S ;! l.jGjs f-o sa cftnlcal,..,;,-t pI. ~tl es~ b P Vi) ~ rI C -: A. causes of hypergammagiobulinemia: ..J f .. ~ (1) chronic inflammation (called polyclonal gammopathy on a serum protein electrophoresis) (2) monoclonal gammoparhies (e.g., multiple myeloma, called monoclonal gammopathy on a.serurn protein electrophoresis) B. causes of a hypogammagJ.Qbulioemia: (1) B cell deficiency disorders (e.g., Bruton s agammaglobulinemia) (2) nephrotic syndrome (lost in the urine) :(3) chronic lymphocytic leukemia (neoplastic B cells cannot differentiate into plasma

"0

cells)
Immunoglobulin A: 1. fUDCtiOD- important in mucosal' defenses due to its secretory 19A component 2. c1in.ical- Me genetic immune deficiencv: A. sinopulmonary infections B. malabsorption C. allergies D. GI parasitic infections (e.g., giardiasis) Immunoglobulin M: 1. fUDCtiohA. largest immunoglobulin (Ig): (I) pentamer with 10 antigen recognition sites (2) Ii heavy chain is antigen recognition site on B cells B. most potent activator of classical complement pathway

39

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2.

clioicalA. synthesized shortly after birth: increased IgM at birth indicates a congenital infection B. first antibody produced if) acute infections C. monoclonal increase 111 Waldenstrom's macroglobulinemia D. increased in primary biliary cirrhosis E. co ld-reacting antlbccles/giobulins: (I) cold autoimmune hemb.lytic anemias (intravascular hemolysis, RBC agglutination) (2) cold agglutinins (N!ycoplasmaplleumoniae infections) (3) cryoglebulins (produce Raynaud's phenomenon): do not contain Igtvl D: heavy cbaln also antigen receptor on B cells E: reaginic antibody

Immunoglobulin Immunoglobulin

in type r reactions

C reactive protein:

1.

functions~
A. activates complemect B. opsonin clinical=excellent marker for bacterial (increased) versus viral infections (normal) used duting the board review:

2. Questions

A 4-year-old child with recurrent Staphylococcus

aureus infections and an absent respiratory burst

MOST L1KELY has-a/an ...
A. B,

C.
D,

E.

defect in spectrin in the cell membrane defect in microtubule polymerization deficiency ofTgG gamma globulins deficiency ofNADPH oxidase deficiency of rnyeloperoxidase activity of corticosteroids?

D
Vir

Which of the following is MOST responsible for the anti-inflammatory A. Increased leukecyte adhesion to endothelial cells B. Inhibition of phospholipase A2 C. Destruction of eosinophils D. 'Inhibition of oyclooxygenase E. inhibition of lrpoxygenase

B Items 3-5 A. Cellulitis
Suppurative inflammation Fibrinous inflammation Pseudomembranous inflammation Granulomatous inflammation B. C.

E.

D.

A 52-year-old man with chronic renal failure has chest pain and a scratchy 3 component sound heard over the anterior chest
answer: C
@='

A febrileBsyeer-old child, who has not received any immunizations. the oropharynx and prominent cervical lymphadenopathy answer:D

bas a grayish-white

exudate in

40

Note: This

materia! is copyrighted. All rights reserved

A febrile 3 year old child has a diffuse. raised, hot red area of inflammation extending .arouad the righ] periorbital tissue leading to swelling and closure of the eye answer A A newborn chi Idhas fai lure- of separation of the urnbili ca 1cord. Risto] ogle section s of th e surgi cally removed cordreveal an absence of neutrophil margination and emigration j,rito .the interstitial tissue. The clinical and histologic findings in this case are._MOST CLOSELY associa ed with a defect in ... A. activation of the complement system B, microtubule polymerization C. the respiratory burst mechanism D. an adhesion molecule in neutrophile E. the production of myeloperoxidase

A. B. C.

Neutrophils Macrophages Ecsinophits

D.
E.

Mast cells Plasma cells

They represent the epithelioid cells arid multinucleated giant cells in a granuloma

.B

C3a and C5a activate them The granules of these cells contain refractile material 'that form Charcot-Leyden sputum of asthmatics crystals in the

answer; C

41

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An rights

reserved

mmlUlo:pathology
R,isk factors for immune disorders: 1. prematurity autoimmune diseases- e.g., systemic lupuserythematosus lympbop:roliferative disorders- &.g. malignant lymphoma infections- e.g., AIDS 5. immunosuppressive drugs- e.g., corticosteroids B cells: 2. 3. 4.

...

.

1.

peripheraJ

2.

markersA.

blood- ] 0-20% of Iota I lymphocyte count 11. heavy-chains: pre-B eel]

intracytoplasmic

B.
C.

surface j.l and S heavychains: (l) mature B cell

3.

(2) antigen tecognrtion site surface receptors: ( I) IgG Fe receptor (2) CD21• for EBV functioDsA. immunoglobulin (lg) synthesis: (1) no Igs present at birth (2)

B.

4.

testingA. B. C.

(3) (4) IgM synthesis begins at birth (presence ofIgM Indicates congenital infection) IgG synthesis begins in 2-3 rnths: defense against extracellular encapsulated bacteria (e.g., Streptococcus pneumoniae)

newborn IgG antibodies are transplaceritally-derived mtbs) high 19AtIgG in colostrum

from mother (persist 3-5

D.
E.

B cell count: flow cytometry immunoglobulin ~oncentration: order of decreasing concentration 'and 19E detect ischemagglutinins: (1) anti A.IgM in blood group B person (2) none present in newborns and AB blood groups lymph node biopsy: (l) germinal follicles present (2) presence of plasma cells mitogen stimulation: (1) functional test (2) e.g. pokeweed is the mitogen

IgG, 19A, 19M IgO,

;;:jj?

T cells: 1. peripheral hloodA. 60-70% of total lymphocyte count 2.
B.

markers-

lymphopenia in AIDS due to loss of CD'I T helper cells

A.

B.

monoclonal antibody marker studies are used to ,identify T cells and subsets: see inflammation for cluster designation (CD) types ratio ofOD4/CDB 2/1: <1 in AIDS

42

Note: This material is cGpyrighted. All rights reserved

3.

immature T cells have nuclear enzyme terminal deoxynucleotidyl their surface functicnsA. type IV hypersensitivity B. cytokines regulate B cells C. defense against intracellular pathogens (e.g., TB)
testing...

C.

transferase (TdT) on

4.

A.
B.

C.

mitogen assays: functioning T 'cells are specifically activated by phytohemagglutinin and concanavalin A skin tests: (1) evaluate cellular immunity (2) Candida is the main antigen used (3:) absence of an immune response (no redness and induration) indioates anergy or a lack of cellular immunity (e.g., AIDS patient. DiGeorgesyndJ'oQ1e) lymph Dade biopsy: (1) T cells present in paracerticalsreas (2) absent in T cell deficiency states

~~ Bruton's agalJlm~globulinenti~:. -4 VI C 1. pore B celJ immunodencieneySXR disease 2. pa tho genesis- failure of pre- B' cells to differentiate into mature B cells 3. c1inica]- infants develop sinopulmonary (SP) disease: A. Streptococcus pneumoniae .d L ..J_ B. Hemophilus infiuenzae ~3.~tl rr. I)Q('_ ~'q C. Staphylococcus aureus 4. Rx- IV y-globulil'l

Common variable immune deficiency (CVID): l, no inheritance pattern

2.
3.

patbogenesis- intrinsic defect in B cell maturation into antibody-producirrg plasma
clinicalA. presents between 15-35 ys of age

<l_CUS

B.
C.

recurrent sinopulmonary infections: decreased Ig production
giardiasis (1)

4. 5.

malabsorption: celiac sprue (2) lactase deficiency E. auteimmune.disease: pernicious anemia Ia:b-aUIgsdecreased Rx- IV y-globlJlin

D.

Selective IgA deficiency: 1. Me hereditary immunodeficiency

2. 3.

pathogenesisA. intrinsic defect in B cell differentiation into committed B eells synthesizing 19A B. po sible T cell defect that ,Pf6vcptS B cells from synthesizing 19A clinicalA. recurrent sinepulmonary infections: lack of seeretory 19A B. giardiasis C.autoimmune disease D, allergies

43

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All rights reserved

E.
4.

develop anti-Iga, antibodies with exposure to 'blood products: reaction when exposed toblood products with Ig.4. lab- serum and secretory 19A le els decreased synd rome:

danger of anaphylactic

Sex-linked lymphoprolifel'ative

.1.
2.

SXRA. B cell deficiency B. EBV -related disease clinicaiA. hypogarumaglobulinemia B. rnalignam lymphoproliferative

disorders

DiGeorge syndrome (thymic hypoplasia): I, pure T cell defictency- no inheritance pattern 2. pathogenesis (1l failure of the 3rd (inferior parathyroids/thyrnus)/4th (superior parathyroids) pharyngeal pouches to develop 3". clinic.alA. abnormal facies B. hypoparathyroidism: hypocalcemia and tetany C. absent thymic shadow D. truncus arteriosus: cyanotic congenital heart disease E. chronic candidiasis F. Pneumocystis carinii pneumonia (PCP) G. graft: vs host reaction (GVT-I): must irradiate blood to destroydonor immunocompetent lymphocytes 4. RxA. thymic grafts B. bone marrow transplants

~r-

Severe combioed immunodeficiency (SCID): L BIT cell immunodeficiencyA. AR. or SXR disease B. -50% AR pattern haye adenosine deamlnase deficiency: accumulation of adenine, whlch is toxic to BIT lymphocytes 2. clinicalA. P. earinii pneumonia B. diarrhea C. disseminated CMY D. graft vs host reactions: must irradiate blood

3.

IUA B. bone marrow transplant gene therapy: first disease successfully cured with gene therapy SXR disease
O(\jy

Wiskott-Aldricb syndrome: 1. BIT immunodeficiency-

2.

clIntcatA. thrombocytopenia (bleeding) __..:;,. -+he B. eczema C. recurrent sinopulmonary infections
D. increased risk for malignant lymphomas labA. low IgM

.

l/'Il(l)urlil'trCre~'7 t

k""

~

.lfJ(,cf.e.lft-ab",o~M"I;fIeS

3.

44

Note: This material is copyrighted. All rights reserved B. increased IgG, 19A, IgB C. defects in cell mediated immunity develop late Rx-- bone marrow transplantation

4.

Ataxia telangiectasia: 1. BIT immullodefi.ciencyA. AR disease B. develops in 2-5 year olds 2. clinicaJ-

A.
B. C. D.

cerebellar ataxia
telangiectasias in eyes/skin

sinopuhnorrary infections
chromosome instability syndrome: (1) increased susceptibility for chromosomal mutations (2) DNA enzyme repair defects (increased risk for lymphomas/leukemias) thymic hypeplasia

3:.

E. JabA. low IgAitgE B. increased serum c-fetoprotein

AIDS epidemiology: 1. Me acquired immunodeficiency syndromeA. Me COD in black men and women (black/white) between 25-44 B. average life span from the beginning of infection to AIDS defining lesion is ·10years 2. virus cbaracteristicsA. IDV~l RNA retrovirus MC in United States

B.
C.

D.

E. F.

O.

H. I.
J.

tOe CD4 molecule of T helper l<:e115 and other cells: ( 1) uionocytes/macrapbages/ dendr itic cells/mi crogl ial cell s ( eNS macrophage) (2) astrocytes p24 core protein surrounds viral genomic RNA: (1) only increased during l'D.itiallnfectionand when the patient develops AIDS (2) 2 separate peaks _WILE, J>~innillg and end) CD4 T helper oeU is lysed by the virus: usually direct HlV cytotoxicity reverse transcriptase converts igenomic RNA into proviral double stranded DNA: integrated into host cell's DNA with vitally encoded integrase enzyme after transcription, HI\! messenger RNA i_s translated into various proteins: (1) env encodes gp120/gp41 (2) pot encodes reverse transcriptase/irrtegrase (3) gag encodes p24 core antigen viral core consists of genomic RNA surrounded by an inner membrane composed .of p24 antigen: assembled near the host cell's plasma membrane budding of the progeny virion through the host cell rnernbrane is where the viral core acquiresthe external envelope to become a mature HIV virion bodY 'fluids containing the virus: (1) blood (most infective body fluid) (2) saliva (?chemical in saliva inactivates virus, virus is not transmitted by kissing) (3) semen (4) amniotic fluid (5) breast milk (breast feeding contraindicated in HfV+ women)

HN-2Me in third world countries gp 120 viral en"\(e10peprotein of virus attaches

cu:

4S

Note: This material is copyrighted, All rights reserved (6) (7) (8) (9) spinal fluid

wine
tears bronchoalveolar

3.

4.

5.

6.
7.

8.

9.

10.

l l.

lavage material modeoftransmlsslon in the United States in descending orderA. receptive anal intercourse between men B. vaginal intercourse male to female: infected semen bas more surface area to infect C. female to male: less surface area in male urethra to infect mode of transmission in womenA. heterosexual transmission in minority females who are IV drug abusers B. sharing contaminated needles and/or vaginal intercourse with males who are I-DV positive mechanism of transmission by anal intercoursedirect inoculation into the blood from mucosal trauma or an open wound: A. syphilitic chancre B. proctitis blood transfusion transmission riolk- 1:·676,.000per unit mode of transmission in health care workersA. accidental needle stick from an IDV+ patient B. 03% (1/300) risk mode of transmission to children+ A. vertical transmission (mother to fetus) from an infected mother ,(90%) B. most cases are transplacental, followed by breast feeding Rx of pregna nt women who are mv positiveA. AZT B.reduces the rate of newborn's developing AIDS from. -25-30% to 7.6% positive enzyme Immunoabsorbent assay (EIA) test fotBIV in a newbo.rnA. due to transplacental transmission of the IgG antibody. from the infected mother B. document HIV infection in newborn. b detection of mv RNA by peR (best test) and p24 antigen capture assay reservoir cells for viraj replication- monocyte lineage cells most often located in lymph nodes enzyme immunoabsorhent flllsay (EIA)A. initial screening test B. detects anti-gp120 antibody c. sensitivity '99.5 -99.8% D. poor specificity due to low prevalence of HIV positivity in the general population E. usually positive in 4-8 wks western biotA. confirmatory test for indeterminate or positive ElA B. positive western blot: presence of p24 'and gp41 antibodies and either gp120 or gpl 60 antibodies C. combined positive- predictive value of a positive EWwestetrn blot is 99.5%

AIDS testing:
1.

