c Health Sciences

HIGH-YIELD PRINCIPLES IN

Public Health Sciences

[' ll is a mathematical fact that fifty percent of all doctors graduate in the Epidemiology/
bottom half of their class." Biostatistics 246
— Author Unknown
Ethics 253
“There are two kinds of statistics : the kind you look up and the kind you
make up." The Well Patient 258
— Rex Stout
Social Sciences 259
“On a long enough time line, the survival rate for everyone drops to zero.”
— Chuck Palahniuk
“There are three kinds ol lies: lies, damned lies, and statistics ."
— Mark Twain

I
A heterogenous mix of epidemiology, biostatistics, ethics, law, healthcare
delivery, patient safety , quality improvement, and more falls under the
heading of public health sciences. Biostatistics and epidemiology are the
foundations of evidence-based medicine and arc verv high-yield. Make
sure vou can apply biostatistical concepts such as sensitivity , specificity ,
and predictive values in a problem-solving format.

Medical ethics questions mav seem less concrete than questions from
other disciplines. For example, if a patient does or savs something.
what should you do or sav in response? Many medical students do not
diligently study these topics because the material is felt to be easy or a
matter of common sense. In our opinion, this is a missed opportunity.

In addition, the key aspects of the doctor-patient relationship ( eg,

communication skills ) are high-vield. Last, the exam has also recently
added an emphasis on patient safety and quality improvement topics.
which arc discussed in this chapter.

245
246 SECTION II PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS

1 PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS

Observational studies
STUDY TYPE DESIGN MEASURES /EXAMPLE
Cross- sectional study Collects data from a group of people to assess Disease prevalence.
frequency of disease (and related risk factors) at Can show risk factor association w ith disease, but
a particular point in time. does not establish causality.
Asks, "What is happening?”
Case-control study Compares a group of people with disease to a Odds ratio (OR ).
group without disease. “ Patients w ith COPD had higher odds of a
Looks for prior exposure or risk factor. history of smoking than those without COPD.”
Asks, “ What happened? '’
Cohort study Compares a group with a given exposure or risk Relative risk ( RR).
factor to a group without such exposure. “ Smokers had a higher risk of developing COPD
Looks to see if exposure affects the likelihood of than nonsmokers.”
disease.
Can be prospective (asks, “ Who will develop
disease?’’) or historical (asks, “ Who developed
the disease [exposed vs nonexposed] ?”).
Twin concordance Compares the frequency with which both Measures hcritability and influence of
study monozygotic twins or both dizygotic twins environmental factors (“ nature vs nurture” ).
develop the same disease.
Adoption study Compares siblings raised by biological vs Measures heritability and influence of
adoptive parents. environmental factors.

Clinical trial Experimental study involving humans. Compares therapeutic benefits of 2 or more treatments,
or of treatment and placebo. Study quality improves when study is randomized, controlled, and
double-blinded ( ie, neither patient nor doctor knows whether the patient is in the treatment or
control group). Triple-blind refers to the additional blinding of the researchers analyzing the data.
Four phases ( “ Does the drug swim?”!
DRUG TRIALS TYPICAL STUDY SAMPLE PURPOSE
Phase 1 Small number of healthy volunteers. “ Is it safe?” Assesses safety, toxicity,
pharmacokinetics, and pharmacodynamics.
Phase II Small number of patients with disease of “ Does it work?” Assesses treatment efficacy,
interest. optimal dosing, and adverse effects.
Phase III large number of patients randomly assigned “Is it as good or better?" Compares the new
either to the treatment under investigation or treatment to the current standard of care tanv
to the best available treatment ( or placebo). improvement ?!
Phase IV Postmarketing surveillance of patients after “Can it stay? " Detects rare or long-term
treatment is approved. adverse effects. Can result in treatment being
withdrawn from market.
 PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMI 0 L06 Y / BI0 STATISTICS SECTION II 247

Evaluation of Uses 2 x 2 table comparing test results with the Disease

diagnostic tests actual presence of disease. TP = true positive; © ©
FP = false positive; TN = true negative; FN = PPV
TP FP = TP/ITP + FP)
false negative. iRevisedl
NPV | Figure |
Sensitivity and specificity are fixed properties FN TN = TN/ON + FN)
of a test. PPV and NPV vary depending on
..
Sensitivity Specificity Prevalence
TP TN
disease prevalence. = TP/ fTP + FN) = TN/TTN + FPL (T? FN * fP 4 TNl

Sensitivity (true ¬
Proportion of all people with disease who lest = TP / ( TP + FN)
positive rate ) positive, or the probability that when the = 1 - false-negative rate
disease is present, the test is positive. -
SN N-OUT = highly SeNsitive test, when
Value approaching 100% is desirable for ruling Negative, rules OUT disease
out disease and indicates a low false negative - If sensitivity is 100%, all negatives must be TNj
rate. High sensitivity test used for screening in
diseases with low prevalence.
Specificity (true ¬
Proportion of all people without disease who = TN / (TN + FP)
negative rate) test negative, or the probability that when the = 1 - false-positive rate
disease is absent, the test is negative. SP-P-IN = highly SPecific test, when Positive,
Value approaching 100% is desirable for rules IN disease
ruling in disease and indicates a loss false- If specificity 100%. all positives must be Tl'4
positive rate. High specificity test used for
confirmation after a positive screening test.
Positive predictive Proportion of positive test results that are true PPV = TP / (TP + FP )
value positive. PPV varies directly with pretest probability
Probability that a person who has a positive test ( baseline risk, such as prevalence of disease):

Negative predictive
result actually has the disease.
Proportion of negative test results that are true
high pretest probability high PPV'
NPV = TN / ( TN + FN)
—
value negative. NPV7 varies inversely with prevalence or pretest
Probability that a person with a negative test
result actually does not have the disease.
probability: high pretest probability low NPV' —
POSSIBLE CUTOFF VALUES
.t Disease lease A = 100% sensitivity cutoff value
absent present
| B - practical compromise between specificity anti sensitivity
C = 100% specificity cutoff value
£
£ TN TP lowenna the cutoff point T Sensitivity t NPV
B - A ( T FP 4 FN) T Specificity X PPV
FP
A B C
Raising the cutoff point T Specificity T PPV
B C ( tFNXFP) i Sensitivity 1NPV
Test results
For example, in diabetes screening, raising the blood glucose level at which a patient is diagnosed will X sensitivity. T specificity. T PPV.
and X NPV. The opposite changes occur with decreasing the blood glucose level at which a patient is diagnosed. 13

Likelihood ratio A measure indicating how likely a given test sensitivity

I.Ri in¬
result would occur in a patient with the 1 - specificity
I New I condition vs a patient without the condition.
Ifssil _ I - sensitivity
specificity
248 SECTION II PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS

Quantifying risk Definitions and formulas are based on the classic Disease
2 x 2 or contingency tabic. © ©
si
II © a b

II© c d

Odds ratio Typically used in case-control studies. OR a /bj ad

OR “ “

depicts the odds of an event ( eg. disease!

occurring giving a certain exposure ( a / b) vs ^ d be

the odds of an event occurring in the absence

of that exposure ( c/d1
Relative risk Typically used in cohort studies. Risk of a /( a + b )
RR =
developing disease in the exposed group c/(c + d )
divided by risk in the unexposed group ( eg. if
2\7c of smokers develop lung cancer vs 17c of

_
nonsmokers, RR = 21/1 = 21 ). If prevalence is

——
low, OR = RR .
RR = 1 no association between exposure and
disease.
RR > 1 e x p o s u r e associated with t disease

Attributable risk
RR < 1
—
occurrence.

occurrence.
exposure associated with t disease

The difference in risk between exposed and

unexposed groups, or the proportion of
AR
a
a+b c+d
c _
disease occurrences that are attributable to
the exposure (eg, if risk of lung cancer in
smokers is 21'/? and risk in nonsmokers is 1%,
then 20% of the lung cancer risk in smokers is
attributable to smoking).
Relative risk reduction T he proportion of risk reduction attributable to RRR = 1 - RR
the intervention as compared to a control (eg,
if 2% of patients who receiv e a flu shot develop
the flu, while 8% of unvaccinated patients
develop the flu , then RR = 2 /8 = 0.25, and
RRR = 0.75 ).
Absolute risk T he difference in risk (not the proportion )
ARR
c _ a
reduction attributable to the intervention as compared c+d a+b
to a control (eg, if 87c of people who receive
a placebo vaccine develop the flu vs 27c
of people who receive a flu vaccine, then
ARR = 8% - 17c = 6% = .06 ).
Number needed to Number of patients who need to be treated for 1 NNT = 1 /ARR
treat patient to benefit .
Number needed to Number of patients who need to be exposed to a NNH = 1/AR
harm risk factor for 1 Datient to be harmed.
PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS SECTION II 249

Incidence vs Incidence H of new cases [ during a specified Incidence looks at new cases ( incidents).
prevalence rate # of people at risk time period )
II of existing cases (at a point in Prevalence looks at all current cases.
Recurrence Prevalence •
t otal It of people time)
ill a population
Prevalence Incidence rate x average duration
Tril?fT
Mortality Cure 03
1 - prevalence of disease
Prevalence - incidence for short duration disease- Prevalence - pretest probability.
leg, common cold ).
Prevalence > incidence for chronic diseases, due to
t prevalence
— t PPV and t NPV

.
large II of existing cases ( eg diabetes).

Precision vs accuracy
Precision (reliability )! The consistency and reproducibility of a teslj Random error 1 precision in a test,
The absence of random variation in a test. t precision -» i standard deviation ,

Accuracy (validity)!
-
t precision » t statistical power ( 1 pi.—
Tire trueness of test measurement
^
The absence of systematic error or bias in a test.
Systematic error i accuracy in a test.

External validity Applicability of obtained results bevond the

«
cohort that was studied.

X
X X

X *
X
o §
X
X

X
Accurate, not precise Precise, not accurate Accurate and Not accurate,
precise not precise
250 SECTION II PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS

Bias and study errors

TYPE DEFINITION EXAMPLES STRATEGY TO REDUCE BIAS
Recruiting participants
Selection bias Error in assigning subjects to Berkson bias — study population Randomization
a study group resulting in selected from hospital is Ensure the choice of the right
an unrepresentative sample. less healthy than general comparison/reference group
Most commonly a sampling population
bias. 1 lealthy worker effect — study
population is healthier than
the general population
Non-response bias-
participating subjects differ
from nonrespondents in
meaningful ways
Performing study
Recall bias Awareness of disorder alters Patients with disease recall Decrease time frottt exposure
recall by subjects; common in exposure after learning of to follow-up
retrospective studies. similar cases
Measurement bias Information is gathered in a Association between HPV and Use objective, standardized,
-
systemic ally distorted manner. cervical carreer not observed and previously tested methods
when using non-standardized of data collection that arc
classifications planned ahead of tinre _
—
I lawthorne effect participants Use Dlacebo grouD
change their behavior in
response to their awareness of
being observed
Procedure bias Subjects in different groups arc Patients in treatment group
not treated the same. spend more time in highly Blinding and use of placebo
reduce influence of
specialized hospital units
participants artd researchers
Observer- expectancy Researcher’s belief in the If observ er expects treatment on procedures and
bias efficacy of a treatment changes group to show signs of interpretation of outcomes
the outcome of that treatment recovery, then he is more as neither are aware of group
(aka Pygmalion effect; self- likely to document positive allocation
fulfilling prophecy). outcomes
Interpreting results
Confounding bias When a factor is related to both Pulmonary disease is more Multiple/repeated studies
the exposure and outcome, common itt coal workers Crossover studies (subjects act
but not on the causal than the general population; as their own controls)

—
pathway - factor distorts or however, people who w ork in
confuses effect of exposure on coal mines also smoke more
outcome. frequently than the gerteral
population
Lead-time bias Early detection is confused Early detection makes it
with t survival. seem as though survival has
increased, but the natural
history of the disease has trot
changed
Matching ( patients with
similar characteristics in both
treatment atrd control groups)
Restriction
Randomization
Measure “ back-end” survival
(adjust survival according to
the severity of disease at the
time of diagnosis)
252 SECTION I I PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — EPIDEMIOLOGY / BIOSTATISTICS

Outcomes of statistical hypothesis testing

Correct result Stating that there is an effect or difference when
one exists (null hypothesis rejected in favor of
alternative hypothesis).
Stating that there is not an effect or difference
when none exists ( null hypothesis not
rejectedl.
Incorrect result
Type I error (a) Stating that there is an effect or difference Also knorvn as false-positive error.
when none exists (null hypothesis incorrectly
rejected in favor of alternative hvpothcsis).
a is the probability of making a typeI error, p is a = you accused an innocent maij
judged against a preset a level of significance You can never “prove" the alternate hypothesis,
(usually 0.05 ). If p < 0.05, then there is less but you can reject the null hypothesis as being
than a 5% chance that the data will show very unlikely.
something that is not really there.
Type II error ((5) Stating that there is not an effect or difference Also knorvn as false-negative error.
when one exists ( null lnpothesis is not rejected
when it is in fact false ).
P is the probability' of making a type II error. P P = y ou blindly let the guilty man go freet
is related to statistical power ( 1 - p), which is If you t sample size, you t porver. T here is power
the probability' of rejecting the null hy pothesis in numbers.
when it is false,
t poyver and l P by:
• t sample size
t expected effect size
t precision of measurement

Confidence interval .
For a given X% Cl rvc arc X% confident that
the true mean of the target population falls
within the calculated interval
Cl for population mean = x ± Z( SEM )
.
SI M = cr / yj( N ) |q = sample standard deviation.
N = sample size ]
Jl'he 95'/f Cl (corresponding to - .05 ) is often
used.
If the 95% Cl for a mean difference between 2
variables includes 0, then there is no significant
difference and H0 is not rejected.
If the 95% Cl for odds ratio or relative risk
includes 1, llu is not rejected.
If the Cls betyveen 2 groups do not overlap
— .
statistically significant difference exists

—
If the Cls betyveen 2 groups overlap usually
.
For the 95% CI Z = 1.96. no significant difference exists.
For the 99% Cl, Z = 2.58.
 PUBLIC HEALTH SCIENCES BEHAVIORAL SCIENCE — ETHICS SECTION I I 253

Common statistical tests

f-test Checks differences between means of 2 groups. Tea is meant for 2.
Example: comparing the mean blood pressure
between men and women.
ANOVA Checks differences between means of > or more > words: ANalysis Of YAriance.
groups . Example: comparing the mean blood pressure
between members of ” different ethnic groups.
Chi-square (%2) Checks differences between 2 or more Pronounce Chi-tegorical.
percentages or proportions of categorical Example: comparing the percentage of members
outcomes (not mean values). of s different ethnic groups who have essential
hypertension.