2.

tests for monitorlng immune statusA.

B.

CD4 T helper cell count HIV RNA by peR: best overall testtD monitor vira] burden.

AIDS immunologic abnormalities: 1. lympbopenia- low CD~count

46

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2. 3. 4. S. 6. 7. 8. 9. AID 1. 2.

bypergammagiobulinemiapolyclonal stimulation ofB,eells anergy to skin testing decreased mitogen blastogenesis of T cells decreased production of eytokines dysfunctional NK cells increased p24 antigens CDJCDB ratio < 1 PPD Skill test- >5 mm induration is positive test clinical:

by EBV and CMV

3.

4.

a.

acuteHIV syndrome- mononucleosis-lise syndrome 3-6 wks after contracting the virus asymptomatic, clinically latent phaseA. viral replication in dendritic cells in lymph nodes B. average span of 4--1 0. ys early symptomatic phaseA.,tlOil-AIDS defining infections: (1) ora] thrush (2) oral hairy leukoplakia (EBV glossitis) (3) recurrent H. simplex)H genitali« (4) condyloma acuminata (HPV) (5) shingles (H zoster) (6) rnolluscum contagiosum (poxvirus) B. generalized lymphadenopathy C. thrombocytopenia: (1) Me hematologic abnormalityin AIDS (2) immunocemplex destruction (type ill hypersensitivity) or antibodies directed against platelet antigens (type hypersensitivity) AIDSpositive plus: A. CD4 T helper cell count: <200 tellslj.lL specific malignancies: e.g., Kaposi's sarcoma C. specific infections: e.g., P. carinil pneumonia

mv

n

AIDS-defining malignancies: 1. Kaposits sarcomaA. Me malignancy B. associated with Herpesvirus 8 2. Burkitt's Iympboma- EEV 3'. invasive cervical cancer- HPV 4. amid squamous cancer- HPV 5. primary CNS malignant IymphomaA. HIV +EBV B. rapidly increasing, due to AIDS
)J.

AIDS-defining

opportunistic

bacterial

tnfecttons:

1.

MAIA. B. fever night sweats

C.
D. 2. 4.
}.Ii

weight Joss

infectious Gause of a Whipple's-like syndrome kansasii M tuberculosis recurrent pneumonia- usually Streptococcus pneumoniae

47

Note: Tills material is copyrighted, AU rights reserved

5.
,1.

Salmonella septicemia

AIDS-defining

2.

candtdlasts-, A. MC overall fungal infection B. airways/esopbagus
coccidioidomycosis cryptococcosis-1vlC histoplasmosis fungal eNS

P.

fungal infectio,ns: carinii pneumonia- MC AIDS-defmiJlg ,infeCtiori opportunistie

3.

4. 5.

Infection

l'\IDS-d~finiDg opportunistic Viral i~fectiol1s: 1:. CMYA. retinitis: (1) MCC of blindness in AIDS (2) Rx with 'ganeiclovir (3) use foscamet if ganciclovir does not work B. esophagitis C. diarrhea D. cholecystitis (J1SMLE· 2. H. sonpte»A. chronic ulcers B. esophagitis .,
j.

C. bron chiti s/pneumoni a mV~related encephalnpathy-. AIDS-dementia
RIV-related wasting syndromeA. weight loss B. fever C. chronic diarrhea D. fatigue progressive multifocalleukoencephalopatbyA. papovavirus

4.

5.

B.

demyelinatingdisease

2. 3.

AIDS-defining eppertuaistic parasitic viral infections: 1. CNS t6xaplasmosiB- MCC of a focal space· occupying leSion in AIDS

cryptosporidiosisA. Me pathogen in diarrhea
partially acid-fast oocyst

B.

isosporiasis- AIDS diarrhea

AIDS miscellaneous infections: 1. viral bepanis- HBV mast common type 2. bacillary angiomatosisA. due to Bartonella henselae B. simulates Kaposi's sarcoma 3. infection Imalignancy encountered with CD4 T helper count 200-500 ceUs/J..I,LA hairy leukoplakia/oral candidiasis

B.
4.

TB

C. recurrent bacterial pneumonia: Streptococcus pneumoniae infections encountered with CD4 T helper count' 100-200 ceIls/J.LLA. PCP

48

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B.
5,

Herpes virus C. disseminated histoplasmosis infeetions encountered witll CD4 T helper count <100 cells/uL> A. disseminated MAl: usually <7S,celtslfAL B. Candida esophagitis C. eMV retinitis/esophagitis D. Toxoplasma encephalitis E. Cryptosporidiosis: diarrhea F. cryptococcal meningitis

AIDS organ pathology: 1. tongA MC Orl!8n jnvol-ved

B. C.
2.

PCP

TB

D. Streptococcus pneumoniae pneumonia hematologic systemA. thrombocytopenia: Me hematologic manifestation B. cytopenias C. anemia of chronic disease D. autcimmune bemolytic anemia E. non-Hodgkin's malignant lymphoma: (1) B cell immunob lastic (2) poor prognosis

3.

renal diseaseA.

B.

focal drugs (1) (2) (3)

segmental glomerulosclerosis: nephrotic syndrome with nephrotoxicity: amphotericin (Rx of systemic fungal infections) pentamidine (Rx of PCP) foscarnet CRx of disseminated CMV)

4.

CNSA, AIDSRdementia complex: ..,. (1) MC CNS lesion (2) multinucleated giant celts are fused microglial cells vacuolar myelopathy: (I). posterier column and lateral corticospinal tract disease (2) sim ilar to B 12 deficiency b ut not due to B 12 defic iency ascending type of paralysis: similar to Guillain-Barre syndrome toxoplasmosis: focal epileptic seizures CMV retinitis: MCC of blindness esophagitis: (1) Candida MC

B.
C.

D.
E.

5.

GIJIiverA.

(2)
B.

HSV

C.

(3) CMV biliary tract disease: {l) CMV (USMLE) (2) cryptosporidium (partially acid-fast oocyst) colitis: (1) CMV (2) cryptosporidium

49

Note: This material is copyrighted. All rights reserved (3) MAT sJdnA. Kaposi's sarcoma: Me cancer in AIDS B. bacillary angiomatosis C. dissemiaated molluscum contagiosum D, disseminated seborrheic dermatitis: Malassezia.furfur ~ AIDS drug treatment: 6. 1. 2. initial drug regimen used in Rx ofHIV- 2 nucleoside analogs (e.g. AZT lamivudine) protease inhibitor (e.g., indinavir) tests to monitor Rx ofmv~ A. J-ITV R.NA by polymerase chain reaction (PCR): (1 ) monitors viral burden during (2) best test B. CD4 T helper count: (l) immune status (2) prophylaxis marker mechani m of action (MOA) of nucleoside drugs-cbloek reverse transcriptase MOA of protease inhibitors ..... suppress }lIV replication b blocking protein processing later in the IDV cycle MOA of uounueleoside reverse transcriptase inhibitor - uon-cornpetitively transcriptase: e.g., nevirapine side-effects of AZTA. headache B insomnia C. G1 intolerance D. bone marrow suppression: ( 1) macrocytic anemia unrelated to BIZ deficiency (2) neutropenia (3) anemia E. proximal muscle .disease F. dark blue nails '" side-effects of didsnosineA. pancreatitis B. hepatitis C. peripberal neuropathy side-effects of lamivudine (3TC)A. rash B. peripheral neuropathy C. bone marrow toxicity side effects of indinavir- protease inhibitor associated with renal stones side-effect of DOD-n ucleoside reverse transcriptase inhibttors- rash CD4 belper TeeU count for prophylaxis against PCPA. <200 ceUsI).LL inhibit reverse

3. 4. 5. 6.

7.

8.

9. 10. Ll ,

B.
12. CD4 A. B. CD"

Rx with TMP/S:MX
helper T cell count for prophylaxis <1 00 cells/ul. Rx with TMP/SMX helper T cell count for prophylaxis <50-1 00 cells/ul. against toxoplasmosjs~

}3.

against lVIAI-

A.

50

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B.

R.x with azithromycin

Recommendations to prevent AIDS: J. abstinence 2. latex condoms with non-opxynol-9 Immunizations ill mv positive patients:

viral spermicide

1.
2. 3.

SALK.A. B. killed vaccine live vaccine nor recommended

...

HEV
influenza

4. 5.
6.

Hemophilus influenza b (Hib)
Pnenmococcal A. B. vaccine

m eas I esIm Jl m ps/ru beUa0nly live viral vaccine permitted in BIV positive patients natural infection is worse than the potentia! infection from the vaccination

COD in AIDS: 1. bacterial inf~c1ionA. MCCOD B. S. pneumoniae C. disseminated MAl D. disseminated CMV 2. wasting disease Functions of the complement system: 1. augment vessel/cellular events in acute inflammation2. lyse cells 3. participate in cytotoxic anmunttj-A. type Ilantibody (IgG/lgJvf) complement-mediated

B.
4.

type

m immunocornplex

reactions

complemen patbways- classical and alternative pathways A. both converge on C3 ~ B. activates the membrane-attack complex (J\ifAC)

C.
S.

MAC is cytolytic

6.

function of decay acceleratlag factor (DA.F)A. located on cell membranes B. enhances degradation ofC3and C5 convertase: protects c-ellagainstlvIAC C. deficient in paroxysmal nocturnal hemoglobinuria function of Cl esterase inhibitorA. negative control on the activation QfCI in the classical pathway B. deficient in hereditary angioneurotic edema

destruction

Testing of comp lement system: 1. classical pattrway- low C4 OJ C2 if-activated 2. alternative pathway-low factor B if activated 3. in.tegrity of both pathways- low C3, if either system is activated 4. activation increases the concentration of split fragments- e.g., C3a, CSa, C3b 5. functional assessment of the complement system- total hemolytic complement assay (CHso) Complement disorders: 1. acquired (MC) or hereditary

51

Note: This material is copyrighted. All rights reserved 2.

3.

4.

5.

6.

low serum complement levelA. Me used up in antibody-complement reactions R. e.g, immunocomplex diseases like SLE paroxysmal nocturnal bemoglobinuria (PNB)A. acquired. stem cell disorder associated with a membrane-defect decay accelerating factor (DAF) E, intravascular destruction by !vIAe of: (1) RBC (anemia, hemoglobinuria) (2) WBCs (neutropenia, infections) (3) platelets (thrombocytopenia bleeding) C esterase lnhfbitor deficiency (bereditary angioedema)A. AD disorder B.. excessive release of C2-clerived kinins: (1) increase vesselpermeability (2) recurrentswelling of the face and oropharynx (MC COD) C. lab: (1) low C4 (most sensitive screen) (2) Jaw C2 (3) normal C3 4) low enzyme assay D. Rx: androgens C2 deficiencyA. MC hereditary complement deficiency B. increased incidence- of autoimmune disease: particularly SLE C5-C9 deficiency- associated with disseminated gonoceecemia

involving the loss of

Major Histocompatibility Complex (MHC): I. collectively known as HLA (human leukocyte antigen) system- located on chromosome 6

2.

gene productsA. class t and II antigens: membrane-associated B. located on all nucleated cells
C. D.

glycoproteins

E.

F.

markers of identity ffi.A-A. ~B, gene loci code for class I antigens: (1) recognized by CDs cytotoxic T cells (2) mature RBCs lack class Tantigens HLA·O/DRlDPfDQIDO gene loci code for class II antigens: (1) recognized by CD4 helper T cells (2) located on antigen-presenting cells (rnacrophages Langerhans cells in the skin, B cells activated T cells) individuals inherit 1 HLA haplotype from each pareo; in eodominant fashion: both haplotypes are expressed

-c

Laboratory assessment in transplantation:
1. uses for BLA testingA. transplantation work-ups B. paternity suits c. identifying patients at risk for certain disorders: e.g., HLA B-27 and ankylosing spondylitis transplantation success requirementsA. ABO blood 'group compatibility: most important test B. absence of preformed anti-Hl.A cytotoxic antibodies in the recipient's serum

2.

Note: This material is copyrighted. All rights reserved C.
3. 4. 5,.

closematches

for HLA-A, B and D loci between recipient and donor

lymphocyte crossmatchscreens for recipient anti-Hl.A antibodies against donor lymphocytes lymphocyte micro cytotoxicity tcst- identifies HLA-A and B derived class 1 antigen profiles em recipient and donor lymphocytes using known test sera mtxed lymphocyte re-actionA. used for class II antigen (D loci) matching B. functional lymphocytes from the recipient, and previously irradiated (killed) donor lymphocytes ane mixed together witb tritiated thymidine to detect the degree of compatibility between their D loci: increased radioactivity indicates incompatibility C. recipient's lymphocytes are irradiated (killed) and functional donor lymphocytes are reacted against the host's HLA-D loci to check for a' graft versus host reaction (GVH) rejection: siblings are best source: chance ora sibling having another sibling wil'h a 0 1, or 2 haplotype match is 25%, 50%, and 25%, respectively patents are automatically a 1 haplotype match

Transplant

1.

transplant d.onorsA. B.

2.

graft typesA. autograft: (1) transfer of tissue from se If to self (2) best survival
syngeneic graft (isograft): graft between identical twins allograft: graft between unrelated individuals n xenograft: (1) transplant of tissue from one species to another (2) e.g .. pig heart transplant hyperacute njectionB. C.

3.

A.

B.
C.

usuallyoccur causes:

withinminutes

of vascular attachment of the allograft: e.g., kidney/heart

(1) ABO incompatibility (e.g., 0 person receives an A heart) (2) preformed cytotoxic antibodies directed against donor antigens pathology: (1) small vessel injury with thrombosis (2) type II hypersensitivity

4.

acute rejectionsA.

B.

Ie rejection: usually occur within the first 3 mths of the transplantation pathophysiology: (1) cell mediated reaction most important
a. b, (2) interaction between donor macrophages and host cytotoxic/helper T cells extensive interstitial Infiltrate in the graft, edema and cytosine damage to

antibody-mediated (type 11 necrotizing vasculitis with vessel damage and thrombosis: intimal thickening with obliteration of the vessel lumen for cider

the tissue

c.
D.

grafts reversible with immunosuppressive drugs cyclospcrin A: (1) blocks CD4 helper cell release ofIL-2 (2) side effects of cyclosporine include a. dose-related nephrotoxicity b. interstitial fibrosis

53

Note: This material is copyrighted. All rights reserved c. d. e. hypertrichosis hemolytic uremic syndrome hepatotoxicity

f.
g.

hyperkalemia
hypertension

h.
E.

lymphoproliferative malignancy

F. G.
5.

OKT3: monoclonal antibody directed against.the en, antigen receptor azathioprine: inhibits proliferation of activated T cells

prednisone: ... blocks IL-l and cytokine production from T cells (2) lymphotoxic

(1)

chronic )'ejectionsA. irreversible: generally occur over a period of months to years B. pathogenesis: not well characterized C. pathology: extensive fibrosis and chronic ischemia owing to vessel damage with intimal thickening and luminal obliteration

Graft versus host (GVH) reaction:

1.

transplant typesA. bone marrow

B. C.
2.

liver transplants blood transfusions in patients with T cell immunodeficiencies

pathogenesisA. donor lymphocytes produce IL-2, Which activate NK cells B. activated NK cells are called Iymphekine-activated NK cells or LAKs C. LAKs are the primary effector cells in acute GVH reactions

3.

patbologyA. B. extensive epithelial cell necrosis in the biliary tract with jaundice maculopapular skin rash

C.

diarrhea

Types of transplants: 1. corneal transplants-"

2.

A best overall allograft survival rate 13. can transmit Creutzfeldt Jakob disease renal transplantsA. cadaver. 1 y graft survival rate is 80% B. living-donor: 1 y graft survival rate is 90% C. increase graff survival if patient receives multiple blood transfusions prior to surgery: ?
induces tolerance to the allograft

D.

COD in renal transplant patients: (l) opportunistic infections (CMV, Aspergillus)

3.

(2) acute myocardial infarction bone marrow transplantsA. indications:

(l)
(2) (3)

B. C.

aplastic anemia leukemia certain immunodeficiencies (see above) donor bone marrow contains pluripotentiai stem cells: repopulate recipients lymphoid, erythroid, myeloid megakaryocytic series recipient assumes the donof.~sABO group

54

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D.
4.

danger of disseminated CMV and GVH

heart transplantsA. adul s: (J) chronic ischemic heart disease (2) congestive cardiomyopathy

B.
5,

children: 'endocardial fibroelastesis

C. survival: -80% 1 ysurvival liver transplantsA. adults: (1) cirrhosis (2) severe hemophilia (liver synthesizes factor VIII

B.
C.

children: biliary atresia
survival: 90% 1 y survival

Complications of immunosuppressive therapy: I. D;IalignancyA.squamous cell carcinomas of the skin:

immunosuppress! on

MC overall

malignancy

associated

with

2.
3.

cervical cancer C. malignant lymphomas: immunoblastic D. basal cell carcinoma infection aplastic anemia

B.

HLA haplotypes and disease: 1. rislalA. familial predispcsitice to disease B. Weak penetrance: (1) disease is not invariable C. predisposition to autoimmune disease important BLAreiationsbipsA. HLA-A3: ,11(1) hemochromatosis (2) risk 7%

(2)

usually requires exposure to an envsonmentat factor (e.g. virus

2.

B. C.

(I) (2)

HLA-B81DR3: celiac disease
risk 13%

HLA-B27:
. (1) ankylosing spondylitis (2) risk 80% ( (3) highest risk (4) high penetrance HLA-DR2: (1) multiple sclerosis (2) risk 3%

D. E.

F.

ID..A-DR3fDR4: (I) type I insulin-dependent diabetes mellitus (2) risk 3%

r-n.A-DR4:
(1)

rheumatoid arthritis

55

Note: this material is copyrighted. All rights reserved (2) risk 6%

Type 1 byperse~~iti'Vity reactions:

1. 2.

atopy- familial predisposition pathogenesisA. B.

(multifactorial inheritance) to develop an allergic reaction

IgE antibody-mediated mast cell/basophil activation', (1) pollens ~ (2) anaphylatoxins C 3'1 ;C5q

C. D.

(3) drugs (e.g., penicillin) release of preformed chemical mediators: e.g. histamine (see inflammation) sequence of mastcell/basophil sensitization to al lergens: (I} antigen processing by rnacrophages/dendritic cells-o (2) interact with CD." TH2 cells, which release IL 4 5 6---).
(3)

(4)
(5)

(6) (7) 3.

!Ls stimulate B cell proliferation/differentiation-e lL~4'causes B ce lIs to s..vitch synthesis. from IgM to IgE-+ IgE antibodies attach to mast cell/basophil cell membrane-sallergens (e.g., pollens) Gfoss-Iink !\Va subjacent 19E antibodies on mast cells/basophils causing the release reaction (see inflammationj-; late phase reaction (enhances acute inflammatory reaction) involves synthesis of

prostaglandins/leukotrieaes
clinical examplesA. skin: (1) eczema (face, flexor/extensor B. C.

from arachidonic acid

surfaces) (2) hives eyes: seasonal conjunctivitis nose: (1) seasonal rhinitis (2) membranes boggy and pale blue
respiratory tract: (1) asthma

(2)
E.

anaphylactic reactions diarrhea

GI tract: (1) cramping

(2}
F.

hypersensitivity to bee/wasp/hornet stings: (1 J anaphylactic reactions to bee stings are Me COD due to venomous animal. bites in United States (2) skin (diffuse urticarial swelling) (3) respiratory tract (wheezing, laryngeal swelling/obstruction') (4} cardiovascular (hypotension, arrhythmias) (5) 1U of anaphylsctic teactibn:s~ sc, administration of aqueousepinephrine l.: 1000 dil ution ,~iUSMl7E).

4.

lab testsA. total 19E concentration: paper-based radioimmunosorbent
B.

test (PRIST) procedure

C.
D. E.

prick skin testing of allergens: (1) .most sensitive test (2) :wbea,1and Ilare types of reactions Involving histamine o;l'SJ\.I~ measurement of specific IgE antibodies: radioallergosorbent test (RAST) nasal smears: look for eosinophils

eosinophilia 56

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5.

nSMLE'sCen3l"iosA patient is stung by a bee and begins to have respiratory difficulty, flushing, and abdorninal cramping: Rx with aqueous epinephrine 1: 1000 se (.0.01 mLfkg se or IM) .B. man went under a house to work on pipes an d came out screaming; m ultiplewheals over the body that later developed into vesicles, and pustules: fire ant bites

Type IT cytotoxic hypersensitivity reactions: 1. ~ involves antibody reactions with or withour-eomplement ~ 2. antibody (1gGlIgM)comple:Dlent~mediated ceUlysis.A. antibody attachment to a target cell with subsequent !ViAe cell destruction of the cell B. e.g., ABO mismatch C. e.g., hyperacute transplant reaction. antlbcdies attaeh to targetnssue-s 3. A. activate complement system-s B.. chemotactic agents (e.g. CSa) attract neutrophils-s C. neutrophi.ls damage tissue D.. e.g., Goodpasture's syndrome: anti-glomerularfpu.lmonarycapill.ary basement. membrane antibodies 4.. hem.atopoietic cells tRBes, leukocytes, platelets) coated by IgG and/or C3b are pbagocytosed and destroyed by macrophageaA.. warm aurolmmune hemelytic anemias and. cytopenias B.. Rb/ABO hemolytic disease of newborn 5. antibody-dependent cell-med iated cytotoxicity JADCQA. cells/helminths coated by specific TgGllgE antibodies, respectively (without complement) are destroyed by cells (e.g, NR cells/eosinophils, respectively) with low affinity IgGllgE Fe receptors B. e.g., NK destruction of tumor cells C. e.g., eosinophil destruction of'helrninths coaled by IgE antibodies T)r-..<>l! hy(':f7l5 6. IgG autoantjb~dies (~bo~t cODlpJem~nt) against re~eptorsA. myasthema gravis-anti-scetylcholine receptorann bodies B. Grave's disease; IgG thyroid-simulating Ig directed against TSH receptor lab testiDg~ ~ 7. A. direct Coombs' test: detects IgGand/or CJ on R.BCs B. indirect Coombs' test: ( I) detectsspecific anribodl es in the serum (2) e.g., anti-D in Rb HDN C, immunofluorescent studies that localize .deposits of antibody and/or complement in tissue: e.g .. antibodies in Goodpasture's , D. major eressmatch: patient serum against donor RBCs E. lymphocyte crossmatch: check for recipient anti-Hl.A antibodies directed against donor IDA antigens F. lymphocyte microcytotoxicity test: used for I{LA profi·Lingof donor/recipient

f\bncyfc,,~'1 ("

r
V/~

Type TIl immuaocomplex (Ie) hypersensitivity reactions: 1. . pathogenesis of systemic reacnonsA. circulafing IGs (antigen + IgGJIgM) deposit in target tissue (e.g., glomerulus" small vessel)-» B. activate complement systern-e C. chemotactic agents recruit neatrophils/macrophages that damage the tissue 2. pathogenesis of localized Ie reactions (Arthus reacti.ons)A. first antigen exposure results in antibody production

57

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3.

second exposure to antigen deposited in tissue leads antigen-antibody Cs-? complement system activation-s(2) neutrophil/macrophagedamage of tissue clinical examples of systemic reactioDSA. serum sickness: Rx ofratrlesnake envenomations with use of horse serum antitoxins B. SLE glomerulonephritis (ON): anti-DNA + DNA IGs C. post-streptococcal ON: anti-bacteria; antigen antibodies + bacterial euttigen lCs D. Henoch-Schonlein purpura: anti fgA antibodies against 19A E. polyarteritis nodosa: (1) HBsAg -I- anti-FIBs lCs (2~ "serum sickness-like" prodrome in HEV infections
(1)

B.

4.

5.

'" Type IV T cell-mediated hypersensitivity reactions: 1. det'initi.oD- antibody-independent cellular immune reactions Involving CDA helper T cells (DRH reactions) and CDs,cytotoxic T cells 2'. types of DRH reaetionsA. allergic contact dermatitis: (] ) poison ivy (2) nickel (3) soaps B. skin tests: (1) tuberculin sensitivity (2) patch test jp contact dermatitis: suspected irritant placed on a patch and applied to the skin C. granulomas: (l) histoplasmosis (2) TB (3) sarcoidosis 3. pathogenesis of allergic contact de't'matitisA exposure to low molecular weight antigen (must penetrate skinj-» B. antigen phagocytosed/processed by Langerhans cells-»
58

glomerulonephritis (5) urticaria F. rheumatoid arthritis: IgM antibodies against IgG (rheumatoid factor) clinical e. ample of an Arthus reac iOD- Farmer's lung: A. antigen is thermophilic actinomycetes B. interstitial pneumonitis lab testingA. immunocomplex (Ie) assays: Raji (uses Burkitt's lymphoma cells, detects les activating alternative pathway) -B. complement assays: ( 1.) low Ievels from IC uti IIzation (2) classical pathway activation: B. low C4/C2 low C3 b. normal factor B (3) alternative pathway activation: a. low factor B + C3 b. normal C4/C2 C. immunofluorescent testing of tissue: band test on skin in SLE to detect anti-DNA + DNA antibodies deposited in basement membrane

(3) (4)

vasculitis

+

Note: This material is copyrighted. A(,J rights reserved processed antigen transported to regional lymph nodes and presented to T lymphocytes-» D T lymphocytes become sensitized to the antigen (memory T'cellsj-» E. antigen reexposure causes local release ofcytokines from the previously sensitized. T lymphocytes causing an inflammatory reaction (vesicles, erythema) F. lJ'Sl\!ILE" question on child with a vesicular rash after running through bushes: poison ivy pathogenesis of a positive PPD- see inflammation notediscussion pathogenesis of cytotoxic T cell reactioDsA. cytotoxic T cells normally interact with class 1 antigens on nucleated cells-» B. alteration of class] antigens on target cells activates cytotoxic T cells to release perforins that destroy the ce Il C. examples: (1) neap Iastic/virally infected cell (2) foreign antigens in a transplant cell :(3) destruction ofhepari is B infected hepatocytes C.

4. 5.

59

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Fluids and Hemodynamicst:ACid

Base
space of extracellular fluid compartment);

Types of edema (excess fluid in interstitial 1. translldateA. protein poor «3 'gldL)

B.
C.

cell-poor

2.

3.

a lterations in S tarling's fortes are present: 1) increased hydrostatic pressure (2) decreased oncotic pressure (hypoalbuminemia) C. clinical presentations: (1) dependent pitting edema: correlates with an increase in toml body Na:" (2) body cavity effusions (e.g., ascites) exudateA. increased vessel permeability in acute inflammation B. protein >3 gldL C. cell-rich: neutrophils -"J I"!:. D. clinical presentations: (1) swelling of tissue but_no pitting__edema_ (2) pus in cavities: e.g., peritonitis lympbedemaA. due to obstruction of lymphatics with egress of lymphatic fluid: (1) protein (2) lymphocytes (3) chy lomicrons, with triglycer ide (preducessupranate) B. initjally pitting edema. but eventually .nOll-pitting edema C. clinical examples: (1) post-radical mastectomy (MCC in United States)

(2)
(3)

Examples

1.
2. 3.
rJr

(4) oftransndate from increased hydrostatic pressure: left heart failure (LBF)- hydrostatic pressure in pulmonary vein overrides pulmonary capillary oncotic pressure dependent pitting edema in right heart failure (RHF) volume overload from increase ~p. lsotontc saline (Q.9%) or hypertonic saline (3%.) of transudate from decreased oneotie pressure: nephrotic syndromeA. >3.5 g urine protein loss per day B. minimal change disease MeC in children

filariasis peao d' orange of inflammatory carcinoma: plugging of dermal lymphatics by tumor scrotal/vulvar lyrnphed ema in lymphogram! lorna venereum ___", ~jl(fO.yJIQ -f1(4C ~D '''rr.-ff s C

Examples

1.

C.
2.

membranous glomerulorrephritls

MeC in-adults

3'.
4.