Pearson correlation r is always between -1 and +1. The closer the absolute value of r is to 1, the stronger the linear
|coefficientl correlation between the 2 variables.
——
Positive r value positive correlation (as one variable t, the other variable t )
.
Negative r value negative correlation (as one variable t the other variable t ).
.
Coefficient of determination = r ~ lamount of variance in one variable that can be explained bv
variance in another variahltl).
re 0 8

r!
re a 4

i.
r= 0

• i
FPQ — aft td corfie "
.. ••
'V
•
m
-
r* 0.4 -
re 0.8

I
• ••
Strong positive Weak positive Weak negative Strong negative
No correlation
correlation correlation correlation correlation

BEHAVIORAL SCIENCE — ETHICS

Core ethical principles

Autonomy Obligation to respect patients as individuals ( truth-telling, confidentiality), to create conditions
necessary for autonomous choice (informed consent), and to honor their preference in accepting
or not accepting medical care.
Beneficence Physicians have a special ethical ( fiduciary ) duty to act in the patient ’s best interest. May conflict
with autonomy (an informed patient has the right to decide) or what is best for society ( eg,
mandatory TB treatment). T raditionally, patient interest supersedes.
Nonmaleficence "Do no harm.” Must be balanced against beneficence; if the benefits outw eigh the risks, a patient
may make an informed decision to proceed (most surgeries and medications fall into this
category).
Justice To treat nersons fnirlv and eonitahlv. T his does not nhvavs imnlv eouallv ( ep triapel.
254 SECTION I I PUBLIC HEALTH SCIENCES BEHAVIORAL SCIENCE — ETHICS

Informed consent A process (not just a document/signature) that
requires:
Disclosure: discussion of pertinent
information
Understanding: ability to comprehend
Capacity: ability to reason and make one’s
own decisions ( distinct from competence, a
legal determination )
Voluntariness: freedom from coercion and
manipulation
Patients must have an intelligent understanding
of their diagnosis and the risks/benefits of
proposed treatment and alternative options,
including no treatment.
Patient must be informed that he or she can
revoke written consent at any time, even orally.
Exceptions to informed consent:
Patient lacks decision-making capacity or is
legally incompetent
• Implied consent in an emergency
Therapeutic privilege — withholding
information when disclosure would severely
harm the patient or undermine informed
decision-making capacity
Waiver — patient explicitly waives the right of
informed consent

Consent for minors A minor is generally am person < 18 s ears old.
Parental consent laws in relation to health
care vary b\ state. In general, parental consent
should be obtained, but exceptions exist for
emergency treatment ( eg, blood transfusions )
or if minor is legally emancipated leg, married,
self supporting, or in the military1
Situations in which parental consent is usually
not required:
Sex (contraception, STIs, pregnancy)
Drugs (substance abuse)
Rock and roll (emergency/trauma)
Physicians should always encourage healthy
minor-guardian communication. ^

Physician should seek patient assent even il

patient consent is not required.

Decision- making Physician must determine w hether the patient is psychologically and legally capable of making
capacity a particular health care decision. Note that decisions made with capacity cannot be revoked
simply if the patient later loses capacity
Components:
Patient is > 18 years old or otherwise legally emancipated
Patient makes and communicates a choice
Patient is informed (knows and understands)
Decision remains stable over time
Decision is consistent with patient ’s values and goals, not clouded by a mood disorder
Decision is not a result of altered mental status (eg, delirium, psychosis, intoxication )
 PUBLIC HEALTH SCIENIO r BCHAVIUKAL SuttfU— tifTTo

Advance directives Instructions given by a patient in anticipation of the need for a medical decision. Details vary per
state law .
Oral advance directive Incapacitated patient’s prior oral statements commonly used as guide. Problems arise from variance
in interpretation. If patient was informed, directive was specific, patient made a choice, and
decision was repeated over time to multiple people, then the oral directive is more valid.
Living will ( written Describes treatments the patient wishes to receive or not receive if he/she loses decision-making
advance directive) capacity. Usually, patient directs physician to withhold or withdraw life-sustaining treatment if he/
she develops a terminal disease or enters a persistent vegetative state.
Medical power of Patient designates an agent to make medical decisions in the event that he/she loses decision ¬

attorney making capacity. Patient may also specif)' decisions in clinical situations. Can be revoked by
patient if decision-making capacity is intact . More flexible than a living will.
Do not resuscitate DNR order applies only to cardiopulmonary resuscitation.
order

Surrogate decision- If a patient loses decision-making capacity and has not prepared an advance directive, individuals
maker (surrogates) who know the patient must determine what the patient would have done. Priority of
— —
surrogates: The spouse ChiPS in spouse adult Children Parents
relative
^
— —
Siblings
—
other

Confidentiality Confidentiality respects patient privacy and autonomy. If patient is not present or is incapacitated.
disclosing information to family and friends should be guided by professional judgment of
patient 's best interest. The patient may voluntarily waive the right to confidentiality (eg, insurance
company request ).
General principles for exceptions to confidentiality:
Potential physical harm to others is serious and imminent
Likelihood of harm to self is great
No alternative means exists to warn or to protect those at risk
Physicians can take steps to prevent harm
Examples of exceptions to patient confidentiality (many are state-specific ) include the following
( " The physician's good judgement SAVED the dav" f
Suieidal/homicidal patients
Abuse ( children, elderly, and /or prisoners)
Tarasoff decision — California Supreme Court decision requiring physician to directly inform
and protect potential victim from harm.
Epileptic patients and other impaired automobile drivers.
Reportable diseases ( eg, STls, hepatitis, food poisoning ); physicians may have a duly to warn
public officials, who will then notify people at risk. Dangerous communicable diseases, such as
TB or Ebola, may require involuntary treatment ]
'

IFTBnitRH 256

SITUATION
SECTION II

Ethical situations
PUBLIC HEALTH SCIENCES

V A I: L J i 1 J 'I :
BEHAVIORAL SCIENCE — ETHICS

Patient is not adherent.
Patient desires an unnecessary
procedure.
Patient has difficult)' taking
Attempt to identify the reason for nonadherence and determine his/her willingness to
change; do not coerce the patient into adhering or refer him / her to another physician.
Attempt to understand why the patient wants the procedure and address underlying
concerns. Do not refuse to see the patient or refer him / her to another physician . Avoid
performing unnecessary procedures.
Provide written instructions; attempt to simplify treatment regimens; use teach-back

| medications.
Family members ask for information Avoid discussing issues with relatives without the patient ’s permission.
about patient’s prognosis.
B A patient s family member asks you Attempt to identify why the family member believes such information would be
not to disclose the results of a test
i if the prognosis is poor because
I the patient will be “ unable to
handle it.”
A 17-year-old girl is pregnant and
requests an abortion.
A 15-vcar-old girl is pregnant and
wants to keep the child . I ler
parents want you to tell her to give
the child up for adoption.
A terminally ill patient requests
physician assistance in ending
his/ her own life.
Patient is suicidal.
Patient states that he/she finds you
attractive.
A woman who had a mastectomy
says she now feels “ ugly.”
method (ask patient to repeat regimen back to physician ) to ensure comprehension .
detrimental to the patient’s condition . Explain that as long as the patient has decision¬
making capacity and does not indicate otherwise, communication of information
concerning his/her care will not be withheld . 1 lowever, if vou believe the patient
might harm himself or others if informed, then you may invoke therapeutic privilege
and withhold the information!
Many states require parental notification or consent for minors for an abortion. Unless
there are specific medical risks associated with pregnancy, a physician should not
sway the patient ’s decision for an elective abortion ( regardless of maternal age or fetal
condition ).
The patient retains the right to make decisions regarding her child , even if her parents
disagree. Provide information to the teenager about the practical issues of caring for
a baby. Discuss the options, if requested . Encourage discussion between the teenager
and her parents to reach the best decision .
In the overw helming majority of states, refuse involvement in any form of physician-
assisted suicide. Physicians may, however, prescribe medically appropriate analgesics
that coincidentally shorten the patient ’s life.
Assess the seriousness of the threat . If it is serious, suggest that the patient remain in the
hospital voluntarily; patient can be hospitalized involuntarily if hc/she refuses.
Ask direct , closed-ended questions and use a chaperone if necessary. Romantic -
relationships with patients are never appropriate.
Find out why the patient feels this way. Do not offer falsely reassuring statements (eg,
“ You still look good").

Patient is angry about the long time Acknowledge the patient 's anger, but do not take a patient ’s anger personally. Apologize
he /she spent in the waiting room . for any inconvenience. Stay away from efforts to explain the delay.
Patient is upset with the way he /she Suggest that the patient speak directly to that physician regarding his/her concerns. If the
was treated by another doctor. problem is with a member of the office staff, tell the patient you will speak to that person .
An invasive test is performed on the Regardless of the outcome, a physician is ethically obligated to inform a patient that a
wrong patient. mistake has been made.
 PUBLIC HEALTH SCIENCES
Ethical situations ( continued )
SITUATION
A patient requires a treatment not
covered by his/her insurance.
-
A 7 year-old boy loses a sister to
cancer and now feels responsible.
Patient is victim of intimate partner
violence.
Patient wants to trv alternative or
holistic medicine.
Phvsician colleague presents to
work impaired.
Patient is officiallv determined to
suffer brain death. Patient ’s family
insists on maintaining life support
indefinitely because patient is still
moving when touched.
A pharmaceutical company offers
vou a sponsorship in exchange for
advertising its new drug
An adult refuses care because it is
against his/her religious beliefs.
Mother and 15-vear-old daughter
arc unresponsive following a car
accident and are bleeding internally.
Father says do not transfuse because
they are Jehovah s Witnesses .
BEHAVIORAL SCIENCE — ETHICS SECTION II 257
APPROPRIATE RESPONSE
Never limit or deny care because of the expense in time or money. Discuss all
treatment options with patients, even if some arc not covered by their insurance
companies.
At ages 5 -7, children begin to understand that death is permanent, that all life
functions end completely at death, and that everything that is alive eventually
dies. Provide a direct, concrete description of his sisters death. Avoid cliches and
euphemisms. Reassure that the boy is not responsible. Identify and normalize fears
and feelings. Kncourage play and healthy coping behaviors (eg, remembering her in
his own way).
Ask if patient is safe and has an emergency plan. Do not pressure patient to leave his or
her partner, or disclose the incident to the authorities.
Find out win and allow patient to do so as long as there arc no contraindications.
medication interactions, or adverse effects to the new treatment .
If impaired, incompetent, or unethical colleague threatens patient safety, report the
situation to local superv isory personnel. Should the organization fail to take action .
alert the state licensing board.
Gently explain to family that there is no chance of recovers , and that brain death is
eauivalent to death Movement is due to spinal arc reflex and is not voluntary. Patient
should be withdrawn from life support
Reject this offer. Generally, decline gifts and sponsorships to avoid any appearance of
conflict of interest. The AMA Code of Ethics does make exceptions for gifts directly
benefitting patients; gifts of minimal value; special funding for medical education
of students, residents, fellows: grants where recipients arc chosen bv independent
institutional criteria; and where funds are distributed without attribution to sponsors.
Work with the patient bv cither explaining the treatment or pursuing alternative
treatments with the patient . However, a phvsician should never attempt to force adults
to receive care if it is contrary to their religious beliefs.
Transfuse daughter, but do not transfuse mother. Emergent care can be refused bv the
healthcare proxy for an adult, particularly where patient preferences are known or
reasonably inferred, but not for a minod
 SECTION II PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — THE WELL PATIENT

1 PUBLIC HEALTH SCIENCES — THE WELL PATIENT

Early developmental Milestone dates are ranges that have been approximated and vary by source. Children not meeting
milestones milestones may need assessment for potential developmental delay.
AGE MOTOR
Infant Parents
0-12 mo Primitive reflexes disappear —
Moro ( by 3 mo ), rooting ( by
4 mo), palmar (by 6 mo),
Babinski ( by 12 mo)
Posture — lifts head up prone ( by
1 mo), rolls and sits (by 6 mo),
crawls (by 8 mo), stands ( by
10 mo), walks (by 12-18 mo)
Picks — passes toys hand to
hand (by 6 mo), Pincer grasp
(by 10 mo)
Points to objects (by 12 mo)
Toddler Child
12- 36 mo Cruises, takes first steps ( by
12 mo)
Climbs stairs ( by 18 mo)
Cubes stacked— number
= age (yr) x 3
Cutler \(— feeds self with fork
and spoon (by 20 mo)
Kicks ball ( by 24 mo)
Preschool Don't
3-5 yr Drive — tricvcle ( > wheels at
3 yr)
Drawings — copies line or
circle, stick figure ( by 4 yr)
—
Dexterity hops on one foot
(by 4 yr), uses buttons or
zippers, grooms self ( by 5 yr )
SOCIAL
Start
Social smile (by 2 mo)
Stranger anxiety ( by 6 mo)
Separation anxiety ( by 9 mo)
Rearing
—
Recreation parallel play ( by
24-36 mo)
—
Rapprochement moves away
from and returns to mother
( by 24 mo)
Realization— core gender
identity - formed (by 36 mo)
Forget, they're still
Freedom — comfortably spends
part of das ass ay from mother
(by 3 vri
Friends — cooperatise play, has
imaginary friends ( by 4 yr)
VERBAL /C0GNIT1VE
Observing,
Orients— first to voice ( by
4 mo), then to name and
gestures (by 9 mo)
Object permanence ( by 9 mo)
Oratory — says “mama” and
" dada" (by 10 mo)
Working,
—
W ords 200 ssords by age 2
(2 zeros), 2-word sentences
Learning!
Language — 1000 ssords by age
3 ( 3 zeros), uses complete
sentences and prepositions
(by 4 yr)
—
Legends can tell detailed
stories ( by 4 vr|

Car seats for children Children should ride in rear-facing car seats until thev are 2 sears old and in car seats with a
harness until thev are 4 sears. Older children should use a booster seat until thev are 8 sears
old or until the seat belt fits pi operlv. Children < 12 sears old should not ride in a seat ss ith an
airhaa
 PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — SOCIAL SCIENCES SECTION II

Changes in the Sexual changes:

elderly Men— slower ereetion/ejaculation, longer refractor) period
= Women— vaginal shortening, thinning, and dryness.
Sleep patterns: I REM and slow-wave sleep; t sleep onset latency] t early awakenings
^
t suicide rate.
1 vision and hearing.
I immune response.
I renal, pulmonary, and Cl function .
1 muscle mass, t fat .
Intelligence docs not decrease!