5.

malabsorptionA. celiac disease B. Crohn's disease hypertropbic gastritis kwashiorkor: decreased intake of protein but normal number of total calories dependent pitting edema in cirrhosis

60

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Example of transudate from botb Increase ,in hydrostarie pressure and decrease in oncotic pressure: ascites io cirrhosisJ. increased portal vein pressure- portal vein hypertension 2. decreased oncotic pressurehypoalbuminemia from·decr;eased synthesis Body fluid 1. total A. B. compartments: .. body water (TnW)~ ... -60% body weight in kg: e.g., 70 kg x 0.60 :: 421iters distributed between intracellular f.Juid (leF, -~.o%) and extracellular compartments (-20%) rcr ~2/3 larger than ECF total body-potassium (TBKl is primarily located in leF compartment

fluid (ECF)

c.
D.

2.

c.

interstitial fluid compartment -2/3 larger than vascular compartment vascular compartment: heart, arteries; arterioles, capillaries, venules, veins total body sodium (TBNa") is limited to ECF compartment: (I) Na+ kept out ofICF compartment by the Na+/K+ ATPase pump (2) most of the TENa + is located ill the interstitial compartment: an increase of TEN ain this compartment results in pitting edema

POsm
Normally

ICF

approximates serum Na"" Volume
5iR.U", JSM.:;"

Plasma osmolality (pOsm): 1. formula for POsrn- POsm = 2"(senml Na +) + serum glucose/I g + serum blood ure; nitrogen (BUN)/2.8 = 275-295 mOsm/kg 2. impermeant solutes (limited to ECF)A. sodium: most important impermeant s,61ute B. glucose C.aiterations in sodium (increased or decreasedj/glucese (increased only) set up osmot,if adients that control Y@ter mQ..~emen' S between ECF and ICF by law of osmosis: water moves from low concentration to high concentration permeant solutes (freely move between ECF and lCF)3. A.. urea B. alcohol C. permeant solutes caarretestablish osmotic gradients for water movements: osmolality the same il;l. ECF and reF 4. effective os-molality (EOsm)A. refers to tmpermeant solutes that control water movements:nonna.!!_" serum Ns"'

most im·· ant
B.

D.

c.

in hyperglycemia, glucose overrides serum Na EOsrn = 2 (serum Na"1 + glucose/IS EOsm reflects the tonicity of the ECF /

as the main

osmotic force

("0;

.,;oj

'I sf

"

61

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Types of tonicity in ECF: 1. tonicity prhuarily depends on the serum Na+ and glucose concentrations 2. isotonic condition (normal EOsm)A. OCCUTS when both the serum sodlurn/glucose are normal

B.
3.

DO

osmotic gradient

hypotonic condition (low EOsm)-, A. refers to hyponatremia ... B. osmotic gradient directs water into the lCF (expanded) A.

4.

hypertonic condition (higb EOsm)causes: hyperglycemia: MeC osmotic gradient directs water from the rCF into the EeF hyperglycemia effect on serum Na+: water added to the ECF produces a dilutional hyponatremia correction for dilutional effect on serum Na" when hyperglycemia is present: (1) corrected serum Na" = measured serum Na" + (serum glucose/I 00 x 1.6} (2) e.g., serum Na:+ = 130 roEqfL, serum glucose = 1 000 mg/dl.; corrected serum Na" = 130 - (1000/100 x 1.6)= 146 mEglL (3) corrected serum NaT represerr s what the concentration of Na+ would be if the serum glucose was normal
(1) (2) hypernatremia

B.
C.

D.

Facto rscontrolling ECFvolu me: L thirstA. increased POsm due to hypernatremia, hyperglycemia B. presence of angiotensin II from the reni n-angi oten sin-al dosterone (RAA) 'system RAA system- see below 2. antidiuretic hormone (ADB)3.

A.

stimuli for ADH release in the CNS: (1) increased POsm
(2)

4.

volume depletion (overrides PQam as the major stimulus for ADH release) (3) direct reflexes from left atrium in the presence of volume depletion B. inhibition ofADH: (1) lowPOsm (2) atrial natriuretic peptide (ANP): present when atria are volume expanded as in left and right heart failure renal N a+ rea bSOl'ptioD- see below

Concept of effective arterial blood voJume (EABV): z: "5 1. definition- amountof total, circulating volume required to stimulate baroreceptors arch and carotid sinus: correlates with stroke volume and cardiac output

V;eo

in the aortic

2.

usually parallels EeF volumeA. e.g., isotonic lQSS of fluid contracts ECF compartment and decreases BABV
B. exception:

(1)
.(2} (3)

(4)

Starling's force alterations trap transudate in the interstitial space (expandedj-» increases total EeF volume-e decreases EABV. since the venous return to the right heart is decreased examples: a. right heart failure with an increase in venous hydrostatic pressure causes a movement of fluid (transudate) into the interstitial space: EABV is decreased

62

Note: This material is copyrighted. All rights reserved b. 3. cirrhosis is associated with hypoalbuminemia, which causes a movernent of fluid (transudate) into tile interstitial space: EABV is decreased

baroreceptorsA. low pressure baroreceptors: left atrium/major thoracic veins B, high pressure baroreceptors: carotid sinus/aortie arch innervated nerves

by J.. and X cranial'

J tv

o.."f

Physiologic events witb a decrease in EABV: 1, eli uical exam plesA. hypovolemia: (I) blood loss (2) other fluid loss: diarrhea sweat B. decreased cardiac output: e.g, myocardial infarction 2, underfilling of arterial vessels-A, inhibits cranial nerves IX and X innervating the high pressure baroreceptors B. increases sympathetic activity and catecholamine release 3. catecholamine functionsA. tachycardia: chronotropic effect S, increases cardiac contractility: (I) raisessystelle blood pressure (BP) (2) inotropic effect C. peripheral vasoconstrietien: raises diastolic BP D. systemic venoconstriction: increases return of blood to right heart E'. stimulates hypothalamic synthesis/posterior pituitary release of antidiuretic hormone (ADH): (1) increases reabsorption of free water in the collecting tubules of the kidneys (2) vasoconstriction of peripheral resistance arte rio les ' F. activates the renin/angiotensin/aldosterone CRAA) system: direct sympathetic stimulation 4. RAA system acti-VRtio,nA. activation of juxtaglomerular (10) apparatus (modified smooth muscle) in afferent arteriole: (1) direct stimulation by jhe sympathetic nerVGUS system (2) reduced renal blood flow (3) activation of macula densa (see below) B. renin (enzyme not a hormone) released from JG apparatus: angiotensinogen converted into angiotensin I (AT I) C. angiotensin convertingenzyme (ACE) in the lW1gS converts AT I into angiotensin 11(AT U): example of noncornpetiti e inhibition D, Am stimulates synthesis/release of aldosterone in zona gtomerulosa by activating 18hydroxylase: corticosterone converted into aldosterone 5, AT func(ionsA. vascconstriction of peripheral resistance arterioles: increases diastolic BP B. stimulation of aldosterone synthesis/release C. stimulates thirst center ~:ED.... ' constricts mesangial cells in the glomerulus: decreases. glomerular filtration rate by reducing the overall surface area fer filtration constricts efferent arteriole: peritubular capillaries are the run-off vessels originating from the efferent arterioles

n

6,

aldcstercnefunetionsA. increases renal Na+ reabsorption
B. increases renal K+ and

Et secretion
63

No~f4Ct.( 5UN/C1e.atifli ne. M.D:
Note: Thismaterial is copyrighted. All rights reserved 7.

__ /0: I

role of atrial natriuretic peptide (M"P) in volume conrolA. released from left/right atrium with atrial distention: e.g., leftlright heart failure B. inhibits ADH release: increased ANP does nor override stimulus for ADH release by increased POSlll or volume depletion (P MLlll question)

C.
D.

inhibits all AT

n functions

8.

inhibits renal reabsorption of NaT: direct natriuretic effect role of kidney--derived prostagtandln ~ in volume controlA. inhibits ADH B'. inhibits renal Nat reabsorption C. intrarenal vasodilator of afferent arterioles: offsets intrarenal vasoconstrictive AT II OD efferent arterio le

effects of

9.

increased renal reabsorption of Na +A. increased proximal tubule reabsorption.of.Na': (1) isosmotic reabsorption (same urine osmolality after reabsorption) (2) increased glomerular filtration fraction (FF): iFF == .,l,glomerular filtration ratelJ,.,l,renal plasma flow therefore, more N<i+is filtered (3) peritubular capillary hydrostatic pressure (Pi-D is lower than peritubular capillary
oncotic pressure (Po) a. decrease in renal blood flow automatically decreases PA. b. results in massive isosmotie reabsorption of Na+ and water back into the

B.
C. r.ir

increased aldosterone-enhanced reabsorption ofNa+: see below tonicity of fluid reabsorbed by the kidneys rhat returns to the ReF is slightly hypotonic:

ECF

slightly more water than salt
Physiologic events that occur with an increase in EABV: 1. clinical examplesA. isotonic gain of fluid: patient given too much isotonic (0'.9%, normal) saline

B. C.
D.

primary aldosteronism: benign tumor ill zona glemerulosa inappropriate NDH syndrome (SiADH)

____,.- n,/ G

~

~ I/Yl).((J!, e ,

2. 3,.

hypertonic gain of fluid: (1) 3% hypertofJic saline infusion (2) overzealous NaHC03 infusions to correct metabolic acidosis /' DO Inhibition of bigb pressure barnreceptors[,10 catecholamine effects no stimulus for ADH releaseA. loss offree water in the urine: normal dilution B. exception is SiADH where free water is reabsorbed when it should be excreted
00

4.

A. 5.
6.

activation of RAA systemno AT II or aldosterone effect

7.

B. renal blood flow is increased j ANP- natriuretic effect decreased glomerular Oltration fraction: A. J,FF ee Tglomerular filtration rate/T? renal plasma flow B. decrease in the filtered load of Na" PH>PoA. noproximal tubule re absorption ofNa + B. all other solutes normally reabsorbed in the proximal tubule are also lost in the urine

(J?

Effect of infusion of 3 % hypertonic saline (tTSMLE:}~ ]. increase POsm- due to hypernatremia 2. incresse in serum ADH64

Note: This material is copyrighted. AU rights reserved.
A. increase in POsm stimulates its release increased POSltl overrides effect of ANP release on inhibiting ADH schematic

B.
C.

POSU1

B
A

C
D

SerumADH (1) A = dilution in a normal person with low POsm inhibiting ADH (2) B = patient with diabetes inspidus with high POsm and low ADI-! (3) C = patient given 3% hypertonic saline with b:ighPOsm and high ADH: could .also represent normalconcentration (4) D = patient with SiADH with low POsm and high ADH
Physiologic effects of hemorrhage: sequence as described for decrease in EABV Proximal renal tubule functions (see nephron diagram):

1.
2.

primary site for N a+ reabsorption primary site for reclamation ofHeOl'A. If ions 'in the tubule are exchanged wIth Na"' in the urine B. Ir in proximal tubule lumen combines with filtered HCOa' to form H2CO] C. brush border carbonic anhydrase dissociates H2CO; into H20 and COl. which are reabsorbed back into the proximal tubule D. H2C03 is reformed in the proximal renal tubule cell with the aid of intracellular carbonic
anhydrase

3.

4.

H2C03 in the proximal renal tubule dissociates into I-f and HCO)·.anions F. HCO:; is reabsorbed into the peritubular capillaries G. W ions reclaim more bicarbonate H. note that th,i~ is. not a m~chanism for excreting H-I- ions since they are reused to reclaim more bicarbonate site for type rr proximalrenal tubular acidosis (RTA)A. renal threshold for reclaiming HC03- is lowered from the normal of 24 mEq/L to -15 mEqfL B. filtered HCO)- is lost in the urine (urine pH >5.5) C. HCOs anions lost in the urine as NaHCO) are replaced by cr anions leading to a normal anion gap metabolic acidosis primary nephron site for synthesis of ammoniaA. glutamine (non-toxic vehicle for carry NH4 + in blood) from the blood enters the proximal
tubules

E.

B.

in the pro xima I tubules, ketoglutarate
(1) (2)

glutamine

is enzymatically

converted

into 1:'JH.t +

0:.-

H20

e-ketcglutarate

is used to synthesize glucose, which is metabolized

to CO2 and

(3)

CO2 + H20 combine to form H2C03 which dissociates in o newly synthesized HC03'+F HC03~ is reabsorbed back into the blood, while W combines ith NHJ in the cell to form N"Hj1'

65

'f.h In :Ascenamg

iriili

ADH present (concentration), *R20
1200 mOsm '!tHIO negative CH10

ADH absent (dilution) positive CH10

"'H20

A = Aldosterone "'H10 free water: mostly generated in Na+/K+I2Cr cotransport pump ADH = antidiuretic bormone TAL = thick ascending limb (diluting segment) nCT:::: distal convoluted tubule . H* = hydrogen ion that can be secreted with HP04- (H2P04)! which is 'titratable

=

acidity or NHa (NIl'jel)

Proximal tubule: • carbonic anhydrase i.nhihitor- blocks reclamation of bicarbonate, which is,exert/ted as NaHC03 or KHeOl: • proximal renal tubular acidosis" .1059 ofK+ and Na Ascending \11 bule: • loop di uretic- blocks N a+i'IC"2C cotransport pump: + impairs generation of free water, 1 + calcium is also lost in the urine (Rx of hypercalcemia), + hyponatremia, hypokalemia metabolic alkalosis • thiazide diuretic- blocks Na-l'/Cr pump: +aUows calcium reabsorption with the help of'parathormone (useful in calcium stone formers), • hyponatremia, hypokalemia, metabolic alkalosis Distal/collecting tubule: • spiroDolactODe~ blocks aldosterone (A) pumps: + blocks Na:r/K+ exchange pump, • blocks W/K A'I'Paseexchange pump, +K- sparer •• normal anion gap metabolic acidosis

r

Functional Aspects of the Nephron

Note: This material is copyrighted. All rights reserved NH/ is secreted into the lumen of he tubule (substitutes for H" in the Na'nr exchange mechanism): reabsorbed in 'the thick ascending limb in the medulla-and cortex (NIL.t substitutes for K+' in the NatfK:12Cr cotransport pump) and then secreted into the collecting duct forfinal excretion in the urine as NH4C! site forreabsorption ofA. glucose: cetransport with Na.+ B. urea c. amino acids .... D. phosphate: inl1Lbited by parathormone carbonic anhydrase inbibitorsA. acetazolamide blocks the enzyme B. HC03- cannot be reclaimed: 'combines with Na"ior K'· to form NaHCO,lKHCOl. which are lost in the mine C. acts-as a proximal tubule diuretic D. produces normal anion gap metabolic acidosis: see below (4).

5.

6.

Fun etions of thin deseen cling lim b: 1. o'nly permeable to water 2. urine becomes hypertonic (maximum Henle

of 1200 mOsm/kg)

b the time it reaches the loop of

Functions of thin ascending limb: 1. impermeable to water but permeable to Na + and 2. UOsm decreases

cr

Functions oftbick ascending limb (TAL meduJlary segment): 1. generatio of free water via the active Na'"-IC -2 cr co-trans port pum pA. water in the urine up to this, pump is obligated: 20 mL of water must accompany every solute excreted B. free water is solute free; essential for normal dilution and concentration of urine C. every Na", Kt-" cr reabsorbed leaves, be-bind its obligated water in the tubule lumen: now it is free 'Water D. UOsm -15'0 mOsmlkgafter leaving TAL medullary 'segment: most of the water is now 2.

loop diuretics block tws cotransport pl1mp-

free water

,.

;tf;k- /I~

..

,.;;iif_"J,;zt;J l?" "t

tWuz/tU

3.
4.

A.ability to generate free water is impaired B. 'hyponatremia occurs, since dilution requires the loss of free water in the urine C. what should be free water is still obligated water when a patient is on a diuretic pump also reabsorbs calcium (!Uo..t H-eWDce/ 0- loop diuretics are a mainstay to Rx

~~Icemia
reabsorbs some oI~"TB./INRJ secreted by the proximal ubule-A. substitutes for K+ in the Na IKner cotransport pump B. NI~"' INH3 eaters the medullary interst: tial tissue C. NHl eventually diffuses into the collecting ducts where it is excreted into the urine and combines with H" to form NRiCI

Functions cf tbe cortical TAL segment: 1. Na+ICr PUolP in early distal tubule_§bare the same ·channel for reabsorption 2. Na+ channel is blocked by thiazidesA. channel is open for PTH-enhanced B, potential for bypercalcemia

Na+ and Ca+-r {f"""""=-;-.;=~.-...~;.:.:..:.:.t:~W-"C~tiOIlS
. Ca ++ reabsorption

66

Note: This material is copyrighted. All rights reserved thiazides are used in removing -Ca++ from urine in hypercalciurie patients who are stone formers D. thiazides are a commonly used diuretic ill' the Rx of congestive heart failure and hypertension a small 1U11O'Unt of free water is generated in the pump

C.

3.

:FunCtiODS ofthe macula densa: • 1, interacts with the juxtaglomejular (JG) apparatu on afferen arterioleA. modified chemoreceptor B. senses volume and Na-loalterations in the, distal tubule 2. increased Na+ in the urine inhibits renin release aud vice versa Punctions of aldosterone-enhanced ATPase Na-+-IC' exchange pump in distal coUecting tubule and collecting ducts: 1.. Na + is reabsorbed in exchange for K+A. main site for K+ excretion B. if K+ is depleted Na+ exchanges with}f the latter reclaiming RCO)-: potential for metabolic alkalosis 2. effect of increased distal delivery of Na-lofrom more proxima) acting diuretics (e.g., loop diuretic or thiazide djuretic)G1~ CA iVth;b;-tv.lS A. augmented Na+fK+ exchange reads to hypokalemia B, hypokalemia is prevented ifthe patient takes K" supplements C. ifNa,+ exchanges with H" due to depletionof K • bicarbonate is reclaimed and metabolic 3. alkalosis is produced/'il' _ ~ ~ A I I~, _ I ~. _) aldosterone blocker(:!:¥lAINL " ~/Wl ~jf.1 ~ A. spironolactone inhibits aldoste one function on the pump-4 b;,,)S -to b<it:,o/~Rqlsit/e' B. Na-t is Iostin the urtne: diuretic.effect \1'\ fX~e v-P- q(iAr~1:"'.fti&).llt:o...i C. K' is retained in the blood: (1) good for people on diuretics who cannot take K""supplements ("K+ sparer") (2) danger of hyperkalemia ~ ca 11 cmtSe. Cflr.iiqc. q(etSf'it1 di "s1rle. D. ff'is retained: metabolic acidosis E. used with ACE inhibitors in Rx of congestive heart failure: (1) increase! survival of patients (2) maintains ACE )nhibitor block of aldosterone trtamterene/amiloride-l J{rA. block Na+ channel B. not true aldosterone blockers

(bold S:lrrnJQ~J..fy

I.)

4.

~.(~N~)

FUnctions of the .aldosteroae enhanced H" (K+ ATPase pump and H" ATl?a~e pumps in the a~ intercalated cells in the collecting ducts: I. prtmary sites fOI- excretion of excess ionsA. 1--t ions in the tubule exchange for K in the lumen in one of the two pumps B. ir from. both pumps enters the 'lumen and combines with HPOl to produce NaHiP04: called titratable acidity C. F_r+ combine-s with NR3 and cr to form NR.Cl: causes acid pH of urine 2. regeneration of HC03-A. CO2 from the blood enters the collecting duct cells B. CO2 combines with H20 with the aid of carbonic anhydrase to produce H2COl C. H2C01 dissociates into Wand HC03-: (1) newly synthesized HC03- is reabsorbed back into the blood (2) rr exchanges for K+-and is excreted in the urine O~ is excreted into the urine by the

rr

If" ATPase pump

67

Nate: This material is copyrighted. All rights reserved aldosterone blocker (e.g.,. pironolactone) .effect- C_ A. cannot excrete It" ions ~ -!hoy ";.jl C6fWltUf)P c 1 B. develop a. normal anion gap metabolic acidosis site for ~pe I ~istal RTAtXf'1P'~~ic;1\ I(/~ bftl(!ks +~:~ fl(f1Jf1 A. dysfunetional pump B. H' ions cannot be excreted and combine with er anions: produce norma! anion g;:lP metabolic acidosis C cannot regenerate HC03' D. urine cannot be acidified after Infusing l\Tf~CI into the patient: wine pH >5.5 E. K" is lost in the urine: severe hypckalemia with muscle weakness _..::,mllS!lf' ((fI~,o1 frlbllJ~Q(> collecting tubules are the site for diffu$ion of NIll from the medullary interstitial tissue (see #17) in.to the lumen where it enmbines with H" to produceNRiCI

3.

4.

~ 'W

Normal dilution of urine: I. UOsm i.n late distal collecting tubule/collecting duet is -ISO mOs,mlkgfree water and a little obligated water that must accompany solute 2. when POsm is low. ADH is inh"ibitedA. absence of ADH causes toss of free water in the urine

primarily contains

B.
3. po

low UOsril
:If.

A.
B. C. D.

~kn:ow how to calculate fa)' USMLE)= free water clearance, V = volume of urine in mLlmin CO~ijl = 0 igated water ' to calculate COsm: COsm = UOsm x VIPOsm a positive CH20 indicates dilution (free water is lostin the urine)': it could also indicate acute tubular necrosis and absenceof normal renaldillltionfcQ_flcentratiou example; urine volume 10 ml, POsm 250 mOsm, UOsm ]50 mOsm: eOSIn = 1SO x 10/250 = 6 mL, C}'hO = 10 - 6 =4-4 mL

.elearaaee

CH20 = V - COsrn where CH20

4.

5.

effect of diuretics on CBlOA. loop diuretics inhibit tbe generation of free water by blocking the Na+{K ncr cotransport pump: Na + remains in the urine with. its obligated water B. patients with unrestricted intake of water are not able to generate enough free water to eliminate in the urine: devefop hyponatremia summary of'normal dilutionA. low UOsm: maximum dilution is 50mOsm/kg B. absence ofADH C. positive CI·hO

Normal concentration of urine: 1. increase in, POsmis a stimulus for ADH release 2. ADH renders tbe late distal and collecting ducts permeable 1Q free wa.ter (not N a....cannot reabsorb obligated water)~ A. urine is concentrated B. maximum ofUOsm of 1200 mOsm/kg 3. negative CHz.O (free water is reabsorbed back into the blood)-e.g., urine volume 10 mL, POsm 300 mOsm)kg, UOsm 9QQmOsm/kg:COsm = 900 x 10/300 == 30 mL CB20 = 10- 30 = -20 mL 4. ability to concentrate urine is the first abnormality in renal failure ~ S. summary of norma) concentranonA. high UOsrn B. presence of ADH C. negative CI-hO

i<

68

Note: This material is copyrighted. All rights reserved

Factors controlling serum Na + concentra.tion (NOTE- arrow represent degrees of magnitude): 1. serum Na" - TBNa+/TBW' A. TBNa = total body sodium B. TBW = total body water C. daily serum N a+ concentration reflects TBW status: (1) hyponatremia usual IX indicates a gain in TB W (2) hypernatremia usually indicates a loss in TBW, D. daily weight reflects TBNa+ status: increased weight usually indicates an increase in TBNa'" 2. physical exam approximates TBNa+ statusA. J..-TBNat: (1) signs of volume depletion ...;;.,,:---------(2) dry mucous membranes
(3) (4) decreased skin turgor (skin tenting) drop in BP/increase in pulse when rising from supine position Jl)ositive tilt test. dependent pitting edema a. most of the Na is located in interstitial fluid compartment b. reason for pitting edema c. it is not possible to have pitting edema selely due to an increase in water in the interstitial space body effusions: e.g. ascites

B.

tTBNa+:
(1)

rl . d 'IS
• ~_~It.
\,:01-'

~

eC f
Clr

-t 1.11

.~) (bl~~~(o~Ii6 (2)

C. 1.
2.

normal TBNaT: normal skin turgor

Cltnical examples and treatment (Rx) of isotonic loss of fluid:

clinical- most cases of adult diarrhea
patbopbysiologyA. no osmotic gradient: equal loss ofNa" and water B. {.EABV

C.
D.

E.
3. Rx-

ECF contracted (interrupted normal compartment

nonna1 serum Na+: Hserum Na"::::; J, TBNa"'/-l.-TBW lines in schematic): signs of volume depletion

rcr

A.

IV crystalloid solutions: (1) 0.9% normal saline a. contains 154-mEq/L of NaCl per liter b. distributed in plasma, which is 93% water c. final concentration in plasma is 0.93 x 154 = 143 mEq/L, which is isotonic
(2) Ringer's lactate a. most physiologic IV solution b. contains Kt, bicarbonate (lactate converted reactions) into bicarbonate by oxidation

B. c.
D.

r(USMLE;

primarily used in Rx of volume depletion from diarrhea only isotonic fluids remain in ,Eeli' compartment and raise blood pressure

c.

5% dextrose and water or 0.45% salinecennot raise the blood pressure: they are hypotonic solutions requ ires -3 liters of norma [ saline for 1 liter to remain in vascular compartment: (1) 1 liter in vascular compartment (2} 2 liters in interstitial fluid compartment

69

Note: This material is copyrighted. All right'> reserved

IeF normal
heigol of squares = POsm (serum Na) width.of squares compartments versus the normal in dark lines

Note:

= volume,

'hash marks

=

change, occurringin

the

Clinical example and Rx of isotonic gain of fluid: 1. clinical- excessive IV administration of 0.9% normalsaline 2. pa.thopbysiologyA. no osmotic gradient equal gain ofNa+ and water,

or Ringer's .lactate

B.

D,

3.

E. lb:A. restrict salt/water intake B. diuretics

normal Na+: -H-senl1i1 tEAB ECF expanded: ( 1) dependent pitti ng edema/p lrn nary edema (,2) TBNa t is increased in inter'. titi 1 compartment normalICF compartment: ITO osmotic gradient

serum

Na~J-lrnNa~/iTBW

only ReF expanded

ICF
IeF normal,

hECF

:

Volume expanded Pathogenesis of hyponatremia: 1. decreased serum Na+-concentration<136 mEqlL 2. generally indicates a problem with dilution (inability to lose free water in the lddneys)A. gain of pure water in the ECF must be countered by a loss of pure water in the mine B. lass of obligated water is not the S31l1,e as losing pure water 3. clinical manifestationsA. mainly eNS due to cerebral edema from water movement into cells: (1) mental status alterations (2) seizures

>

B. 1.

neuromuscular system: muscle cramps
due to a hypertonic loss of fluid:

Hyponatremia

cJinicaIA.

B.

diuretics: MCC (LrJ0iS) Addison's disease(l) Lossof aldosterone effect (2) same pathophysiology as aldosterone block~~

C ,1bi' J 11- "'IjPq riO

~J

Jp.{..fl

Prt"1

P ('P ....

~

I

ISDN J

70

IeF

ECF

Volume

ISOTomc

LOSS: ~ SERUMNa+

= .J..TBNa-l-J,TBW I
OnlyECF
con tracted

IeF

J.E~ ~

normal

IeF

Volume contracted
• Adlllt diarrhea

ISOTONIC GAIN:

f-7

SERUMNa-l-

= iTBNa+

/ tTBW OnlyECF expanded

ICF

l'ECF

IeF
normal Volume expanded • Excessive isotonic saline

Note: This material is copyrlghted.AJI

rights reserved

2.

C. salt losing 21-hydroxJrlasedeficiency pathopbysiologyA. osmotic gradient favoring water movement into the B. J...EABV

reF

C.
D.

,1serulTINa-l-= J..J. TBNa+/,1 TBW

(l)
E. 3.

ECB contraction: signs of volume depletion (2) TB a+ 'is decreased ICF expansion: osmoticgradient

is present

R,\A.

B.
C.

0.9% normal saline 3% hypertonic saline rarely used rapid intravenous fluid correction of hyponatremia with s;:llirIremay result irp central pontine myelinolysis: irreversible demyelinating syndrome
J,POsm

f .. ··

" .. ~
irCF
,1E~F
l

[ Ie.

ox an"dCdj1...
p

1

.

.

'4volume

con,trade!'