PUBLIC HEALTH SCIENCES — SOCIAL SCIENCES

Disease prevention
Primary Prevent disease before it occurs (eg, HPV
vaccination)
Secondary Screen early for and manage existing but
.
asymptomatic disease (eg Pap smear for
cervical cancer)
Tertiary Treatment to reduce complications from Quaternary — identifying patients at risk of
disease that is ongoing or has long-term effects unnecessary treatment, protecting from the
(eg, chemotherapy) harm of new interventions ( eg, electronic
sharing of patient records to avoid duplicating
recent laboratory and imaging studies!

Types of insurance plans

Health Maintenance Patients are restricted ( except in emergencies! to a limited panel of providers w ho arc in the
Organization network.
Payment is denied for any service that does not meet established, es idencc-hascd guidelines.
Requires referral from primary care provider to see a specialist.
Point of Service Patients arc allowed to sec providers outside of the netw ork, hut have higher out-of-pocket costs,
including higher copays and deductibles, for out-of-netw ork services.
Requires referral from primary care provider to see a specialist .
Preferred Provider Patients are allowed to see physicians who are within or outside of the network. All serv ices have
Organization higher enpavs and deductibles.
Do not need a referral from primary care provider to see a specialist.
Exclusive Provider Patients arc limited (except in emergencies) to a network of doctors, specialists, and hospitals.
Organization Does not require a referral from primary care provider to sec a specialist.
a PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — SOCIAL SCIENCES

Patient payment models

Capitation! Patient pays a fixed, predetermined fee in advance to cover all medical serv ices. Used in HMO
insurance plans!
Discounted fee- for- Patient pays for eaeli individual service at a predetermined, discounted rate,
service
Global payment Patient pays for all expenses associated with a single incident of care with a single payment . Most
commonly used during elective surgeries, as it covers tile cost of surgery as w ell as the necessary
pre - and postoperative visits.

Medicare and Medicare and Medicaid— federal social MedicarE is for Elderly .
Medicaid health care programd that originated from MedicaiD is for Destitute.
amendments to the Social Security Act.
Medicare is available to patients > 65 years old. The 4 parts of Medicare:
< 65 with certain disabilities, and those with Part A: Hospital insurance, home hospice
end-stage renal disease. care
Medicaid is joint federal and state health Part B: Basic medical bills ( eg, doctor’s fees,
assistance for people with very low income. diagnostic testing!
Part C: ( Parts A + B = Combrj) delivered by
approved private companies
Part D: Prescription drugs

Hospice care Medical care focused oil providing comfort and palliation instead of definitive cure. Available to
patients on Medicare or Medicaid and in most private insurance plans whose life expectancy is
< 6 months.
During end - of-life care, priority is given to improving the patient 's comfort and relieving pain, and
care often includes opioid medications. Facilitating comfort is prioritized over potential side
effects leg, respiratory depression). This prioritization of positive effects over negative effects is
known as the principle of double effect.

Common causes of death (US) by age

< 1 YR 1-14 YR 15-34 YR 35-44 YR 45-64 YR 65+ YR
#1 Congenital Unintentional Unintentional Unintentional Cancer Heart disease
malformations injury injury injury
#2 Preterm birth Cancer Suicide Cancer 1 leart disease Cancer
#3 Maternal Congenital Homicide Heart disease Unintentional Chronic
pregnancy malformations injury respiratory
complication! disease
262 SECTION II PUBLIC HEALTH SCIENCES PUBLIC HEALTH SCIENCES — SOCIAL SCIENCES

Swiss cheese model In complex organizations, flaws in multiple

processes and systems may align to cause FaAtrts m defense strategy

patient harm. Focuses on systems and Hazard

conditions rather than an individual's error.

N 'i i

II M|" Swapped
Figure

Types of medical May involve patient identification, diagnosis, monitoring, nosocomial infection, medications,
errors procedures, devices, documentation, handoffs. Errors causing harmful outcomes must be disclosed
to patients.
Active error Occurs at level of frontline operator (eg, wrong Immediate impact.
IV pump dose programmed).
Latent error Occurs in processes indirect from operator hut Accident waiting to happen.
impacts patient care ( eg, different types of IV
pumps used within same hospital ).

Medical error analysis

Root cause analysis Uses records and participant interviews to
identify all the underlying problems that led to
an error. Categories of causes include process,
people (providers or patients), environment,
equipment, materials, management.
Failure mode and Uses inductive reasoning to identify all the ways
effects analysis a process might fail and prioritize these by
their probability of occurrence and impact on
patients.
Retrospective approach applied after failure
event to prevent recurrence.
Plotted on fishbone ( Ishikawa, cause-and-effect )
diagram. Fix causes with corrective action
plan.
forward-looking approach applied before process
implementation to prevent failure occurrence.
 32 SECTION II BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR

BIOCHEMISTRY — MOLECULAR

Chromatin structure DNA exists in the condensed, chromatin form

in order to fit into the nucleus. Negatively
charged DNA loops tw ice around positively
DNA double- helix charged histone octamer to form nucleosome
“ beads on a string.” Histones are rich in the
amino acids lysine and arginine. HI binds to
HI histone
(linker) the nucleosome and to “ linker DNA,” thereby
DNA stabilizing the chromatin fiber.
In mitosis, DNA condenses to form
chromosomes. DNA and histone synthesis
ELK:h omatir Supercoiled occur during S phase.
Nucleosome
(H2 A, H2B, structure
H3, H4) X 2 Heterochromatin

Revised
Figure eta phase
chromosome

Heterochromatin_ Condensed, appears darker on EM (labeled H HeteroChromatin = Highly Condensed.

in gj Transcriptionally inactive, stericallv Barr bodies (inactive X chromosomes) are
inaccessible t methvlation, 1 acetylation!
, heterochromatin.

Euchromatin Less condensed, appears lighter on EM ( labeled Eu = true, “ truly transcribed.”

DNA methylation
Histone methylation
Histone acetylation
E in Hi Transcriptionally active, stericallv Euchromatin is Expressed.
accessible.
Template strand cytosine and adenine are
methylated in DNA replication, which allows
mismatch repair enzymes to distinguish
between old and new strands in prokaryotes.
DNA methylation at CpG islands represses CpG Methylation Makes DNA Mute.
transcription.
Usually reversibly represses DNA transcription, Histone Methylation Mostly Makes DNA Mute.
but can activate it in some cases depending on
methylation location.
Relaxes DNA coiling, allowing for transcription. Histone Acetylation makes DNA Active.

DNA methylation
Histone methylation
Histone acetylation
Transcriptionally active, sterically accessible. Euchromatin is Expressed.
Template strand cytosine and adenine are
methylated in DNA replication, which allows
mismatch repair enzymes to distinguish
between old and new strands in prokaryotes.
DNA methylation at CpG islands represses CpG Methylation Makes DNA Mute.
transcription.
Usually reversibly represses DNA transcription, Histone Methylation Mostly Makes DNA Mute.
but can activate it in some cases depending on
methylation location.
Relaxes DNA coiling, allowing for transcription. Histone Acetylation makes DNA Active.

BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR [i

Nucleotides NucIcoSidc = base + ( dcoxylribose ( Sugar ).

NucleoTide = base + (deoxy )ribose + phosphaTe; s' end of incoming nucleotide bears the
linked by V-V phosphodiester bond. triphosphate ( energy source for the bond ).
Triphosphate bond is target of the V hydroxyl
attack ]
.
PURines (A G) — 2 rings. IT Rc As Gold.
PYrimidines (C,U,T)-1 ring. CUT the PY (pie).
I Thymine has a methyl.
Deamination of cytosine makes uracil. G-C bond ( t H bonds) stronger than A-T bond
Deamination of adenine makes guanine. ( 2 11 bonds; "G - C bonds arc like Graze Glue ” ),
Uracil found m KNA ; thvminc in DNA .
Methylation of uracil makes tliviuinc ]
t G-C content
DNA.
— t melting temperature of

.
Purine (A C) .
Pyrimidine (C U, T)

CO,
—
GAG Amino acids necessary for purine
Carbamoyl / - Aspartate synthesis:
Aspartate Glycine phosphate » -A / Glvcine
\‘ c
C ^N10 -Formyl -
N
c
c Aspartate
Glutamine
tetrahydrofolate C c
\N
/ N N
N10 -Formvt - ..\
Genetic code features
Unambiguous Each codon specifies only 1 amino acid.
Degenerate/ Most amino acids are coded by multiple codons. Exceptions: methionine and try ptophan encoded
redundant by only 1 codon (AUG and UGG, respectively).
Commaless, Read from a fixed starting point as a continuous Exceptions: some viruses.
nonoverlapping sequence of bases.
Universal Genetic code is conserved throughout Exception in humans: mitochondria .
evolution .
Wobble Accurate base pairing is usually required only in Codons that differ in srd , "wobble” position may
first 2 nucleotide positions of mRNA codon . code for same tRN.Vamino acid .
 BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR SECTION II 35

DNA replication Eukaryotic DNA replication is more complex than the prokaryotic process but uses many
enzymes analogous to those listed below. In both prokaryotes and eukary otes, DNA replication is
semiconservative and involves both continuous and discontinuous ( Okazaki fragment ) synthesis,

Prigin of
and occurs in the V —
V direction!
Particular consensus sequence of base pairs Al’-rich sequences ( such as '1 VIA box regions!
)
replication Q _ in genome where DNA replication begins. are found in promoters and origins of
May be single ( prokaryotes) or multiple replication.
(eukaryotes).
Peplication forkQ Y-shaped region along DNA template where
leading and lagging strands are synthesized.
pielicaseQ Unwinds DNA template at replication fork.
pingle- stranded Prevent strands from reannealing.
binding proteinsjjj
pNA Create a single- or double-stranded break in the Irinotecan /lopotecan inhibits eukaryotic
topoisomerases J helix to add or remove supercoils. topoisomerase 1.
Etoposide/teniposidc inhibit eukaryotic
topoisomerase II.
Fluoroquinolones inhibit prokaryotic topoisomerase
11 ( DNAgvrase ) and topoisomerase IV|
PrimaseJQ Makes an RNA primer on which DNA
polymerase III can initiate replication.

pNAJpolymerase llljgj Prokary otic only. Elongates leading strand
by adding dcoxynuclcotidcs to the V end.
Elongates lagging strand until it reaches
primer of preceding fragment. V -* 5'
exonuclease activity “ proofreads" each added
nucleotide.
Prokary otic only. Degrades RNA primer;
PNA polymerase IJJJ
replaces it w ith DNA.
PNA ligasej] Catalyzes the formation of a phosphodiestcr
bond within a strand of double-stranded DNAj
Telomerase F.ukarvotes only An RNA -dependent DNA
polymerase that adds DNA to V ends of
chromosomes to avoid loss of genetic material
with every duplication.!
— —
DNA polymerase 111 has 5' V synthesis and
proofreads with V 5' exonuclease. _
Drugs blocking DNA replication otten base
modified V OH, pres enting addition of the next
nucleotide ("chain termination" ).
Sam functions as DNA polymerase lll;!ilso
^
excises RNA primer w ith 5' -» V cxonucleasc.
loins Okazaki fragments.
Often dysregulated in cancer cells, allowing
unlimited replication.

,QTopoisomerase DNA polymerase III 5’

u Ongmof replication
Helicase

^
Leading strand

Replication fork Lagging strand 5

Okazaki fragment
Id
Area o( interest Single - stranded RNA primer
Origin of replication binding protein
Leading strand Lagging strand
a ( u
DNA tigase Revise
Fa Primase
i ovvnM
V
A polymerase III
Lagging strand Leading strand III
DNA polymerase I
0
 BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR

DNA repair
Single strand
Nucleotide excision Specific endonucleases release the Defective in xeroderma pigmentosum, which
repair oligonucleotides containing damaged bases; prevents repair of pyrimidine dimers because
DNA polymerase and ligase fill and reseat the of ultraviolet light exposure.
gap, respectively. Repairs bulky helix-distorting
lesions. Occurs in G( phase of cell cycle.
Base excision repair Base-specific Glvcosylasdremoves altered base Important in repair of spontaneous/toxic
and creates AP site (apurinic/apyrirnidinic). deamination.^
One or more nucleotides are removed bv .
“ GEL PLease’’= (Glvcosvlase Endonuclease,
AP-Endonucleas which cleaves the 5' end. Lvase, Polymerase b. Ligase)
^
Lyase cleaves the V end. DNAIj)lymerase-P
fills the gap and DNA jjjgasc seals it. Occurs
throughout cell cycle.
Mismatch repair Newly synthesized strand is recognized, Defective in Lynch syndrome (hereditary
mismatched nucleotides are removed, nonpolyposis colorectal cancer [HNPCC]).
and the gap is filled and rescaled. Occurs
predominantly in G-, phase of cell cycle.
Double strand
Nonhomologous end Brings together 2 ends of DNA fragments to Mutated in ataxia telangiectasia and breast /
joining repair double-stranded breaks. No requirement .
ovarian cancers with BRC AI mutation;
for homologv. Some DNA mav be lost. Fanconi anemia]

DNA /RNA / protein

synthesis direction
DNA and RNA arc both synthesized 5' V.
—
The 5' end of the incoming nucleotide bears
mRNA is read 5' to V.
The triphosphate bond is the target of the
the triphosphate (energy source for bond ). V hydroxyl attack . Drugs blocking DNA
Protein synthesis is N-terminus to C-terminus. replication often have modified V OH,
preventing addition of the next nucleotide
(“chain termination").