Hyponatremia due to a hypotonic gain of water 'with salt: 1. clinical- dependent pitting edema states A. congestive heart failure B. cirrhosis 2. pathogenesis of hyponatremia in right heart failurevenous system in right heart failure: A. ~E.ABV from decrease in cardiac output B. hypotonic gain off1uid froij'l kidn-eys (see #10)
C. hyponatremia

increased hydrostatic

pressure

In

3.

(1) J.serum Na- = iTBNa+ liiTBW (2) tTBNa,-'- distributes in ECF leading to pitting edema (3) tiTBW distributes in EeF and reF, the latter by osmosis D. bypotonic fluid reabsorbed from kidneys is redirected into interstitial compartment by increased hydrostatic pressure in venous system pathogenesis of hyponatremia ill cirrho~is- decrease in synthesis of albumin in cirrhosis: A. decrease in oncotic pressure B. transudate containing excess Na+ is redirected into interstitial space (dependent pitting edema)

C.

0)

J,venous return to heart leads to:

~EABV

D.
E. 4. Rx-

(2) hypotonic gain of fluid from kidneys hyponatremia: J,serum Na-l' = iTBNa+/ttTBW hypotonic fluid from kidney is redirected into the interstitial space due to the decreased oncotie pressure restrict intake of salt and water

A.

Note: This material is copyrighted. All rights reserved B. diuretics: (1) loop diuretics for CfIT (2) spironolactone safer than loop diuretics in cirrhosis (see hepatobilisry notes) heart failure: (1) decrease afterl oad ~e. g., vasodilators (2) decrease preload: e.g., diuretics (3) ACE inhibitors decrease both .afterload (block ATII) and preload (block aldosterone)

C.

J,POsm ICF expanded

· · · ·
<

..........

5'

t

..

ReF expanded, pitting

.' .'
.'

:

iICF
,

liECF

. .

edema due to iTBNat

:
, .. ~ .... ~... ~

a ......

"10

Volume expanded
W

Hyponatremia due to a gain in pure water: L clinical- syndrome of inappropriate ADH (SiADH), A. '0( ectopic secretion in, small cell carcinoma of lung:

Mec of SiADH

B.

drugs (1) -llfchlorpropamide

(54I~t\~u.($S) --=J> &/1QfJce 4c1i'v:ty of ItON-

\

--_./.

2.

tPoW"~~ L. IJ.O 1:;..... ~

(2) cyclophosphamide (3) morphine C, .....CNS injury D. lung infections: TB patbophysiology of SiADHA. hypotonic gain of pure water: BCFIICFexpanded

(see schematic)

.J...serumNa + = TBNa +rtiTBW
C. normal skin turgor since TBNa -I: is normal: (1 ) iTB W alone cannot produce pitting edema (2) majority ofwater is directed into ICF a. severe menta! status abnormalities b. chance for herniation tEABV: (1) PH> Po: increase in renal bleed flow (2) loss ofNa+ in urine a. random UNa+ >40 mEq/L b. proximal tubule cannot reabsorb any filtrate c. urea and uric acid also lost in urine: reason for Lowserum urea and uric acid d. low serum BUN and uric acid

D.

E.

iUOsrn:
(1) (2) presen:ceof ADH causes increased concentration of urine due to. constant reabsorption of free water patient should be diluting urine with a gain in water but patients with SiAnH are concentrating urine due to inappropriate presence of ADH

... j.

RxA. B.

restrict Water
demeclocycline for small cell cancer patients: (1) produces nephrogenic diabetes insipidus (2) no need to restrict water

72

HYPERTONIC LOSS: tSERUM NaT - {;

~POsmr~'

~

iIeF
ICF

ECF
contracted

,l..ECF

expanded

411

.Volume contracted • Diuretics

..

• Addison's disease
HYPOTONIC GAIN: "--'S=E=R ...UM:;;,.:!..,;-,..:.N.;.Ja:....·· _!...~~~___:_;,-=-~

_-----..._
EeF expanded,
pitting edema

J_POsm ICF
exnanded

tier
I..--

iECF
---'-_-.-l .

due to 1'TBNa +

Volume expanded • Congestive heart failure
• Cirrhosis

HYPOTONIC GAIN:
~ ••• Iii •• ~ .5. io. I. •••• • ••••••• ••••• •• I • 1,., •••• I· t ••• "I

J,POsm ~ 1

trcr
J.,.._

1
tECF:
-'-_--' .....

IeF
expanded
\ ......

ECF expanded, no pitting edema since TBN a+ is normal

Volume expanded • Inappropriate ADH syndrome

• Excessive water intake

-I-ICF
ICF contraction

Slight ECF contraction, no. signs volume depletion due to. normal TBNa+
,~.,."
I .,

.

..... ~ ••••

Volume contracted • Diabetes insipidus • Jnsensible water loss (e.g., fever)

....

,

~ ••

I ••

i" • 'f'"

.1

.

~

Note: This material is copyrighted. All rights reserved

ECF" expanded no pitting edema- normal TBNa"

[CF expanded

Volume expanded
qr

Pathopbysiology of hypernatremia: 1. definition- serum Na'" concentration> 147m Eq!L, 2. pathophysiologyA. loss of pure water: purists call this dehydration

when there is only a Joss of water and

no salt C. D. 3.
mixed loss of hypotonic fluid hypertonic gain ofNa+ patient usually has no access to water: cannot increase TBW, which would alter serum Na+ concentration clinical- CNS signs and symptoms: A. convulsions B, increased reflexes B.

Hypernatremia doe to Il pure water loss: 1. clinicalA. central and nephrogenic diabetes insipidus: lack ADH or tubule refractory to ADI-I B. loss of insensible Water: fever with evaporation of water from mucous membranes pathophysioiogy2.

A. B. C. D, E.

hypotoni c loss of purewater: t seru m N a+ = TEN a+IJ,-i TB W EABV slightly decreased: not enough to show signs of volume depletion ECF slightly contracted: not enough to show signs of decreased skin turgor ICF contraction: osmotic gradient is present normal hydration/skin turgor: no signs of volume depletion since TBNa';' is normal
water by mouth if possible

3.

RxA.

B. C.

IV 5% dextrose and water rapid correction of fluid losses in hypernatrernia may result-in brain herniation anddeath

tPOsm

f····'"'·..···Ii······.'····f·t .
-iICF

~~~

sligbt ECF contraction, no sign volume depletion- normal
TBNa+

J,ECF;

l...:::Z::--------

ICF contraction Volume contracted

73

Note: This material is copyrighted.

All rights reserved

r:::sr

Hypernatrernia due to a hypertonic gain ofNa;-:
I. clinicaJA. excess 3% hypertonic saline B. excess NaHCO] C. TV infusion of'Na" containihg antibiotics

2.

pathophystologyA. B. hypertenic gain of more salt than water: tserum Na+ iEABV

= t1TBNa+;tTBW

C.

ECF expanded:
dependent pitting edema/pulmonary edema TBNa+ is increased reF contracted: osmotic gradient is present (1) (2) restrict Na" diuretics
:_

D.
3.

RxA. B.

tPOsm

:

~

I .. ~ "

, .. ~

'f' •• "

: :

t

Eell' expanded, pitting edema- t TBNa+

CF contracted

.........
Volume expanded
r::1r'

/

Hypernatremia due to mixed loss of bypotonic l1uid: 1. clin,ica.lA. sweating B. osmotic diuresis: ~ (1) glucosuria in diabetic ketoacidosis or hyperosmolar nonketotie coma (2) use of mannitol (3) increased urine urea: obstruction of urine flow (prostate hyperplasia), protein intake C. baby diarrhea; hypotonic loss rather than isotonic loss as in adults

increase in

2.

pat.hopbysiologyA. loss of more water than salt: (1) iserum Na+ ,J.,TBNa+jJ.,J.TBW (2) ,.!..EABV (3) ECF contracted greater than with pure water loss due to J.TBNa : signs of volume depletion (4) rCF contracted..osmotic gradient is present 3. RxA. baby diarrhea: (1) give hypotonic salt solutions available in stores (2) if volume depleted, give 0.9% normal saline first to raise BP then give 0.45 normal saline B. osmotic loss of 'fluid or sweating: (1) give 0.9% saline to restore blood pressure

=

74

f················ ·f····················· ..
.11CF
ICF contracted

ECF expanded pitting edema present due to

iECF
, ~~ ~

ITBNa+

~

Volume expanded
• Hypertonic saline (e.g., 3%)

HYPOTONIC LOSS: tSERUM Na tPOsm
ICF ECF contracted greater than with pure water loss

r"'' ' ' ........;m·1 ~. .
. ~ ~~ ~ ...... , ...... ~..... ..
.....
;~

contracted

due to..l, TBNa

Volume contracted • Sweating • Osmotic diuresis (e.g., glucesuria) • Baby diarrhea

fV6(

,Jl_1"'

t

J~
/J

1,'

~'~1

Note: This material is copyrighted. All rights reserved (2) give 0.45% saline once pressure is stable

tPOsm

f················r···1
;

.

:

severe ECF contraction, greater contraction than pure water loss due to los of'TONs""

Volume contracted
Types of shock: bypovolemic shock1. A. hemorrhage: Mec of shock B. excessive fluid loss: (1) sweat

...

..

(2)

diarrhea

2. 3. 4.

(3) severe burns (4) vomiting . ;?Y ~~~ c.ardiogenic sback- e .. ., acute myocardial infarction g r" . I septic (end atoxic) shock- e.g., gram negative endotoxic shock ~,-14<./' neurogenic shock- e.g., toss of vasomotor tone in venules/small veins:

~. A~"":h.
au,..u

A.
B.
CJr

fainting

spinal cord injury

.

ed ~

if ;'r~--v:
i(

~J

J~~

-.L ~

Massive blood loss: I. loss of >20% olthe blood volume(about 1000 mI) results in. hypovolemic sbock 2. hemoglobin (Hb)/b.ematocrtt (lIet) cbangesA. no initial effect due to toss of whole blood: loss of equal amounts of plasma and RBCs B. vascular contraction around the reduced volume of blood C. plasma replaced-first and uncovers Me deficit in hours to days D. infusion of crystalloid solutions lmmedlately uncovers RBC deficit 3. changes in pulmonary capillary wedge pressure (PCWP)A. measured with Swan-Ganz catheter (SGC) threaded into right heart B.. peW}> indicates left ventricular end-diastolic pressure C. decreased PCWP in hypovolemic shock

4.

mixed venous oxygen content (MVOz}A.

B.
C. D. 5.

measured with SGC in r1ght heart best indicator of tissue hypoxia

indicates bow much or how 'little oxygen was extracted from the blood delivered to tissue

6.

decreased in hypovolemic shock: decreased cardiac output allows tissue to extract more O2 than usual cliniealA. cold/clammy skin: vasoconstriction of vessels in skin from catecholamine release B. hypotensive C. rapid weak pulse: compensatory response kidney in hypovolemic shockA. renal medulla most adversely affected in shock B. ischemic acute tubular necrosis common

75

Note: This material is copyrighted. All rights reserved 7.

* ~!Uv~J"j. .Jf~ Jwdt:c
.lLl/,,_.,.~-&_
increased PC"rp

~

M tr0.;l

~~~IU~!
~

7

Rx- IV crystalloid solutions while waiting for whole blood

Cardiogeuie shock: 1, cli.Dlca:l- similar clinical findings as in hypovolemic shock 2. changes in pulmonary capillary wedge pressure (pCWP)-

owing to ·a.
< ---

3. 4.

back-up of hydrostatie pressure into the pulmonary venous system mixed venous oxygen eentent (MVD2t- c_ All. J /Il- .- -T.'7: A. decreased in cardiogenic shock40 'hIe. .J;~W) ~ ~

~~w~,;:ur-tw...Lc.-t-6.;J

B. decreased cardiac output allows tissue to extract more O2 than usual kidney in cardiogenic bock- same as in hypovolemic shock

_.;J

Septic shock: I. patbogenesisA. endotoxlns are lipid component of cell w,aU of gram negaive bacteria: (l) endotoxlns bind to the CD'4 receptors on leukocytes/endothelia! cells (2) direct irij~Lryand/or release of ehemical mediators B, interleukin (Il.l-Iztumor necrosis factor (TNF) released from macrophage activation: increases neutrophil adhesion to vessels C. nitric oxide is released frOID damaged endothelial cells: vasodilator of peripheral resistance arterioles D. activation of alternative complement pathway:

E. F.

G.

release of anaphylatoxins C3'a and CS·a cause histamine release andvasodilatation pancreatic release of myocardial depressant factor warm skin: peripheral-arteriolar vasodilatation tram above vasodilators increased blood flow through micrectrculation: (1) reduced O2 exchange in tissue-s tissue hypoxia (2) increased return of blood to heart-s high output cardiac failure

(1) (2)

2.

3.

clinicaJA. E. coli sepsis fr0IU indwelling urinary catheter Met B. urinary retention secondary to prostate hyperplasia also common cause differences from hypovolemic7 cardiogentc sbockA. warm skin (1 I). t . »

B. C. 4.

increased cardiac output increased MV02: tissue cannotextract

O2 from increased flow rate

complicationsA. multiorga.n dysfunction

Me

COD
\'

B,

c.

dissemmated i tra ascular coagulation (Ole) ARDS: (jJ \J p) (1.) from neutrophil-injury (2) endotoxic shock is MeC of ARDS endotoxin

D. E.

ischemic acute tubular necrosis severe absolute neutropenia: increased synthesis of adhesion molecules stimulated by

Acid-base physiology: 1, primary alterations in the arterial PCOl-

A.

respiratory acidosis: (1) tPaC02 (2) 4-pl-l - tHCO)liiPaC02

76

Note: This material is copyrighted. All rights reserved
B.

respiratory alkalosis:

2.

(J) j,PaC02 (2) ipH - tHC03/J..J..PaC02 primary alterations in arterial IleOl"A. metabolic acidosis: (1) J,HCOj

(2) B.