Start and stop codons

mRNA start codons AUG ( or rarely GUG). At 1C inAUGurates protein synthesis.
Eukaryotes Codes for methionine, which may be removed
before translation is completed.
Prokaryotes Codes for N-formylmethionine ( fMet). fMet stimulates neutrophil chemotaxis.
mRNA stop codons UGA, UAA, UAG. UGA = U Go Away.
UAA = lT Are Away .
UAG = U Are Gone .
UJ 8 SECTION II BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR

Functional
organization of a
eukaryotic gene CAAT box
Transcription start
(mRNA synthesized 5'

TATA box
— 30
ATG = Start codon
Polyadenylation
signal
- 1 i—— "
i I I
iRevised
Coding strand 5' CAAT TATAAT Exonl GT AG Exon 2 GT AG Exon 3 AATAAA }y Figure
i i
I
Promoter 5' UTR Intron 1 Intron 2 3' UTR

Regulation of gene expression

Promoter Site where RNA polymerase II and multiple
other transcription factors bind to DNA
upstream from gene locus ( AT-rich upstream
sequence with TATA and CAAT boxes).
Enhancer Stretch of DNA that alters gene expression by
binding transcription factors ( eg activator
protcinsi
Silencer Site where negative regulators ( repressors) bind.
Promoter mutation commonly results in
dramatic 1 in level of gene transcription.
Enhancers and silencers may be located close to,
. far from, or even within (in an intron) the gene
whose expression it regulates.

RNA polymerases
Eukaryotes RNA polymerase I makes rRNA imost I, II, and III are numbered in the same order
numerous RNA, rampant). that their products are used in protein
RNA polymerase II makes mRNA ( largest RNA, sy nthesis: rRNA, mRNA, then tRN.U

.
massive) mRNA is read 5' to V. a-amanitin, found in Amanita phalloides (death
RNA polymerase III makes sS rRNA, tRNA cap mushrooms ), inhibits RNA polymerase II.
(smallest RNA, tiny). Causes severe hepatotoxicity if ingested.
No proofreading function, but can initiate J\ctinomycin D inhibits RNA polymerase in
chains. RNA polymerase 11 opens DNA at both prokary otes and eukaryotes.
promoter site.
Prokaryotes 1 RNA polymerase (multisubunit complex) Rifampin inhibits RNA polvmerase in
makes all s kinds of RNA. prokaryotes.
40 SECTION II BIOCHEMISTRY BIOCHEMISTRY — MOLECULAR

tRNA
Structure 75-90 nucleotides, 2° structure, doverleaf form, anticodon end is opposite 5' aniinoacy! end. All
tRNAs, both eukaryotic and prokaryotic, have CCA at 5' end along with a high percentage of
chemically modified bases. The amino acid is covalently bound to the 5' end of the tRNA. CCA
Can Carry Amino acids.
T-arm: contains the TH'C (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-
ribosome binding. T-ann Tethers tRNA molecule to ribosointj
D-arm: contains diliydrouridine residues necessary for tRNA recognition by the correct aminoacyT-
tRNA synthetase. D-arm Detects the tRNA bv aminoacvl-tRNA svnthctascj
-
Acceptor stem: the 5 CCA-5' is the amino acid acceptor site.
Charging Aminoacyl-tRNA synthetase ( 1 per amino acid; “matchmaker”; uses ATP) scrutinizes amino acid
before and after it binds to tRNA If incorrect, bond is hydrolyzed. The amino acid-tRNA bond
has energy for formation of peptide bond. A mischarged tRNA reads usual codon but inserts
wrong amino acid.
Aminoacyl-tRNA synthetase and binding of charged tRNA to the codon are responsible for
accuracy of amino acid selection.
Structure Charging Pairing
(aminoacylation) ( codon- anticodon)
Arruno acid Amino acid

r ’”- 0 ,
’
^0

Acceptor stem -
OH -
l: 5
Aminoacyl-tRNA
Ir
* 3

t 5

-
Ti -arm -*- „ D-arm
synthetase
ATP
t IF2
(Initiation factor )
V 0 C 0 > * * *c
. .. .....,
^ii.
/
* •* * r» a

Variable armS o
»
e
’ ii
"
Anticodon
loop
*
" «“"
r

Anticodon 15 CAU 5 I-C* «

'
: :” c
^Wobble
position
, ..u
c cC cC a
mRNA
S’ *•
1
r
Codon
'
(S’ AUG 5 ) Et
Protein synthesis
Initiation .
Initiated by CTP hydrolysis; initiation factors
( eukaryotic IP's ) help assemble the 40S
ribosomal subunit with the initiator tRNA
-
PrOkaryotcs: 10S + 50S » 70S lOdd ).
_
Kukaryotes: 40S + 60S -* 80S ( Even ).

Suithesis occurs troin N - lermimis to

and are released when the mRNA and the C-terminns
ribosomal 60S subunit assemble with the
complex. —
ATP tRNA Activation ( charging).
Elongation 1. Aminoacyl-tRNA binds to A site (except for
—
GTP tRNA Gripping and Going places
(translocation ).
initiator methionine)
2. rRNA ( “ ribozyme") catalyzes peptide bond Think of “ going APE":
formation, transfers growing polypeptide to A site = incoming Aminoacyl-tRNA .
amino acid in A site P site = accommodates growing Peptide.
A Ribosome advances 5 nucleotides toward 5' E site = holds Empty tRNA as it Exits.
end of mRNA, moving peptidvl tRNA to 1'
site (translocation) f < sl
ssr \
Termination Stop codon is recognized by release factor,
and completed polypeptide is released from rO fc U
S' E
P
*
Revised
ribosome.
sV Figure

i ' - - 40S

B
\42 SECTION II BIOCHEMISTRY BIOCHEMISTRY — CELLULAR

BIOCHEMISTRY — CELLULAR

Cell cycle phases Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins,
cyclin-dependent kinases (CDKs), and tumor suppressors. M phase (shortest phase of cell cycle)
includes mitosis ( prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis
,
( cytoplasm splits in two). C| and G( arc of variable duration.

REGULATION OF CEIL CYCLE

Cydin- dependent Constitutive and inactive.
kinasej '
XX
Cyclins Regulator) proteins that control cell cycle H

events; phase specific; activate CDKs. X

Cydin- CDK complexes Phosphorylate other proteins to coordinate
cell cycle progression; must be actu ated and
inactivated at appropriate times for cell cycle
to progress.
XX
Tumor suppressors pot induces p2l, which inhibits CDKs /i
—
hypophosphorylation (activation) of Rb
H inhibition of G,-S progression. Mutations in
tumor suppressor genes resuli in unrestrained vs *'. , .
•

Rb p53 modulate
cell division (eg. Li-Fraumeni syndrome). G restriction point 10

CEUTYPES
Permanent Remain in G0, regenerate from stem cells. Neurons, skeletal and cardiac muscle RBCs. .
Stable (quiescent) Enter G| from Gn when stimulated. Hepatocytes, lymphocytes.
Labile Never go to G(), divide rapidly w ith a short G( . Bone marrow, gut epithelium, skin, hair follicles,
Most affected b\ chemotherapv. germ cells.

Rough endoplasmic Site of synthesis of secretory (exported) proteins Mucus-secreting goblet cells of the small
reticulum and of N-linked oligosaccharide addition to intestine and antibody-secreting plasma cells
many proteins. are rich in RER.
Nissl bodies ( RER in neurons) — synthesize
peptide neurotransmitters for secretion.
Free ribosomes — unattached to any membrane;
site of synthesis of cytosolic and organellar
proteins.

Smooth endoplasmic Site of steroid synthesis and detoxification of Laver hepatocytes and steroid hormone-
reticulum drugs and poisons. Lacks surface ribosomes. producing cells of the adrenal cortex and
gonads are rich in SER.
 BIOCHEMISTRY BIOCHEMISTRY — CELLULAR SECTION II 43

Cell trafficking Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma
membrane. Modifies N-oligosaccharidcs on asparagine. Adds O-oligosaccharides on serine and
threonine. Adds mannose-6-phosphate to proteins for trafficking to lysosomes.
Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to
lysosomes for destruction or back to the membrane/Golgi for further use.
l-cell disease (inclusion cell disease/mucolipidosis type II) — inherited lysosomal storage disorder;
—
defect in N-acetylglucosaminyl-l-phosphotransferase failure of the Golgi to phosphors late
mannose residues ( ic, i mannosc-6-phosphatc) on glycoproteins
—
proteins arc secreted
extraeellularly rather than delivered to lysosomes. Results in coarse facial features, clouded
.
corneas, restricted joint movement, and high plasma levels of lysosomal enzymes Often fatal in
childhood.
Signal recognition particle (SRP)
Abundant, cytosolic ribonucleoprotein that

$ Clathrin ***** y traffics proteins from the ribosome to

the RER. Absent or dysfunctional SRP
-* proteins accumulate in the cytosol.
K> COM
Late
Early
endo 1

Vesicular trafficking proteins

10 COMI
endosome

—
COPI: Golgi Golgi ( retrograde); cis Golgi
—
FR. .
-
—
aiK
COPI1: ER cis-Golgi (anterograde).
1 vo (COP11 ) steps forward ( anterograde); one
Golgi f '(GOPI ) step back ( retrograde ).

—
apparatus
9 Clathrin: trans-Golgi lysosomes; plasma
—
membrane endosomes (receptor-
CIS

Endoplasmic
c:* mediated endoeytosis [eg, LDL receptor
activity]).

reticu inn

Nuclear envelope S

Peroxisome Membrane-enclosed organelle involved in catabolism of vcry-long-chain fattv acids ( through

( - oxidation), branchcd-chain fatty acids, amino acids, and ethanol.
i _
.
Diseases o| the iicroxisoine coiiiiimiiK K - nl to neurologic diseases due I deficits in ssnthesis
"
( .
il plasmalogens, imporlant phospholipids in irnelin. PeroxiMiin il diseases include Zellweger
syndrome i hypotonia, seziures. hepatomegaly, earlv deathi and Refsum disease iscalv skin, ataxia.
cataracts/night blindness, shortening of 4th toe, cpiphvseal dvsplasia ).
 BIOCHEMISTRY BIOCHEMISTRY — CELLULAR !

Cytoskeletal elements A netw ork of protein fibers within the cytopl:asm that supports cell structure, cell and organelle
movement, and cell division.
TYPE OF FILAMENT PREDOMINANT FUNCTION EXAMPLES
Microfilaments Muscle contraction, cytokinesis Actin, microvilli.
Intermediate Maintain cell structure Vimentin, desmin, cytokeratin, larnins, glial
filaments fibrillary acid proteins (GFAP), neurofilaments.
Microtubules Movement, cell division Cilia, flagella, mitotic spindle, axonal trafficking,
centrioles.

Immunohistochemical stains for intermediate filaments

STAIN CELL TYPE IDENTIFIES
ViMEntinj MEsenchvmal tissue leg. fibroblasts. MEsenchvmal tumors leg. sarcoma), but
endothelial cells, macrophages! also manv other tumors (eg. cndoMEtrial
carcinoma, renal cell carcinoma.
MEningiomai
DesMin Muscle Muscle tumors (eg, rhabdomyosarcoma)
Cytokeratin Epithelial cells Epithelial tumors (eg, squamous cell carcinoma )
GFAP NeuroGlia ( eg, astrocytes, Schw ann cells, Astrocytoma, glioblastoma
oligodendroglia)
Neurofilaments Neurons Neuronal tumors (eg, neuroblastoma)

Microtubule Cylindrical outer structure composed of a Drugs that act on microtubules ( Microtubules
Positive
helical array of polymerized heterodimers Get Constructed Yerv Poorly ):
end (+) of a- and [J- tubulin. Each dimer has 2 GTP Mebendazole (antihclminthic)
Heterodimer bound. Incorporated into flagella, cilia, mitotic Griscofulvin (antifungal)
spindles. Grows slowly, collapses quickly . Colchicine (antigout)
Also involved in slow axoplasmic transport in
neurons. _
VincristineA'inblastine (anticancer )
Paclitaxel (anticancer )
Molecular motor proteins — transport cellular
Protofilament cargo toward opposite ends of microtubule Negative end Near Nucleus
tracks. Positive end Points to Periphery
Negative Dynein— retrograde to microtubule (+ -* — ).
end H
—
Kinesin — anterograde to microtubule ( •+).
 BIOCHEMISTRY BIOCHEMISTRY — CELLULAR SECTION II 45

Cilia structure 9 doublet + 2 singlet arrangement ol
microtubules farrows in Q).
P Basal bods ( base of cilium below cell
membrane) consists of 9 microtubule triplets
( arrow in Ehvitli no central niieroliihulei
Axonemal dynein — ATPase that links peripheral
9 doublets and causes bending of cilium by
differential sliding of doublets.
Kartagener syndrome (1° ciliary dyskinesia) —
immotile cilia due to a dynein arm defect.
Results in 1 male and female fertility due tet
immotile sperm and dysfunctional fallopian
lube cilia, respectively; t risk of ectopic
pregnancy. Can cause bronchiectasis,
recurrent sinusitis, chronic ear infections,
conductive hearing loss, and situs inversus ( eg,
dextrocardia on CXRll

Sodium-potassium Xa+-K+ ATPase is located in the plasma Pl MPKIM - PI IMP K2 IN '

pump membrane with ATP site on cytosolic side. Ouabain inhibits by binding to K+ site.
For each ATP consumed, sNV go out of the Cardiac glycosides ( digoxin and digitoxin )
cell ( pump phosphorylatcd ) and 2K* come into directly inhibit the Na -K+ ATPase, which *

the cell (pump dephosphorylated ). _ leads to indirect inhibition of Na+/Ca’+

Plasma membrane is an asymmetric linid
bilaver containing cholesterol, phospholipids.
—
exchange t [Ca’*]j -* t cardiac contractility.

sphingolipids, glvcolipids, and proteins.

Extracellular
3Na+ /*
space •2K*
V*nf
(
A V1 !
Membrane
j. i
* e) A

I I ) •{Vjtf '- fs
• cr« ,
i
' P
Cytosol
5Na+ ATP ADP P
2K*\
a
 BIOCHEMISTRY BIOCHEMISTRY — CELLULAR SECTION II 47

Osteogenesis Genetic bone disorder ( brittle bone May be confused with child abuse.
imperfecta disease) caused by a variety of gene defects
(most commonly COLlAl and COL1 A2 ).
Most common form is autosomal dominant Patients can t BIT’I.
with t production of otherwise normal type I B ( BONES = multiple fractures )
collagen. Manifestations can include: I ( LVL - blue sclerae)
Multiple fractures with minimal I ( TFhTH = dental imperfections!
trauma Q Q; may occur during the birth I ( PAR - hearing loss)
process
Blue sclerae Q due to the translucent
connective tissue over choroidal veins
(Some forms have tooth abnormalities,
including opalescent teeth that wear easily
due to lack of dentin ( dentinogenesis
imperfecta) _
Hearing loss ( abnormal ossicles|
P

Upper
extremity

Ehiers-Danlos Fault)’ collagen synthesis causing
syndrome hyperextensiblc skin, tendency to bleed ( easy
bruising), and hvpermobile joints Q.
Multiple tvpes. Inheritance and severity vary.
Can be autosomal dominant or recessive. May
be associated with joint dislocation, berry and
aortic aneurysms, organ rupture.
Hypermobility tvpc ( joint instability): most
common type.
Classical type ( joint and skin symptoms): caused
by a mutation (eg, COL5AI , COLSAZjin type
V collagen.
Vascular type (vascular and organ rupture l:
deficient type III collagen.

Menkes disease X-linked recessive connective tissue disease caused by impaired copper absorption and transport
due to defective Menkes protein (ATP7A). Leads to i activity oflysyl oxidase ( copper is a
necessary cofactor). Results in brittle, ‘kinky" hair, growth retardation, and hypotonia.
50 SECTION II BIOCHEMISTRY BIOCHEMISTRY — LABORATORY TECHNIQUES

Flow cytometry Laboratory technique to assess size, granularity, Commonly used in workup of hematologic
and protein expression ( immunophenotype ) of abnormalities (eg, paroxysmal nocturnal
individual cells in a sample. hemoglobinuria , fetal RBCs in mother’s blood )
and immunodeficiencies ( eg, CD4 cell count
in HIV ).
Cells arc tagged with antibodies specific to Fluorescent
label
surface or intracellular proteins. Antibodies
Antibody

y w>*
are then tagged with a unique fluorescent
dye. Sample is analyzed one cell at a time by
Anb -CD3 Ab 'J Cell
focusing a laser on the cell and measuring
light scatter and intensity of fluorescence.
Anti -CD8 Ab /1 LT :CI
Huorescence
is detected . Laser makes
labeled cells re¬ label fluoresce
are counted z1

Data are plotted either as histogram (one 10*

measure) or scatter plot (any two measures, as
shown ). In illustration: 10 s
• Cells in left lower quadrant © for both CDS
and CD3.
©
8 102
life
n
Cells in right lower quadrant © for CDS and
© for CDllt Right lower quadrant is empty to1
because all CDS-expressing cells also express ©
CDx i 10 “ 10 10!
• Cells in left upper quadrant ® for CDs and ” 10! ”
10
CM
10*

0 for CPtt © © 63

Microarrays
—
• Cells in right upper quadrant © for CD8
and CDs ( red + blue purple).

Thousands of nucleic acid sequences are arranged in grids on glass or silicon . DNA or RNA probes
are hybridized to the chip, and a scanner detects the relative amounts of complementary binding.
Used to profile gene expression levels of thousands of genes simultaneously to study certain diseases
and treatments. Able to detect single nucleotide polymorphisms (SNPs) and copy number
variations (CNVs) for a variety of applications including genotyping, clinical genetic testing,
forensic analysis, cancer mutations, and genetic linkage analysis.
 BIOCHEMISTRY BIOCHEMISTRY — LABORATORY TECHNIQUES SECTION II 51
-
Note that line art for Enzyme linked immunosorbent assay was deleted and text
rewritten in 8th pass pages for 2016 edition. Please clarify needed changes.

Enzyme -linked
immunosorbent assay
Immunologic test used to detect the presence of either a specific antigen (eg. HBsAg ) or antibody
(eg, anti- HBs) in a patient s blood sample. Detection involves the use of an antibody linked to an
enzyme. Added substrate reacts with cnzvtnc, producing a detectable signal ( eg, color change ).
Major ELISA variations include direct , sandwich , and competitive. Can have high sensitivity and
specificity.

Karyotyping A process in which metaphase chromosomes arc stained , ordered, and numbcrcdJQ according to
morphology, size, arm-length ratio, and banding pattern. Can be performed on a sample of blood ,
bone marrow, amniotic fluid , or placental tissue. Used to diagnose chromosomal imbalances (eg,
autosomal tTisomies, sex chromosome disorders).

Al 19

Fluorescence in situ Fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes (arrows in
hybridization point to abnormalities! )
.. Used for specific localization of genes and direct visualization of chromosomal anomalies at the
IQ molecular level.
\ lu lodclctiiin l i e i : n i n .
on the second copy of that chromosome
a hi
i i t I to .. . -
al the same 1 ir¬

- —
—
Translocation fluorescence outside the original chromosome
Duplication — extra site of fluorescence on one » hromosomc relative I " its lionn ilogous
chromosome

Cloning methods
Cloning is the production of a recombinant DNA molecule that is self- perpetuating.
Steps:
1. Isolate eukaryotic mRNA ( post-RNA processing stepsi of interest.
2. Expose mRNA to reverse transcriptase to produce cDNA ( lacks introns).
v Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes.
4. Transform recombinant plasmid into bacteria.
5. Survis ing bacteria on antibiotic medium produce cloned DNA (copies of cDNA).
’
 BIOCHEMISTRY BIOCHEMISTRY — GENETICS 'i ,

Genetic terms (continued )

TERM DEFINITION EXAMPLE
Mosaicism Presence of genetically distinct cell lines in the McCune- Albright syndrome — due to mutation
same individual. affecting G-protcin signaling. Presents with
Somatic mosaicism— mutation arises from unilateral cafc-au-lait spots with ragged
mitotic errors after fertilization and propagates edges, polyostotic fibrous dysplasia, at least
through multiple tissues or organs. one endocrinopathv (eg. precocious pubertvi
Gonadal mosaicism — mutation onlv in egg or Lethal if mutation occurs before fertilization
sperm cells. If parents and relatives do not (affecting all cells), but survivablc in patients
have the disease, suspect gonadal (or germline ) with mosaicism.
mosaicisni
Locus heterogeneity Mutations at different loci can produce a similar Albinism.
phenotype.
Allelic heterogeneity Different mutations in the same locus ff-thalassemia.
produce the same phenotype.
Heteroplasmy Presence of both normal and mutated
mlDNA, resulting in variable expression in
mitochondrially inherited disease.
Uniparental disomy Offspring receives 2 copies of a chromosome from Uniparental is el ploid ( correct number of
1 parent and no copies from the other parent. chromosomes ), not aneuploid. Most occurrences
1 Ictcrodlsomv (heterozygous) indicates a meiosis
1 error. Isodlsomv (homozygous) indicates a
—
of UPD normal phenotype. Consider UPD
in an individual manifesting a recessive disorder
meiosis II errodor postzygotic chromosomal when only one parent is a carrier.
duplication of one of a pair of chromosomes,
and loss of the other of the original pair.

Hardy-Weinberg If a population is in Hardy-Weinberg Hardy-Weinberg law assumptions include:

population genetics equilibrium and if p and q arc the frequencies • No mutation occurring at the locus
pA qa of separate alleles, then: p" + 2pq + q‘
= 1 and • Natural selection is not occurring
p + q = 1, which implies that: Completely random mating
AA Aa p- = frequency of homozygosity for allele No net migration
pA
P * P =P ' pxq
q- = frequency of homozygosity for allele j ^
Aa aa 2pq = frequency of heterozygosity (carrier
qa
pxq qxq = q> frequency, if an autosomal recessive disease ).
Tlw * frpnupnrv of an YJSnl'prl wrf»«sivp rlunacp
Variable expressivity Patients with the same genotype have varying
phenotypei
Incomplete Not all individuals with a mutant genotype
penetrance show the mutant phenotype.
Pleiotropy One gene contributes to multiple phenotypic
effects.
Anticipation Increased severity or earlier onset of disease in
succeeding generations.
Loss of heterozygosity If a patient inherits or develops a mutation in
a tumor suppressor gene, the complementary
allele must be delctcd /mutated before cancer
develops. This is not true of oncogenes.
Dominant negative Exerts a dominant effect. A heterozvgote
mutation produces a nonfunctional altered protein that
also prevents the normal gene product from
functioning.
Linkage Tendency for certain alleles at 2 linked
disequilibrium loci to occur together more or less often
than expected by chance . Measured in a
population, not in a family, and often varies in
different populations.
2 patients with neurofibromatosis type 1 ( NF1)
may have varying disease severity.
BRCAl gene mutations do not always result in
breast or ovarian cancer.
Untreated phenylketonuria ( PKU ) manifests with
light skin, intellectual disability, and musty hods
odor.
Trinucleotide repeat diseases ( eg, Huntington
disease).
Retinoblastoma and the “ two-hit hypothesis,”
Lynch syndrome ( HNPCC), Li-Fraumeni
syndrome.
Mutation of a transcription factor in its allosteric
site. Nonfunctioning mutant can still bind
DNA, preventing wild-type transcription factor
from binding.
 BIOCHEMISTRY BIOCHEMISTRY — GENETICS 'i ,

Genetic terms (continued )

TERM DEFINITION EXAMPLE
Mosaicism Presence of genetically distinct cell lines in the McCune- Albright syndrome — due to mutation
same individual. affecting G-protcin signaling. Presents with
Somatic mosaicism— mutation arises from unilateral cafc-au-lait spots with ragged
mitotic errors after fertilization and propagates edges, polyostotic fibrous dysplasia, at least
through multiple tissues or organs. one endocrinopathv (eg. precocious pubertvi
Gonadal mosaicism — mutation onlv in egg or Lethal if mutation occurs before fertilization
sperm cells. If parents and relatives do not (affecting all cells), but survivablc in patients
have the disease, suspect gonadal (or germline ) with mosaicism.
mosaicisni
Locus heterogeneity Mutations at different loci can produce a similar Albinism.
phenotype.
Allelic heterogeneity Different mutations in the same locus ff-thalassemia.
produce the same phenotype.
Heteroplasmy Presence of both normal and mutated
mlDNA, resulting in variable expression in
mitochondrially inherited disease.
Uniparental disomy Offspring receives 2 copies of a chromosome from Uniparental is el ploid ( correct number of
1 parent and no copies from the other parent. chromosomes ), not aneuploid. Most occurrences
1 Ictcrodlsomv (heterozygous) indicates a meiosis
1 error. Isodlsomv (homozygous) indicates a
—
of UPD normal phenotype. Consider UPD
in an individual manifesting a recessive disorder
meiosis II errodor postzygotic chromosomal when only one parent is a carrier.
duplication of one of a pair of chromosomes,
and loss of the other of the original pair.

Hardy-Weinberg If a population is in Hardy-Weinberg Hardy-Weinberg law assumptions include:

population genetics equilibrium and if p and q arc the frequencies • No mutation occurring at the locus
pA qa of separate alleles, then: p" + 2pq + q‘
= 1 and • Natural selection is not occurring
p + q = 1, which implies that: Completely random mating
AA Aa p- = frequency of homozygosity for allele No net migration
pA
P * P =P ' pxq
q- = frequency of homozygosity for allele j ^
Aa aa 2pq = frequency of heterozygosity (carrier
qa
pxq qxq = q> frequency, if an autosomal recessive disease ).
Tlw * frpnupnrv of an YJSnl'prl wrf»«sivp rlunacp
56 SECTION II BIOCHEMISTRY BIOCHEMISTRY — GENETICS

Autosomal dominant Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,
diseases familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, hcrcditjrv spherocytosis,
Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias,
neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2, luberous
sclerosis, von I lippel-Lindan disease.
Hereditary Inherited disorder ofblood vessels. Findings: blanchingskin lesions ( telangiectasias), recurrent
hemorrhagic epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also
telangiectasia known as Osler-VVeber-Rendu syndrome.
Li- Fraumeni
syndrome
—
Abnormalities in f P53 ichromosome 17 ) multiple malignancies at an early age. Also known as
SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).
Marfan syndrome
—
FBN1 gene mutation on chromosome 15 defective fibrillin (scaffold for elastin) connective —
tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus
carinatum I more specific ) or pectus excavatunj hvpermobile joints, and long, tapering fingers and
—
toes (arachnodactyly); cystic medial necrosis of aorta aortic incompetence and dissecting aortic
aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally.
Neurofibromatosis Neurocutaneous disorder characterized by cafe-au-lait spots, cutaneous neurofibromas, optic
type 1 (von gliomas, pheochromocytomas, Lisch nodules ( pigmented iris hamartomas). 100% penetrance,
Recklinghausen variable expression. Caused by mutations in the NFI gene on chromosome 17; 17 letters in "von
disease) Recklinghausen.”
Neurofibromatosis Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas.
type 2 NF2 gene on chromosome 22; type 2 = 22.