J-pH - ,.[,,.[,HCOJ";,.[,PaCOi metabolic alkalosis:
(1)

(2)

HC03" ipH ~ ttHCOJ'/iPaC02'

Compensation: 1. brings arterial pH 'close to but not usually into the normal range of 7.35-7.45 2. pH 7.40 = ratio ofHCO:;-tPC02 -20/1A. compensation always move-s in tbe same direct jon as the primary disorder: (J) increase bicarbonate (rnetabol it alkalosis) must be compensated by an increase ill PCO:z (respiratory acidosis) (2) decrease in PC02 (respiratory alkalosis) must be compensated by a decrease in HeG3- (metabolic acidosis) B. compensation for primary metabolic alkalosis is respiratory acidosis C. compensation for primary metabolic acidosis is respiratory alkalosis D. compensation for primary respiratory acidosis is metabolic alkalosis E. compensation for primary respiratory alkalosis is metabolic acidosis 3. types of com pensationA. uncompensated: compensation for thatd is order is still in the normal range B. partially compensated: compensation is outside its normal range and the pH is moving towards normal range C. fuUy compensated: (1) compensation brings pH into t11 normal range (rarely occurs) (2) chronic respiratory alkalosis in high altitude residents is the only known e ception for full co~pensation Respiratory acidosis: 1. alveolar hypoventilatton-

2.

A. reduced ventilation results in hypercapnia: retain CO2 B. PaC02 >45 mm Hg: normal is,33-45 nun Hg acute resptratnry acidosisA. PaC02 >45 rnm Hg B. serum RCO)- s30 mEq/L: (l) indicates no renal compensation has occurred (2) requires 2--4 d for renal compensation to occur
chronic respiratory acidosis -

3.

A. B. 4.

PaC02 >45 mm Hg serum HeOi >30 mEq/L: indicates renalcornpensatien
respiratory center:

has occurred

causesA. depression of CNS medullary (1 ) barbiturates (2) narcotics

(3)

eNS trauma

77

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B. upper airway obstruction: /"" (1) acute epiglottitis (H. i17jluehme)!laryng,otradheobronchitis (parainfluenza virus) '--J2) cafe coronary (food obstruction) C. chest bellows dysfunction: related to weakness/paralysis of muscles of respiration (e.g,

diaphragm):
(1) (2) (3) (4) (5) amyotrophic lateral sclerosis (AL ) polio • Guillain Barre myasthenia gravis brachial plexus injury involving phrenic nerve (C4) COPD (smoking) cystic fibrosis

D.

(1) (2) (3) (4)

primary lung disease:

tk",..."(

.

'M _.;,."i!JI-/,(lJ/ ... f:iOt« .

severe pneumonia
ARDS

'$,

/Sor respiratory acidosissomnolence increased intracranial pressure: respiratory acidosis increases cerebral essel dilatation/permeability C. benign intracranial hypertension additional lab findingsA. bypoxen1ia: low Pa02 B. hypochloremia due to exchange of Cl' anions (chloride s.hi.ft) for HC03" anions reeving cells and entering ECF for non-renal compensation C. hyperkalemia due to excess It. ic:'~s.enter cells fo~~~utf;[ingin excbang~.f0r K;' to rnaintainelectroneutrality ~ I,lh.b,fs WIt"!,. 9fnl~,._j ~ 14ft{ ,1I1!"_ 'J; (fbi ''1-#0 sPC~fl D. secondary polycythemia due to erythropoietin stimu lation of erythropoiesis examples of acute and chronic respiratory acidosisA pH 7.20 acidemia (<7.35), PC02 74 rom Hg respiratory acidosis (>45 mm Hg) HCO)" 28 mEq/L normal: (J) interpretation is acute respiratory acidosis (2) uncompensated (HCG]' is not outside the normal range) B. pH 7.33 acidemia «7.35), PCC, 60 mm Hg respiratory acidosis (>45 mm Hg), HCO.l· illUEglL metabolic alkalosis (>28 mEq/L): ---(1) interpretation is chronic respiratory acidosis (HCO)" >3'0 mEg-ILl (2) partially compensated metabolic alkalosis (hypocapnia)A. B.

6.

.J-t
I""

~/1I.1'

tl'Slv

r

7.

Respiratory alkalosis: 1. alveolar hyperventilation

7J:tl~i-<'P j?<(J\V!l~

:.;i:67~~-J rftc~
.d-y.

A.
2.

PaC02 <33 mm Hg

t:{J::tk ... U (J(/~ tU,.

B.
3.

B. blowing off more CO2 than normal acute respiratery alkatcstsA. HCO~' ~ 18 mEg/L

no renal corapensarion

4.

chronic respiratory a1kalosisA. HC03' <18 mEq/L but> 1'4 mEq/L B. renal compensation is.present causesA. eNS medullary respiratory center stimulation: (1) anxiety

78

Note: This material is copyrighted. AU rights reserved (2) tf.nomnal pregnancy (estrogen/progesteroneeffect) (3) .\I(high altitude .' s , /',

(4):f<"salicylates

---7' and flftkforllC

of)

tlC"tff.li6

(ttl,Xe"

J~ftt.

~

.11

)

5.

6.

7.

(S) endotoxins (6) cirrhosis (toxic products) B. primary lung disease: (1) pulmonary embolus: tachypnea (rapid shallow 'breathing) (2) restrictive lung disease: e.g. sarcoidosis (3) mild to moderate bronchial asthma: respiratory acidosis means patient i tiring and must" be intubated SIS of respiratory a1kalosis- tetany A. alkalosisincreases negative charges on albumin B, albumin binds more ionized calcium without altering the total calcium additional lab abnormalttiesA. hyperchloremia due to intracellular exchange of cr anions for HC03' entering cells in non-renal cempensarien B. hypokalemia due to W ions lea ing cells to lower the pH and K+ moving into cells to maintain electroneutrality C. bypophosphatemia, since alkalosis stimulates g!ycolysisleacl'ing to increased phosphorylation of glucose D. low iODIzed calcium concearratlon in the presence of a. normal total calcium examples of acute and chronic respiratory alkalosi A. pH 7.56 alkalemia (>7.45.), PC~ 24 rnm Hg respiratory alkalosis «33' rnrn Hg), I-IC03' 21 mEq/L metabolic acidosis (<22 mEq/L): (1) interpretation is acute respiratory alkalosis (2) partially compensated metabolic acidosis (HCO)' is outside the norma! range but the pH is not normal} B. pH 7,48 'alkalemia (>7.450), peol 20 111111 Hg respiratory alkalosis {<33 mm Hg), HCO)- 14 mEq/L metabolic acidosis (<22 mEq/L): (1) interpretation is chronic respiratoryalkalosis (RCO," <1 but> 12 mEq/L) '(2) partially osrnpensated metabolic acidosis

e

~

Metabolic alkalosis: 1, loss ofW ions or a gain iu BCD3' anionaA. serum HC03" >28 mEq/L B. normal is 22-28 mEq/L 2.pathoge'De$isA. initial generation of metabolic alkalosis: ( 1) loss of H" ions a. vomiting b. diuretics c. mineralocorticoid excess (2) gain in HC03' a. excessive intakeofHCOi b. oxidative metabolism of acetate, lactate, citrate into HCO,· B. maintenance of increased serum Heel' in metabolic alkalosis: (1) volume depletion must occur to maintain metabolic alkalosis-a (2) J;:EABV increases the proximal reabsorption of Na in exchange for H' ions-e (3) increased Na exchange raises the renal threshold for reclaiming HC03-') (4) allows reclamation of most of the increase in filtered.Hf'O,' load

+n:r+

79

Note: This material is co_pyrighted. All rights reserved 3. causes (discussed separately beJow)A. diuretics! MCC
vomiting primary aldosteronism SIS ot' metabolic alkalosisA. increased risk for ventricular arrhythmias B. hypoxia occurs in myocardial tissue ]fOUl a left shifted O2 dissociation curve induced by alkalosis C. hypoxemia also occurs due to compensation of metabolic alkalosis by respiratory acidosis B. C.

4.

5.

example of metabolic alkalosisA. 7.50 alkalemia (>7.45), PC02
B, C.

47 rnm l-Ig' respiratory acidosis (>45 mm rIg), HCDl 35 rnEg/L metabolic alkalosis (>28 OlEq(L} interpretation is metabolic alkalosis partially compensated respiratory acidosis: PC02 is-outside the normal range and the pH is not in the normal range

Pathogenesis of metabolic alkalosis due to vomiting: 1. parietal cells in bQdy/fundusA. normally synthesize and secrete W ions into the stomach B. corresponding HCO{ anions move into the blood: called the alkaline tide 2. initial generation of metabollc alkalosisA. every mEg of Hel lost in vomitus is counterbalanced by a mEg gain .of I-ICOs· in che blood B, there is an accumulation of unneutralized HCO)' in the blood when HCI is lost from vomiting 3. maintenance of metabolic alkalosisA. ihltlally, the filtered load of HCOl' surpasses tile proximal renal tubule threshold for reclaiming fICO}': 1) urine is alkaline as He03- excess is excreted as NaHC03 (2) there is a significant renal loss ofNa+ as NaHCOJ': random UNa~ > 20 rnEqlL B. loss of cr anions in HC.I decreases serum cr concentration (hypochloremia) and the amount of chloride anions filtered in the urine: random Dcr <20 mEq/L C. excessive vomiting leads to: (1) volume depletion-s-

(2)
(3) (4) (5)

~EABV~

increased proximal tubule reab orption ofNain exchange for inoreased renal threshold for reclaiming HCG3'~ urine pH becomes acid: called paradoxical aciduria

+

H" ions-s

I' L..Jl '1U1<.wr<;

1.'\/

. all..., I~,:::: F-

4.

RxA. correction of volume
B,

depletion with 0.9% normal saline supplemented why it is called ehlortde-responsfve metabolic alkalosis corrects volume deficit and replaces Cl' lost as Bel in the vomitus of metabolic alkalosis due to loop/thiazide

by KC1: reason

Pathogenesis

diuretics:

1.
2.

MCC of metabalicalkalosiaincreased distal delivery ofNaf leads to the followingA. augmented .exchange ofNa"" in the urine for K+ in the tubule atthe Na+/F + aldosteroneenhanced pump

B.

hypokalemia occurs from the inereased exchange

80

Note: Tbis material is copyrighted. All rights reserved
C. Na + exchanges with H'" ions when K" is depleted: (1) increases distalreclarnation ofHC03-~ (2) metaboltcalkalosis

3.

A. B.

RxC.

0.9% normal saline to' replace volume deficits KCl by mouth or in infusion correcting hypokalemia pr~ents metabolicalkalosis: with Na"
of metabolic alkalosis due to primary

enough K+ is available to 'exchange (Conn's syndrome):

Pathogenesis
1,

aldosteronism

causesA MeC is a benign adenoma in the zona glornerulosa B. primary hyperplasia is a less common cause pathogenesisA. continual enhancement ofdistal Na /K-I- aldosterone pump B. increased ..Na:" reabsorption: (J ) mild hypernatremia (2) increased loss of KI- in the urine from the enhanced Na' exchange causes hypokalemia C. K+ depletioncauses.Na" to exchange with I--t ions: (1) increased distal reclamation ofHC03~-4 (2) metabolic alkalosis effect of excess Na + reabsorption into the EeFA. ECF volume increases: increases stroke volumeand raises the systolic blood pressure B. excess Na + enters smooth muscle cells of peripheral resistance arterioles (1) Na+ opens up calcium channels leading to vasoconstriction of smooth muscle cells (2) increases total peripheral resistance-s(3) raises the diastolic blood pressure reason for the lack of pitting edema in primary aldosteroniBmA. tEABV from excess Na+ and water in the ECF compartment B. increased peritubular capillary hydrostatic pressure (PH) prevents proximal tubule reabs orptionotN a + : (1) majority of Na" normally reabsorbed in the proximal tubule is lost in. the urine (2) Na+/K+ aldosterone-enhanced pump-is already maximally functioning and cannot reabsorb the Na": caned "escape mechanism" (4) increased renal loss of Nafrcm the proximal tubule almost offsets the amount of Na+ reabsorbed by aldosterone (5) slight increase in TBNa\ though present, is Dot clinically detectable a pitting edema SIS of primary aldosteronismA. severe muscle weakness: due to hypokalemia (muscle cannot repolarize) B. diastolic hypertension C_ tetany: from alkalotic state (see previous explanation) D. polyuria: (J) severe hypokalemia causes tubular refractoriness to ADH: called vacuolar

2.

3.

4.

5.

(2)
6. summary

nephropathy acquired nephrogenic .. iabetes insipidus d
of lab findings-

A.

low plasma renin activity: (1) increase in renal arterial blood flow inhibits renin release (2) increased aldosterone inhibits renin release 81

Note: This material' is copyrighted. All rights reserved B. C.

D,

mild hypematremia severe hypokalemia severe metabolic alkalosis

Metabolic acidosis: 1. defin'ition- serum HeO,- concentration <22 m£q/L (22-28 mEqIL): could be venous or arterial blood pathophysiology... 2. A. addition efexogenous orendogenous acid: increased anion gap (AG) type B. loss afHeO)-: normal AO type

.

3,

4.
5.

concept of the anion A.:f(/AG = Na - (el: + HCO:;A._AG = 140 mElij/L - (104 rnEqlL 24 mEq/L) = 12 mEq/L +1- 4 mEq/L (8-16 mEq/I) B. when-the most common anions (Cl' and HCO)') are subtracted from the most common cation (N'a~ an apparent AG is present: AG· represents unaccounted 'for anions not in the formula (1) albumin (2 phosphate (3) sulfate (4) lactate C. in increased AG metabolic acidosis, the anion of the acid (e.g., lactate aceteaeetate) replaces the HCn,,- lost to buffering the ir ions of.the acid: (I) electroneutrality is preserved (2) every 1 mEq/L of HCO),' that is 1081 by buffering I-f" ions of the acid is replaced by the anion oftbe acid . . D. example of 8' patient with diabetic ketoacidosis: (1) serurn Na' = 128 mEq/L, serum cr =,89 mEqll serum HCOi = 3.0 mEq/L (2) AG = 128 - (89' -f 3) = 36 (3) AG is 24, mEq'fL above normal and is due tC:I acetoacetate WId !3-hyruoxybutytate anions replacing the I'I"c~- ions lost to buffering of their respective ret ions ,E. in normal AG metabolic; acidosis, HeOl- anions lost in stool or urine are replaced mEq for mEg by or anions, hellj::e maintaining a normal AG and electroneutrality: (1) example serum Na+ = 128 roEq/L serum cr := 110 mEq/l, erum RC03" = 6.0 mEqlL (2) AG=128-(llO+6)=12 (3) note how Clanions increased 1 mEq/L for every 1 mEq/L of BeOJ" lost (4) called hyperchloremic normal AG metabolic acidosis f.·8nothef method of expressing AG is to subtract unmeasured cations (e.g., calcium, magnesium. potassium) from the. unmeasured anions (e .. ., albumin, phosphate, sulfate, g organic acids): (1) AG"'" Unmeasured anions (UA) - Unmeasured cations (UC) (2) 't AG by t VA (e.g., lactate) or J.UC (e.g., hypocalcemia) (3) .),AG by ~UA (e.g., albumin) or "tUC (e.g., hypercalcemia), causes of Increased and normal AG- separately listed below SIS of metabolic acidosisA. hyperventilation: Kussmaul's bresthlrrg (deep, rapid respirations) B. negtLtiv~inotrepic effect on myocardial tissue C. osteoporosis: bone buffers excess H" ions D. warm shock: acidosis vasodilares peripheral resistance arterioles (warm skin)

:arc

82

Note: This material is copyrighted. All rights reserved

6.

example of metabolic acidosisA. pH 7.28 acidemia «7.35), PCQ2 28 m::rn Hg respiratory alkalosis «33 nun Hg), HCOl' l3 tnEq/L metabolic acidosis (<22 mEq/L) R interpretation is metabolic acidosis C, partially compensated respiratory alkalosis: PC02 is outside the norma! range but the pH is not in the normal range

Increased AG metabolic acidosis: .: 1, lactic acidosis- causes: A. end-product of anaerobic glycolysis in tissue hypoxia B. alcoholism (see cell injury) C. liver disease: liver normally converts lactic acid into pyruvate jon the Cori cycle D. phenformin and phenformin-like drugs used in treating type II diabetes 2. ketoacidosis- causes: A. diabetic ketoacidosis: type I diabetes with an excess in AcAc and [3~OHB B.alcoholism: excess in ~~OI-IB C. starvation: starvation ketosis 3. renal failure- retention of organic acids.like phosphoric and sulfuric acid 4. salicylate intoxicationA. salicylic acid is an add B. salicylates uncouple oxidative phosphorylation (1) tissue hypoxia (2) additional component oflactic acidosis 5. ethylene glycol poisoDingA. ethylene glycol is in annfreeze B. ethylene glycol is converted into glycolic and 'oxalic acid by alcohol dehydrcgenase: example of competitive inhibition C. oxalate anions combine" with calcium to form calcium oxalate crystals: crystals obstruct renal tubules and produce oliguric renal failure D. Rx with infus-ion of ethanol: (1) ethanol is metabolized by the same enzyme that metabolizes ethylene glycol (alcohol ,~ehydrogenase) (2) unmetabolized ethylene glycol is removed by dialysis: recail that in competitive inhibition, increasing the substrate (ethanol) reverses the inhibi ion 6. methyl alcohol poisoningA. present in: (1) window shield washer fluid (2) solvents for paints B. m.ethyl alcohol is converted into formic acid by alcohol dehydrogenase: another example of competitive inhibition (1) damages the optic nerve (optic neuritis) (2) could lead to permanem blindness C. Rx similar to ethylene glycol 7. example of increased AG metabolic acidosis- serum Na+ 135 mEq/L (135-147 mEq/L). serum Cl> 98 mEqfL (95-105mEqlL), serum HC03' = 13 mEq/L (22-28 rnEq/L), AG = 23 mEqfL (8-16 mEq/L)

ormal AG metabolic acidosis:
L losing HCO)' and HCD)' is replaced normal AG metabolic acidosis by an equal number of Cl' anioushyperchloremic

83'

Note: This material is copyrighted. All rights reserved
2. diarrheaA. MCC of normal AG metabolic acidosis B. lab ;findings: (1) isotonic loss ofNa+ (normal serum Na.j.) (Q) hypokalemla (3) normal AG metabolic acidosis 3.:*- distal type I renal tubular acidosis~ A. dy functional aldosterone-mediated Wt:rC ATPase pump in colJecting ducts: (1) retain H+ ions which combine with cr ions ill the blood to form Hel (2) cannot regenerate HCQ3' (see above discussion) (3) cannot acidifY urine (urine p _ .5) B. causes; trr--amphotericin B (2) Bence Jones protein C. Rx: increase bicarbonate intake 4. proximal type n (proximal)A. lower threshold for HC03~ reclamation: (l ) normal of threshold of 24 mEq/L is lowered to -15 mEqfL (2) HCOl" is lost in the urine E'LLTirre~bf ,5 > (3) loss of HCO:,' stops when the serum HGOl' equals the new renal threshold of 15

m:Eq/L
causes: (I) heavy metals: e.g., lead (2) Fan coni syndrome with .loss ofa. He030. uric acid {hypouricernia) c. glucose (hypoglycemia) d. amino acids e. (hypokalemia) f. phosphate (hypophosphatemia) (3) primary hyperparathyroidism: excess PTH blocks HC03- reclamation (4) n,e_Ehrotoxicdrugs Caminoglycosides) RJ·:, t5) C'1t lnk:l,:fofs. (1) thiazides are given to produce volume depletion (2) volume depletion raises the renal threshold for reclaiming HCG3" type IV renal tubular acidos"isA. due-to destruction ofthe [uxtaglomerular apparatus in the afferent arteriole leading to low renin and low aldosterone: byporeninemic hypoaldosteronism B. causes: (1) .MCC is hyaline arteriolosclerosis of the afferent arteriole lfl diabetic

r

c.

5.

nephropathy
(2) interstitial nephritis: drugs, Legionella pneumophila C. lab findings relate to low aldosterone: (1) hyponatremia (2) hyperkalemia: onl RTA with hyperkalemia (3) normal AG metabolic acidosis D. Rx: weak mineralocorticoid example of normal anion gap metabolic acidosis- serum Na" 135 rnEq/L (135-147 mEqn..), serum = 110 mEqfL (95-105 mEqlL)~ serum HCO" = 13 mEq/L (22-28 mEq/LJ AG = 12 mEq/L (8-16 mEq/L)

6.

cr

84

Note: This material is copyrighted. All rights reserved

r:;r

Lab Dx of mixed acid-base disorders: 1. blend of ova or more acid-base disorders occurring at the same tlIne--A. e.g., a patient with diabetic ketoacidosis (increased AG metabolic acidosis) is vomiting (metabolic alkalosis) B. in the above case, pH PaC02, and HC03- are all normal, since the 2 conditions are exact opposites • 2. final pH _PaCO_z and HC01~ corlcentrarton depends on the sum of the e .pected value for each compoaentA. e.g., cardiorespiratory arrest with no breathing (acute respiratory acidosis) andcardiac standstill (metabolic acidosis from lactic acidosis) B. note: arrows represent degrees of magnitude I '1

('1."$S-"7l!IS pH

,,':.--<;r,·

~)

'V-

f

)

Respiratory acidosis ( compensation) Metabolic a,cidosis..j,.

J..

PG02 ii(primary) .J, (compensat.ion)

• HCO~-

~I')

t

~~(primary)

Final blood gas
3.

,J,,J,Cextreme acidemia)

t

clues suggesting: a mixed disorder-A. normal pH in the presence of an abnormal FaeO:., arHeo) B. implies full compensation, which i_s extremely rare C. usually indicates a primary acidosis and a primary alkalosis D e.g., salicylate intoxication: (1) pH 7.42 normal (7.35-7.45), PCOl 16 mrn Hg respiratory alkalosis (<33 mm Hg), HC03 10 mEq/L metabolic acidosis (<22 mEqlL), B. extreme acidemia: (2) e.g., primary metabolic acidosis + primary respiratory acidosis in a patient who is in cardiorespiratory-arrest genecal-

r:g-

Potassium:
L

A.
2.

B. C.mamtains cell volume and resting membrane potential K" alterations witb pH (called transcellular sbift)A. acidosis (see schematic); :(1) excess W ions enter RBCs/other cells and K"exits electroneutraliry-s (2) hyperkalemia alkalosis (see schematic): B. (1) I-f' ions exit RECslother cells and K+ enters RBCs/ceUs~ (2) hypokalemia c. exceptions to abovi : }.....-4 (l) diarrhea (1) ~ rJ.. \. If:>~ If', :::.

maintained withi~ a narrow rangeof3.S-S.0 major intraceUular fluid (leF) cation

mEq/L

RBCs/oells

to maintain

I

,.. ',0-)

(2) (3)

renal tubular acidosis (RTA) there is acidosis and hypokalemia in both conditions indicating that more is lost in the body fluid than is-ga ined by a s]1ift out of cells

85

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Hypokalemia: r. <3.5 mEq/L (3.5-5.0 mEq/L) 2. decreased intake- uncomraon 3. transcell ular shlftA. alkalosis: see above discussion'

B.

insulin Rx: (1) insulin.enhances
(2)

Na+/K"'"ATPase pump

C.

132 agonisrs

insul in is used in the Rx of hyperkalemia (catecholamines and albuterol):

4.

5.

6.

7.

J) enhance the Na+/K1' A'I'Pase pump (2) albuterol is used in the Rx of hyperkalemia increased excretionA. 01 losses: ,( I ) diarrhea (2) vomiting B. renal losses: .( I) diuretics: MCC of bypokalemia (2) primary aldosteronism (3) proximal/distal renal RTA SIS of hypo,kalemiaA. muscle weakness B. polyuria: {l) collecting tubules become refractory to ADH (2) acquired nephrogenic diabetes insipidus ECG finding in bypokalemiaA. U wave B. positive wave after T ave Rx- oraVIV K+ supplements

Transcellnlar shift of".K" in alkalosis
.

Cell

...

...

...

Hyperkalemia: 1. >5.0 mEqlL (3.5-5.0 mEqlL) 2. increased tissue breakdownA. rhabdomyolysis: rupture of muscle B. iatrogenic hemalysis ofRBCs: (1) pseudohyperka lemia (2) Me non-pathologic cause of hyperkalemia 3. transcellular shiftA. acidosis: see above discussion B. drugs: (1) digitalis overdose: blocks Na+fK';' ATPase (Dump (2) succinylcholine (muscle relaxant) (3) l3-blockers (e.g, propranolol)

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4.

5. 6. 7.

decreased excretionA. renal failure: :rt'IC pathologic cause of hyperkalemia B.a1dosterone deficiency: (1) drugs (spironolactone) (2) Addison's disease: loss of aldosterone effect {J). destruction' of JG apparatus a. caned hyporeniuemrc hypoaldosteronisrn b. common in diabetic nephropathy SIS of hyperkalemiaA. cardiac arrhythmias B. heart stops in diastole (U ECG finding in hyperkalemia- peaked T wave

or type tv RTA

RxA.

B.

first protect the heart with [V calcium glucenate then redistribute K+: (1) insu lin with glucose infu si on (2) infusion NaHCOJ: create alkalotic state. which drive K+ into cells
(3) albuterol (/' I~on .) then eliminate l(+: . {l) loop diuretics (2) cationic exchange resins (3) dialysis Transcellnlar shift oir in acidosis Cell

C.

....
I....

r'"
r::ir

Thrombosis: t. definition of thrombuJA. intravascular mass attached to the vessel wall B. composed of varying proportions of coagulation. factors, RaCs and platelets 2. pathogenesis of thrombiA. stasis of blood flow: usually venous thrombosis B. turbulent blood flow: usually arterial thrombosis composed of platelets overlying an atheromatous plaque C. hypercoagulabilityusually venous thrombosis D. postmortem clot: not attached to vessel wall 3. composltion of venous thrombiA. dark red mass of fibrin (red thrombus) within which are entrapped RECs, white blood cells, and a few platelets (\) coagulation factors are used up in the clot (2) fibrinogen (factor 1),pr6ti1rombin (factor II), V vm are .consumed in a venous clot B. heparin and warfarin inhibit formation of venous clot since these drugs are anticoagulants C. not prevented by aspirin 4. composition of arterial tbrombiA. composed of platelets held together by fibrin strands

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B. appear firm and pare: (l) pale thrombus (2) relative absence of entrapped RBCs, ~reve~'t~d ~Y aspj~in: d~cre~asesplatel~t aggregation ticlopidml! IS used if patients are allergic tc aSpl~Jn ~

c_
D.
E.

.~
,.J,I1Itb2'I ~ ~

F.

heparin or warfarin GO not prevent arterial .thrombi composed of platelets mural thrombus in the heart after a myocardial infarction are a combination ef'a platelet

1fJ

~

fitCw

y)1.~

,
i

5,

6.

and "venous" clot (1) platelet part of the clot is that portion attached to the damaged endocardial surface {2) "venous' part of the clot is built on top of the platelet clot (3) aspirin and heparin/warfarin prevent these mixedelots risk factors for venous tbrombosisA. surgery: hip replacement worst B. immobility: post-operative state C. obesity D. congestive heart failure (CHF) E. malignancy: lrypercoagulable due tp an increase in fibrinogen V. and VID F. oral' contraceptives: € I) hyperceagulable (2) decreased antithrombin (3) increased fibrinogen, V, VIII risk factors for arteria] thromboslsA. atherosclerosis: most important

m

B.
C. D.

smoking.chemicals damage vessels

hypertension diabetes mellitus

E. F. G.
H_

LDL ~ 16'Om;gldL I-IDLS3 5 mg/dl, family history of premature acute myocardial infarction and/or stroke increased plasma homocysteine: folate deficiency MeC

7. 8. 9.

Me site for venous throm bOSLS- deep veins of the calf Me site for arterial thrombosia- coronary arteries
natural history of venous thrombiA. thrombeemboliaarien: potential for infarction B. dissolution: role of fibrinolytic system C_ organization/possible recanalization: restoration of blood flow D, infection of thrombus: potential for septic embolization and "metastatic" formation natural bistory of arterial tbromblA. infarction B. dissolution by fibrinolytic system C. embolization

abscess

10.

Embolism: I. definition2.

mass to a distant site . site of origin of pulmonary emboJusA. proxima] veins in thigh followed by pelvic veins: B. deep veins of the calf are the Me site for thrombosis: they are not the embolization

vessel occlusion by a mass (e.g. clot" fat gas) with subsequent movement of the

Me

site for

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