Autosomal recessive Albinism, autosomal recessive polycystic kidney disease ( ARPKD), cvstic fibrosis, glycogen
diseases storage diseases, hemochromatosis, Kartagcncr syndrome, mucopolysaccharidoses (except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoscs (except Fabry disease!,
thalassemias, Wilson disease.

inheritance offspring of affected females may show signs of within a family due to heteroplasmy.
disease.
»1-0 Mitochondrial myopathies — rare disorders;
often present with myopathy, lactic acidosis,

Or# LTO and CNS disease, eg, MELAS syndrome

(mitochondrial encephalopathy, lactic
acidosis, and stroke-like episodes ). 2° to
i# (Soh failure in oxidative phosphorylation. Muscle
bio [) s \ otten shows "ragged red fiheis" ( due to
accumulations of diseased mitochondria! )

= unaffected male;H = affected male; O = unaffected female; # - affected female.

66 SECTION II BIOCHEMISTRY BIOCHEMISTRY — GENETICS

Autosomal dominant Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,
diseases familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, hcrcditjrv spherocytosis,
Huntington disease, Li-Fraumcni syndrome, Marfan syndrome, multiple endocrine neoplasias,
neurofibromatosis type 1 (von Recklinghausen disease ), neurofibromatosis type 2, luberous
sclerosis, von Hippel-Lindau disease.
Hereditary
hemorrhagic ^
Inherited disorder of blood vessels. Findings: blanehin skin lesions ( telangieetasias), recurrent
epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also
telangiectasia known as Osler-VVeber-Rendu syndrome.
Li- Fraumeni
syndrome
—
Abnormalities in TP53 ichromosome 17 ) multiple malignancies at an early age. Also known as
SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).
Marfan syndrome
— —
FBN1 gene mutation on chromosome 15 defective fibrillin (scaffold for elastin) connective
tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus
carinatum imore specific ) or pectus exeavatunj hvpermobile joints, and long, tapering fingers and
—
toes (arachnodactvly); cystic medial necrosis of aorta aortic incompetence and dissecting aortic
aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally.
Neurofibromatosis Neurocutaneous disorder characterized by cafe-au-lait spots, cutaneous neurofibromas, optic
type 1 (von gliomas, pheochromocytomas, Lisch nodules ( pigmented iris hamartomas). 100% penetrance,
Recklinghausen variable expression. Caused by mutations in the IVF1 gene on chromosome 17; 17 letters in "von
disease) Recklinghausen.”
Neurofibromatosis Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas.
type 2 NF2 gene on chromosome 22; type 2 = 22.

Autosomal recessive Albinism, autosomal recessive polycystic kidnev disease (ARPKD), cvstic fibrosis, glycogen
diseases storage diseases, hemochromatosis, Kartagcncr syndrome, mucopolysaccharidoses ( except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoscs ( except Fabry disease),
thalassemias, Wilson disease.
$8 SECTION II BIOCHEMISTRY BIOCHEMISTRY — GENETICS

Muscular dystrophies
Duchenne
.*
S' #? - M HWI

V4Wk•
-
——
X linkcd disorder typically due to framcshift
or nonsense mutations truncated or
absent dystrophin proteirt progressive
mvofiber damagrj Weakness begins in pelvic
girdle muscles and progresses superiorly.
-
Duchenne = deleted dystrophin .

—
Dystrophin gene ( DJWD) is the largest
protein-coding human gene t chance of
spontaneous mutation. Dystrophin helps
anchor muscle fibers, primarily in skeletal and
Pscudohypertrophy of calf muscles due to cardiac muscle. It connects the intracellular
, 1
T
•
•V fibrofattv replacement of muscle Q. Gower
—
maneuver patients use upper extremities
to help them stand up. Waddling gait. Onset
cvtoskeleton (actin) to the transmembranc
-
proteins a- and P dystroglycan, which are
connected to the extracellular matrix ( ECM ).
before 5 years of age. Dilated cardiomyopathy Loss of dystrophin results in myonecrosis ,

is common cause of death. t CK and aldolase are seen ; Western blot and
muscle biopsy confirm diagnosis.
Becker X-linked disorder typically due to non - Deletions can cause both Duchenne and
frameshift insertions in dystrophin gene Becker.
( partially functional instead of truncated ). Less
severe than Duchenne. Onset in adolescence
or early adulthood.
Myotonic type 1 Autosomal dominant. CTG trinucleotide repeat My Tonia, My Testicles (testicular atrophy ),
expansion in the DMPK gene -» abnormal My Toupee (frontal balding), My Ticker

—
expression of myotonin protein kinase
myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia.
(arrhythmia).

Fragile X syndrome

— —
X-linked dominant inheritance. Trinucleotide
repeat in FAIR 1 gene mcthylation
1 expression. Most common cause of
inherited intellectual disability and autism
and 2 nd most common cause of genetically
Trinucleotide repeat disorder (CGG) n.
Fragile X = eXtra large testes, jaw, ears.

associated mental deficiency ( after Down

syndrome!Findings: -
post pubertal
 COMPLICATIONS

—
Recurrent pulmonary infections ( eg, i aureus [ early infancy), t' aeruginosa i adolescence] ), chronic
bronchitis and bronchiectasis reticulonodular pattern on CXR, opacification of sinusei
Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D E,
K ), biliary cirrhosis, liver disease. Meconium ileus in newborns.
Infertility in men (absence of vas deferens, spermatogenesis may be unaffected ) and subfertility in
.

women (amenorrhea, abnormally thick cervical mucus ).

Nasal polyps, clubbing of nails.
TREATMENT Multifactorial: chest physiotherapy, albuterol , aerosolized dornase alfa ( DNAse), and hypertonic
saline facilitate mucus clearance. Azithromycin used as anti-inflammaton agent . Ibnprofen slow s
disease progressing Pancreatic enzymes for insufficiency.

X-linked recessive Ornithine transcarbamyla.se deficiency, Fabry Oblivious Female \\ ill Often Give I ler Boys
disorders disease, Wiskott-Aldrich syndrome, Ocular 1 ler x-Linked Disorders
albinism, G6PD deficiency, Hunter syndrome,
.
Bruton agammaglobulinemia Hemophilia
A and B, Lcsch - Nyhan syndrome, Duchcnnc
(and Becker) muscular dystrophy.
—
Lyonization female carriers variabK affected
depending on the percentage inactivation of
the X chromosome earn ing the mutant vs
normal gentj
$8 SECTION II BIOCHEMISTRY BIOCHEMISTRY — GENETICS

Muscular dystrophies
Duchenne
.*
S' #? - M HWI

V4Wk•
-
——
X linkcd disorder typically due to framcshift
or nonsense mutations truncated or
absent dystrophin proteirt progressive
mvofiber damagrj Weakness begins in pelvic
girdle muscles and progresses superiorly.
-
Duchenne = deleted dystrophin .

—
Dystrophin gene ( DJWD) is the largest
protein-coding human gene t chance of
spontaneous mutation. Dystrophin helps
anchor muscle fibers, primarily in skeletal and
Pscudohypertrophy of calf muscles due to cardiac muscle. It connects the intracellular
, 1
T
•
•V fibrofattv replacement of muscle Q. Gower
—
maneuver patients use upper extremities
to help them stand up. Waddling gait. Onset
cvtoskeleton (actin) to the transmembranc
-
proteins a- and P dystroglycan, which are
connected to the extracellular matrix ( ECM ).
before 5 years of age. Dilated cardiomyopathy Loss of dystrophin results in myonecrosis ,

is common cause of death. t CK and aldolase are seen ; Western blot and
muscle biopsy confirm diagnosis.
Becker X-linked disorder typically due to non - Deletions can cause both Duchenne and
frameshift insertions in dystrophin gene Becker.
( partially functional instead of truncated ). Less
severe than Duchenne. Onset in adolescence
or early adulthood.
Myotonic type 1 Autosomal dominant. CTG trinucleotide repeat My Tonia, My Testicles (testicular atrophy ),
expansion in the DMPK gene -» abnormal My Toupee (frontal balding), My Ticker

—
expression of myotonin protein kinase
myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia.
(arrhythmia).

Fragile X syndrome

— —
X-linked dominant inheritance. Trinucleotide
repeat in FAIR 1 gene mcthylation
1 expression. Most common cause of
inherited intellectual disability and autism
and 2 nd most common cause of genetically
Trinucleotide repeat disorder (CGG) n.
Fragile X = eXtra large testes, jaw, ears.

associated mental deficiency ( after Down

syndrome!Findings: -
post pubertal
T
Duchenne

*
. M ifrcte fiber
.
J ——
X-linkcd disorder typically due to frameshift
or nonsense mutations truncated nr
absent dystrophin protend progressise
invofiber damagtj Weakness begins in pelvic
girdle muscles and progresses superiorly.
Duchenne = deleted dystrophin .
Dystrophin gene ( DMD) is the largest
protein-coding human gene -* t chance of
spontaneous mutation . Dystrophin helps
anchor muscle fibers, primarily in skeletal and
Pseudohypertrophy of calf muscles due to cardiac muscle. It connects the intracellular
fibrofattv replacement of muscle Q. Gower cytoskeleton (actin ) to the transmembrane
—
maneuver patients use upper extremities
to help them stand up. W addling gait. Onset
proteins a- and JJ-dystroglycan , which are
connected to the extracellular matrix (ECM ).
before S years of age. Dilated cardiomyopathy Loss ofdvstrophin results in nrvonecrosis.
is common cause of death . t CK and aldolase are seen; W'estcrn blot and
muscle biopsy confirm diagnosis.
Becker X-litrked disorder typically due to non - Deletions can cause both Duchenne and
frameshift insertions in dystrophin gene Becker.
( partialh functional instead of truncated ). Less
'

scs'crc than Duchenne. Onset in adolescence

or early adulthood .
Myotonic type 1
expansion in the DMPK gene abnormal
expression ofmyotonin protein kinase
-• myotonia, muscle wasting, cataracts,
—
Autosomal dominant. CTG trinucleotide repeat My Ponia. My Testicles ( testicular atrophy),

testicular atrophy, frontal balding, arrhythmia .

My Toupee ( frontal balding ), My Ticker
(arrhythmia ).

Fragile X syndrome

— —
X-linked dominant inheritance. Trinucleotide
repeat in FAJR1 gene methvlation
1 expression . Most common cause of
inherited intellectual disability' and autism
aird 2 nd most common cause of genetically
Trinucleotide repeat disorder (CGG ) n.
Fragile \ = cXtra large testes, jasv, cars.

associated mental deficiency ( after Down

svndromcl -
Findings; post pubcrtal
macroorchidism icnlarged testes ), long face
rvith a large jaw, large everted ears, autism ,
mitral valve prolapse.

Trinucleotide repeat Huntington disease, mvotonic dystrophy . Trv ( trinucleotide) hunting for mv fragile cage-
expansion diseases fragile \ syndrome, and Friedreich ataxia. free eggs ( X ).
Mav shorv genetic anticipation ( disease severity
t and age of onset t in successive generations ).
=
Huntington disease (CAG ) n Caudate has i ACh and GABA
Mvotonic dy strophy = ( CTG ) n Cataracts, loupe ( carls balding in men ).
Gonadal atrophy
Fragile X syndrome = ( CGC )n .
Chin ( protruding ) Giant Gonads
=
Friedreich ataxia ( GAA ) j GAit Ataxi 4
 BIOCHEMISTRY BIOCHEMISTRY — GENETICS SECTION II 59

Autosomal trisomies
Down syndrome .
Findings: inlellcctuil disability Hat facies,
(trisomy 21) prominent epicanthal folds, single palmar
crease, gap between 1st 2 toes, duodenal
atresia, Hirschsprung disease, congenital heart
disease (eg, atrioventricular septal defect|,
Brushfield spots. Associated with earlv-onset
Alzheimer disease (chromosome 21 codes for
amyloid precursor protein) and t risk of ALL
and AML.
95% of cases due to meiotic nondisjunction
( t with advanced maternal age; from 1:1500 in
women < 20 to 1:25 in women > 45 years old).
4% of cases due to unbalanced Robertsonian
translocation, most typically between
chromosomes 14 and 21. \% of cases due
to mosaicism ( no association with maternal
nondisjunction; postfertilization mitotic errorj
Edwards syndrome Findings: PR1XCF, Edward: Prominent
(trisomy 18) .
occiput Rockcr-bottom feet Intellectual . Flection age ( 18).
.
disability Nondisjunction Clenched fists.
( with overlapping fingers ), low-set Lars
micrognathia ( small jaw ), congenital heart
disease. Death usually occurs within 1 year of
birth1
Patau syndrome Findings: severe intellectual disability, rocker-
(trisomy 13 ) bottom feet, microphthalmia, microcephaly,
deft liP/Palate, holoProsencephaly,
Polydactyly, congenital heart disease, cutis
aplasia. Death usually occurs within 1 year of
birth.
Nondisjunction in meiosis I
. Incidence 1:700.
Drinking age ( 21).
Most common viable chromosomal disorder and
most common cause of genetic intellectual
disability.
First-trimester ultrasound commonly shows
t nuchal translucency and hypoplastic nasal
bone; 1 serum PAPP-A, t free (3-hCG
Second-trimester quad screen shows
.
1 a-fctoprotcin, t (J-hCG i estriol,
t inhibit! A.
Incidence 1:8000.
2nd most common autosomal trisoimlresulting
. in live birth (most common is Down syndrome).
PAPP-A and free P-hCG are i in first trimester.
Quad screen shows i a-fetoprotein, 1 P-hCG,
1 estriol, i or normal inhihin A.
Incidence 1:15,000.
Puberty (13).
First-trimester pregnancy screen shows J free
P-hCG, i PAPP-A.
Nondisjunction in meiosis II

n
t
Meiosis I

Nondisjunction . M
<
C 3
)
A Meiosis II
C 3
A C 3
C 3 C 3 3

A A
Nondisjunction

\
III lllXDCI- Gametes
ll ll l III
—
n +1
,
Trisomy
n +1
— J
n -1
-

Monosomy
n 1
-
n
, — _ -, ,
Normal
'n II
n 1
J l
n +1
Monosomy Trisomy
.
0
60 SECTION II BIOCHEMISTRY BIOCHEMISTRY — GENETICS

Genetic disorders by CHROMOSOME SELECTED EXAMPLES

chromosome 3 von Hippel-Lindau disease, renal cell carcinoma
4 ADPKD (PKD2), achondroplasia, Huntington disease
5 Cri-du-chat syndrome, familial adenomatous polyposis
6 Hemochromatosis ( HFE )
7 Williams syndrome, cystic fibrosis
9 Friedreich ataxia
11 Wilms tumor, Pglobin gene defects ( eg, sickle cell disease, P-thalassemia)
1? Patau syndrome, Wilson disease, retinoblastoma ( RBI ), BRCA2
15 Prader-Willi syndrome, Angelman syndrome, Marfan syndrome
16 ADPKD iPKDl ), a-globin gene defects (eg, a-thalassemia)
17 .
Neurofibromatosis type 1 BRCA 1, p53l
18 Edwards syndrome
20 Maturitv-onset diabetes of the voung
21 Down syndrome
22 .
Neurofibromatosis type 2, DiC eorge syndrome ( 22ql 1)
X Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)

Robertsonian Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
translocation One of the most common types of translocation. Occurs when the long arms of 2 acrocentric
chromosomes (chromosomes with centromeres near their ends ) fuse at the centromere and the
2 short arms are lost. Balanced translocations normally do not cause any abnormal phenotype.
Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance ( eg.
Down syndrome, Patau syndrome).

Cri- du- chat syndrome Congenital microdeletion of short arm of Cri da chat = cry of the cat.
.
chromosome 5 (46 XX or XT', 5p ). —
Findings: microcephaly, moderate to
severe intellectual disability, high-pitched
crying/mewing, epicanthal folds, cardiac
abnormalities (VSD),

Williams syndrome Congenital microdclction of long arm of chromosome 7 (deleted region includes clastin gene).
Findings: distinctive “ elfin” facies, intellectual disability, hypercalcemia ( t sensitivity to vitamin D),
well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.
Ul HRHlVH
^ BIOCHEMISTRY BIOCHEMISTRY — NUTRITION
Vitamin A ( retinol )
FUNCTION Antioxidant; constituent of visual pigments
( retinal ); essential for normal differentiation topically for wrinkles and Acne ).
-
Retinol is vitamin A, so think retin A ( used

of epithelial cells into specialized tissue
-
( pancreatic cells, mucus secreting cells);
prevents squamous metaplasia. Used to treat
measles and APLj
Found in liver and leaf) vegetables.
Use oral isotretinoin to treat severe cystic acne.
Use all-trails retinoic acid to treat acute
promyelocvtic leukemia .

DEFICIENCY Night blindness ( nyctalopia ); dry, scaly

skin (xerosis cutis ); corneal degeneration
( keratomalacia ); Bitot spots on conjunctiva;
immunosuppression.
EXCESS —
Acute toxicity nausea , vomiting, vertigo, and Isotretinoin is teratogenic.
blurred vision .
—
Chronic toxicity alopecia, dry skin (eg,
scaliness), hepatic toxicity and enlargement ,
arthralgias, and pseudotumor cerebri .
Teratogenic ( cleft palate, cardiac abnormalities),
therefore a 0 pregnancy test and two forms of
contraception are required before isotretinoin
( vitamin A derivative ) is prescribed .

Vitamin B1 ( thiamine )
FUNCTION In thiamine pyrophosphate (TPP), a cofactor for
several dehydrogenase enzyme reactions:
Pyruvate dehydrogenase ( links glycolysis to
TCA cycle )
a-ketoglutarate dehydrogenase (TCA cycle )
Transketolase ( HMP shunt )
-
Think ATP: a ketoglutarate dehydrogenase,
Transketolase, and Pyruvate dehydrogenase.
Spell beriberi as BerlBerl to remember
vitamin Bj .
—
Wernicke- Korsakoff syndrome confusion ,
ophthalmoplegia , ataxia (classic triad ) +

DEFICIENCY
-
—
Branchcd chain ketoacid dehydrogenase
Impaired glucose breakdown ATP depletion
worsened by glucose infusion ; highly aerobic
tissues (eg, brain , heart ) are affected first.
confabulation , personality change, memory
loss ( permanent ). Damage to medial dorsal
nucleus of thalamus, mammillary bodies.
Dry beriberi — polyneuritis, symmetrical muscle
wasting.
In alcoholic or malnourished patients, give
thiamine before dextrose to avoid precipitating
Wernicke encephalopathy Diagnosis made
—
Wet beriberi high -output cardiac failure
(dilated cardiomyopathy), edema.
by t in RBC transketolase activity following
vitamin B| administration .
64 SECTION I I BIOCHEMISTRY BIOCHEMISTRY — NUTRITION

Vitamin B7 (biotin)
FUNCTION Cofactor for carboxylation enzymes (which add “Avidin in egg whites avidly binds biotin.”
a 1-carbon group):
j
Pyruvate carboxylase: pyruvate (3C)
-* oxaloacetate (4C )
Acetyl-CoA carboxylase: acetyl-CoA (2C i
—malonyl-CoA ( 3C)
Propionyl-CoA carboxylase: propionvl-CoA

DEFICIENCY
—
( 3C ) methylmalonyl-CoA (4C )
Relatively rare. Dermatitis, alopecia, enteritis.
Caused by antibiotic use or excessive ingestion
of raw egg whites.

Vitamin B9 (folate)
FUNCTION Converted to tctrahydrofolic acid ( THF), a
coenzyme for 1-carbon transfcr/mcthylation
reactions.
Important for the synthesis of nitrogenous bases
in DNA and RNA.
DEFICIENCY Macrocytic, megaloblastic anemia;
hypersegmented polymorphonuclear cells
( PMNs); glossitis; no neurologic symptoms
( as opposed to vitamin Bp deficiency). Labs:
t homocysteine, normal methylmalonic acid
levels. Most common vitamin deficiency in
the United States. Seen in alcoholism and
pregnancy.
Found in leaf) green vegetables. Absorbed in
jejunum. Folate from foliage.
Small reserve pool stored primarily in the liver.
Deficiency can be caused by several drugs (eg,
.
phenytoin sulfonamides, methotrexate).
Supplemental maternal folic acid at least 1 month
prior to conception and during earlv pregnanevi
1 risk of neural tube defects.
 BIOCHEMISTRY
Vitamin B12 (cobalamin )
FUNCTION Cofactor for methionine synthase (transfers
ClI, groups as methylcobalamin) and
methvhnalonvl-CoA mutase. Important for
DNA synthesis
DEFICIENCY Macrocytic, megaloblastic anemia;
hypersegmented PMNs; paresthesias
and subacute combined degeneration
( degeneration of dorsal columns, lateral
corticospinal tracts, and spinocerebellar tracts)
due to abnormal myelin. Associated with
t serum homocysteine and methylmalonic
acid levels, along with 2° folate deficiency
Prolonged deficiency -» irreversible nerve
damage.
Protein
I
Methionine
B,, Methionine synthase
Homocysteine
Adenosine
Cysteine
Vitamin C (ascorbic acid)
FUNCTION Antioxidant; also facilitates iron absorption
by reducing it to Fc "+ state. Necessary
for hydroxylation of proline and lysine in
collagen synthesis. Necessary for dopamine
P-hvdroxylase, which converts dopamine to
NE
DEFICIENCY Scurvy — swollen gums, bruising, petcchiae,
hemarthrosis, anemia, poor wound healing,
perifollicular and subperiosteal hemorrhages,
“corkscrew" hair.
Weakened immune response.
EXCESS Nausea, vomiting, diarrhea, fatigue, calcium
oxalate nephrolithiasis. Can t risk of
iron toxicity in predisposed individuals
(eg, those with transfusions, hereditary
hemochromatosis).
BIOCHEMISTRY — NUTRITION SECTION II 65
Found in animal products.
Synthesized only by microorganisms. Very large
reserve pool (several sears) stored primarily in
the liver. Deficiency caused by malabsorption
(eg, sprue, enteritis. Diphyllobotlirium latum ),
lack of intrinsic factor (pernicious anemia,
gastric bypass surgery), absence of terminal
ileum ( surgical resection, eg, for Crohn
disease), or insufficient intake (eg, veganism).
Anti-intrinsic factor antibodies diagnostic for
pernicious anemia.
Fatty acids with odd number of
carbons, branched-chain ammo acids
SAM i
,
CH to anabolic
D III IN MS
I
Methylmalonyl- CoA
5- adenosyl
4 Methylmalonyl-CoA
mutase
Succinyt- CoA
Heme TCA
0
Found in fruits and vegetables.
Pronounce “ absorbic” acid.
,
Ancillary treatment for methemoglobinemia by
reducing Fe + to Fe- \
Vitamin C deficiency causes sCurvy due to a
Collagen synthesis defect.
DO SECTION II BIOCHEMISTRY BIOCHEMISTRY — NUTRITION

Vitamin D ,
D = ergocalciferol— ingested from plants.
D, = cholecalciferol — consumed in milk, formed in sun-exposed skin (stratum basale ).
25 - OH D, = storage form.

FUNCTION
- -
l,25 (OH),D (calcitriol) = active form,
t intestinal absorption of calcium and phosphate, t bone mineralization at low levels, t bone
resorption at higher levels.
DEFICIENCY Rickets in children (bone pain and deformity), osteomalacia in adults (bone pain and muscle
weakness), hypocalcemic tetany. Breastfed infants should receive oral vitamin D. Deficiency is
exacerbated by low sun exposure, pigmented skin, prematurity.

EXCESS Hypercalcemia, hypcrcalciuria, loss of appetite, stupor. Seen in granulomatous disease (t activation
of vitamin D by epithelioid macrophages ).

Vitamin E ( tocopherol / tocotrienol )

FUNCTION Antioxidant ( protects RBCs and membranes Can lead to impaired absorption of vitamin K
from free radical damage).
—enhanced anticoagulant effects of warfarin!

DEFICIENCY Hemolytic anemia, acanthocytosis, Neurologic presentation may appear similar

muscle weakness, posterior column and to vitamin Bp deficiency, but without
spinocerebellar tract demyelination. megaloblastic anemia, hypersegmenled
neutrophils, or t serum methylmalonic acid
levels.

Vitamin K ( phytomenadione, phylloquinone, phytonadione)

FUNCTION Activated bv epoxide reductase to the K is for Koagulation. Necessary for the
reduced form, which is a cofactor for the maturation of clotting factors II, VII, IX, X,
.
y-carboxvl ition of glutamic acid residues on and proteins C and S. Warfarin — inhibits
various proteins required for blood clotting. vitamin K-dcpcndcnt synthesis of these factors
Synthesized bv intestinal floral and protein
DEFICIENCY Neonatal hemorrhage with t PT and t aPTT
^
Not in breast milk; neonates are given vitamin
but normal bleeding time (neonates have K injection at birth to prevent hemorrhagic
sterile intestines and are unable to synthesize disease of the newborn.
vitamin K |. Can also occur after prolonged use
of broad-spectrum antibiotics.
 BIOCHEMISTRY BIOCHEMISTRY — NUTRITION SECTION I I 67

Zinc
FUNCTION Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers
( transcription factor motif ).
DEFICIENCY Delayed wound healing, hypogonadism, 1 adult hair (axillary; facial, pubic ), dysgeusia. anosmia,
acrodermatitis enteropathica Q. May predispose to alcoholic cirrhosis.

Malnutrition
Kwashiorkor Protein malnutrition resulting in skin lesions, Kwashiorkor results from a protein-
edema due to 1 plasma oncotic pressure, deficient MEAL:
liver malfunction (fatty change due to Malnutrition
i apolipoprotein synthesis). Clinical picture is Edema
small child with swollen abdomen Q. Anemia
Liver (fatty )

Marasmus Total calorie malnutrition resulting in Marasmus results in Muscle wasting,

emaciation (tissue and muscle wasting, loss of
subcutaneous fat; note wrinkled skin in dj
+/- edema. I

New I
maael
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION II 69

Enzyme terminology An enzyme’s name often describes its function. For example, glucokinase is an enzyme that
catalyzes the phosphorylation of glucose using a molecule of ATP The following are commonly
used enzyme descriptors.
Kinase Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate
.
( eg phosphofructokinase).
Phosphorylase Adds inorganic phosphate onto substrate w ithout using ATP (eg, glycogen phosphorylase).
Phosphatase Removes phosphate group from substrate (eg, fructosc -l,6-bisphosphatasc).
Dehydrogenase Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase).
Hydroxylase .
Adds hydroxyl group i-OH) onto substrate (eg tyrosine hydroxylase).
Carboxylase Transfers CO,groups with the help of biotin (eg, pyruvate carboxylase ).
Mutase Relocates a functional group w ithin a molecule ( eg, vitamin Bp-dependent methylmalonyT-CoA
mutase) .
Synthase /synthetase Combines 2 molecules into 1 { condensation reaction ) either using an energy source ( synthase) or
not ( synthetase ) ( eg, glvcogen synthase ).

Rate - determining enzymes of metabolic processes

PROCESS ENZYME REGULATORS
Glycolysis Phosphofructokinase-I (PFK-1) AMP ©, fructose-2,6-bisphosphate ©
ATP ©, citrate ©
Gluconeogenesis Fructose-1,6-bisphosphatase Citrate ©
AMP ©, fructose-2,6-bisphosphate ©
TCA cycle Isocitrate dehydrogenase ADP ©
ATP ©, NADH ©
Glycogenesis Glycogen synthase Glucosc-6-phosphatc ©, insulin ©, cortisol ©
Epinephrine ©, glucagon ©
Glycogenolysis Glycogen phosphorylase Epinephrine ©, glucagon ©, AMP ©
Glucose-6-phosphate ©, insulin ©, ATP ©
HMP shunt Glucose-6-phosphatc dehydrogenase ( G6PD) NADP ©
NADPH ©
De novo pyrimidine Carbamoyl phosphate synthetase II ATP ©, PRPP ©
synthesis UTP ©
De novo purine Glutamine-phosphoribosvlpvrophosphate AMP ©, inosinc monophosphate ( IMP) ©,
synthesis (PRPP) amidotransferase GMP ©
Urea cycle Carbamoyl phosphate synthetase I X-acetylglutamate ©
Fatty acid synthesis Acetyl-CoA carboxylase (ACC ) Insulin ©, citrate ©
Glucagon ©, palmitoyl-CoA ©
Fatty acid oxidation Carnitine acyltransfcrasc 1 Malonyl-CoA ©
Ketogenesis IIMG-CoA synthase
Cholesterol synthesis HMG-CoA reductase Insulin ©, thyroxine ©
Glucagon ©, cholesterol 0
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION I I 71

ATP production Aerobic metabolism of glucose produces 52 net Arsenic causes glycolysis to produce zero net
ATP via malate-aspartate shuttle (heart and ATP.
liver), 50 net ATP via glyccrol- 5 -phosphate
shuttle (muscle).
Anaerobic glycolysis produces only 2 net ATP
per glucose molecule.
ATP hydrolysis can be coupled to energetically
unfavorable reactions.

Activated carriers CARRIER MOLECULE CARRIED IN ACTIVATED FORM

ATP Phosphors ! groups

NADII, NADPH, FADH2 Electrons
CoA, lipoamide Acyl groups
Biotin co2
Tetrahydrofolates 1-carbon units
S-adenosvbnethionine (SAM ) -
CH groups
TPP Aldehydes

Universal electron Nicotinamides (NAD* from vitamin B;, NADPI 1 is a product of the 1 IMP shunt.
acceptors NADP* ) and flavin nucleotides (FAD* from NADPII is used in:
vitamin IT ). Anabolic processes
NAD* is gcncrallv used in catabolic processes Respiratory burst
to carry reducing equivalents away as NADH. • Cytochrome P-450 system
NADPI 1 is used in anabolic processes ( steroid * Glutathione reductase
and fatty acid synthesis) as a supple of reducing
equivalents.

Hexokinase vs Phosphorylation of glucose to yield glucosc-6-phosphatc serves as the 1st committed step of
glucokinase glycolysis (also serves as the 1st step of glycogen synthesis in the liver). Reaction is catalyzed
he either hexokinase or glucokinase, depending on the tissue. At low glucose concentrations,
hexokinase sequesters glucose in the tissue. At high glucose concentrations, excess glucose is
stored in the liver.
Hexokinase Glucokinase
Location Most tissues, except liver Liver, P cells of pancreas
and pancreatic P cells
K,„ Lower ( t affinity) Higher ( 1 affinity)
Lower (1 capacity) Higher ( t capacity)
Induced by insulin No Yes
Feedback-inhibited by Yes No
glucose- 6-phosphatc
Gene mutation on chromosome No Yes
20 associated with maturity-
onset diabetes of the vouna
72 SECTION II BIOCHEMISTRY BIOCHEMISTRY — METABOLISM

Glycolysis regulation, Net glycolysis (cytoplasm):

key enzymes Glucose + 2 P, + 2 ADP + 2 NAD+ - 2 pyruvate + 2 ATP + 2 NADH + 2 H + + 2 H,0.
Equation not balanced chemically, and exact balanced equation depends on ionization state of
reactants and products.
REQUIRE ATP Glucose
Hexokinase / glucokinase3
Glucose-6- P Glucose-6-P © hexokinase.
Fructose-6-P © glucokinase.
Fructose-6-P Fructose-l,6-BP AMP ©, fructose-2,6 -bisphosphate ©.
Phosphofructokinase -1
-
( rate limiting step) ATP ©, citrate ©.
4
G!ucokirvase in liver and {J cells of pancreas, hexokinase
in all other tissues.

PRODUCE ATP 1, 5-BPG < 5-PG

Phosphoglycerate kinase

Phosphoenolpyruvate Pyruvate Fructose-1 ,6-bisphosphate ©.

Pyruvate kinase
ATP ©, alanine ©.

Regulation by FBPase-1
fructose -2,6 - Gluconeogenesis < Fmctose-6-P *
PFK -1
> Fructose-1, 6-BP *
• Glycolysis
bisphosphate
FBPase -2 PFK - 2
(active in (active in
fasting state) fed state)

Fructose-26-BP

-
—— — — —
FBPase - 2 (fructose bisphospliatase- 2 ' and PFK 2 ( phosphofructokinase-2 are the same bifunctional
enzyme whose function is reversed by phosphorylation by protein kinase A.
-
Fasting state: t glucagon t cAMP t protein kinase A * T FBPase 2, 1 PFK-2 , less glycolysis, -
more gluconeogenesis.
Fed state: t insulin 1 cAMP l protein kinase A i FBPase-2, t PFK-2 , more glycolysis, less
gluconeogenesis.

Pyruvate Mitochondrial enzyme complex linking The complex is similar to the a-kctoglutarate
dehydrogenase glycolysis and TGA cycle. Differentially dehydrogenase complex (same cofactors .
complex regulated in fed/fasting states (active in fed
state).
Reaction: pyruvate + NAD* + CoA aectyl-
COA + C02 + NADH.
Tlie complex contains s enzymes that require 5
— —
similar substrate and action ), which converts
a-kctoglutarate succinyl-CoA ( TGA cycle).

cofactors:
1 . Thiamine pvrophosphate ( Bj ) The Lovelv Co- enzymes For Ncrdi
2. Lipoic acid Arsenic inhibits lipoic acid . Findings:
s. CoA ( B-, pantothenic acid ) vomiting, rice-water stools, garlic breatlijOT
4. FAD ( B7, riboflavin ) prolongation.
-
5. NAD; ( B , niacin)
Activated by:
T NAD*/ NADH ratio
t ADP
 HUNJIM I ;I inIt :
^ i

Electron transport NADH electrons from glycolysis enter mitochondria via the malatc-aspartatc or glyccrol-5 -
:hain and oxidative phosphate shuttle. FAD11, electrons are transferred to complex II (at a lower energy level than
ihosphorylation NADII). The passage of electrons results in the formation of a proton gradient that, coupled to
oxidative phosphorylation, drives the production of ATP.
ADP + P, ATP
NADH NAD- FADH? FAD 7,0;+ 2H' H;0 Mitochondrial
matrix
V VI
* Inner mitochondrial
membrane

Complex I Complex II Complex III Complex IV Complex V Intermembrane

space
JJ
2,4-Dinitrophenol A (succinate T T
) dehydrogenase) J (
Aspirin overdose [Revi
H*
Rotenone AntimycinA
H'
Cyanide. H*
Oligomycin
H
co
rn
I I t B

ATP PRODUCED VIA ATP SYNTHASE

OXIDATIVE PHOSPHORYLATION POISONS

1 NADll - 2.5 ATP; 1 FADH, - 1.5 ATP.

Electron transport Directly inhibit electron transport, causing a
inhibitors i proton gradient and block of ATP synthesis.
ATP synthase Directly inhibit mitochondrial ATP synthase,
inhibitors causing an t proton gradient. No ATP is
produced because electron transport stops.
Uncoupling agents t permeability of membrane, causing a i proton
gradient and t O-, consumption. ATP synthesis
stops, but electron transport continues.
Produces heat.
RotcnONE: complex ONE inhibitor.
“An-5 -mycin” (antimycin) A : complex 5
inhibitor.
CO/CN: complex -t inhibitors ( 4 letters).
Oligomycin.
2,4-Dinitrophenol (used illicitly for weight
loss), aspirin ( fevers often occur after aspirin
overdose), thernrogenin in brown fat .

jluconeogenesis,
rreversible enzymes Pathway Produces Fresh Glucose.
Pyruvate carboxylase
Phosphoenolpyruvate
In mitochondria. Pvruvatc
In cytosol. Oxaloacctatc
— oxaloacctatc. Requires biotin, ATP. Activated bv acetyl-CoA.
Requires GTP
carboxykinase
Fructose-1,6-
— phosphoenolpyruvate.
In cytosol. Fructose- 1,6-bisphosphate . .
Citrate © AMP © fructose 2.6-bisDhosphate ©.
bisphosphatase — fructose-6-phosphate.
Glucose- 6-
phosphatase
In ER. Glucose-6-phosphate glucose.
—
Occurs primarilv in liver; serves to maintain eugiveemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
( Muscle cannot participate in gluconeogenesis because it lacks glucose- 6-phosphatase).

-
Odd chain fatty acids yield I propionyl-CoA during metabolism, which can enter the TCA cycle
( as succinvl-CoA ), undergo gluconeogenesis, and serve as a glucose source. Even-chain fatty acids
cannot produce new glucose, since they yield only acctyl-CoA equivalents.
76 SECTION II BIOCHEMISTRY BIOCHEMISTRY — METABOLISM

Disorders of fructose metabolism

Essential fructosuria
Fructose intolerance
Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since
fructose is not trapped in cells.
Symptoms: fructose appears in blood and urine.
Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose
metabolism.
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-l-phospbate accumulates,
causing a i in available phosphate, which results in inhibition of glycogenolysis and
gluconeogenesis. Symptoms present following consumption of fruit, juice, or hones . Urine dipstick
will be © (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for
inborn errors of carbohydrate metabolism).
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: i intake of both fructose and sucrose ( glucose + fructose).

Fructose metabolism lliver)

Those phosphate
Dihydroxyacetone isomerase

Fructose -
Fructokinase
Fructose-1-P - Aldolase B
Glyceraldehyde- 3-P - Glycolysis

T^T
ATP
ADP Glyceraldehyde - • ADP
Revised
:igure

NADH ATP

NAD*
Glycerol

Disorders of galactose metabolism

Galactokinase Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet.
deficiency Relatively mild condition , Autosomal recessive.
{symptoms: galactose appears in blood ( galactosemia) and urine ( galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile.
Classic galactosemia Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive Damage is caused b\ .
accumulation of toxic substances ( including galactitol, which accumulates in the lens of the eye).
Sy mptoms develop when infant begins feeding ( lactose present in breast milk and routine formula ).
Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can
lead to F coli sepsis in neonates.
Treatment: exclude galactose and lactose ( galactose + glucose: from diet.
Galactose metabolism Fructose is to Aldolase B as Galactose is to
Galactokinase Uridyltransferase
UridylTransferase ( FAB CUT).
Galactose Galactose -l-P Glucose -l-P The more serious defects lead to PO+’ depletion.
T
TV
“

ATP

v_y
ADP UDP-Glu UDP-Gal
Aldose
reductase
Glycolysis/glycogenesis
4 - epimerase
Cialartitol
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION I I 77

Sorbitol An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart .
called sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using
sorbitol dehydrogenase; tissues with an insufficient amount /activity of this enzyme are at risk
.
for intracellular sorbitol accumulation, causing osmotic damage (eg cataracts, retinopathy, and
peripheral neuropathy seen with chronic hyperglycemia in diabetes) .
High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose
reductase.
Liver, ovanes. and seminal vesicles have both enzymes

Aldose reductase Sorbitol dehydrogenase

Glucose Sorbitol Fructose
NADPH NAD *

Lens has primarily aldose reductase Retina, Kidneys and Schwann cells have only aldose reductase ILuRKS),

Aldose reductase
Glucose - Sorbitol
NADPH
*

Lactase deficiency
—
Insufficient lactase enzyme dietary lactose intolerance. Lactase functions on the brush border to
digest lactose (in human and cow milk ) into glucose and galactose.
Primary: age-dependent decline after childhood ( absence of lactase-persistent allele ), common in
people of Asian, African, or Native American descent.
Secondary : loss of brush border due to gastroenteritis ( eg, rotavirus), autoimmune disease, etc .
'

Congenital lactase deficiency: rare, due to defective gene.

Stool demonstrates i pll and breath shows t hydrogen content with lactose hydrogen breath test
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
FINDINGS Bloating, cramps, flatulence, osmotic diarrhea.
TREATMENT Avoid dairy products or add lactase pills to diet; lactose-free milk .

Amino acids Only l,-amino acids are found in proteins.

Essential .
< (Hi.4)
Glucogenic: methionine ( Met ) histidiui . I met his valentine, she is so sweet ( glucogenic ).
valine ( Vail. All essential amino acids need to be supplied in
Glucogeme/ketogcnic: isoleucinc i lie), the die!
phenylalanine (Phc), threonine (Thr),
tryptophan ( Trp).
Ketogenic: leucine (Leu), lysine ( Lys).
Acidic Aspartic acid (Asp ) and glutamic acid (Glu).
Negatively charged at body pH.
Basic Histidine ( His), lvsinc ( Lvs ). arginine lArg). His lvs ( lies) arc basic. Arg and His are reauired
Arg is most basic. during periods of groyvth. Arg and Lys are t in
PIis has no charge at body piI. histones, which bind negatively charged DNA.
Transport of ammonia by alanine and glutamine!

Muscle Liver
Amino acids Alanine Alanine
(NH5) u- Ketoglutarate ,
(NHj) u-Ketoglutarate

Y Glucose
Cahill cycle
. Glucose
u- Ketoacids Glutamate INH3)
A^ i Pyruvate Cori cycle
I
Pyruvate Glutamate (NH3)

I
Lactate
1
Lactate
I
Urea (NH 3)

S3

Hyperammonemia Can be acquired (eg. liver disease) or hereditary Ammonia accumulation — tremor ( asterixis),
( eg. urea cycle enzyme deficiencies). .
slurring of speech, somnolence, vomiting

fikN -
Results in excess NI1 , which depletes
a-ketoglutarate, leading to inhibition of TCA
cycle.
cerebral edema, blurring of vision,

Treatment: limit protein in diet.

May be given to l ammonia levels:
Asterixis
.
Lactulose to acidify the C[ tract and trap
NH+ * for excretion.
Antibiotics (eg, rifaxinrim tqj l colonic
ammoniagcnic bacteria.
Benzoate, phcnylacetatc, or phcnvlhutvrate
hind glycine to form hippurate and lead to
excretion of NILi - ion
^
 Catecholamine synthesis/tyrosine catabolism
Phenylalanine
Phenylalanine
BH< hydroxylase PKU

Homogentisic acid < - Tyrosine

BH, Tyrosine
Alkaptonuria Homoq isate
'
^
oxidase
DOPA
hydroxylase

Maleylacetoacetic acid (Dihydroxyphenylalanine)

1
Albinism
Tyrosinase
• Melanin
B6 DOPA •Carbidopa
Fumarate 1
decarboxylase "
Dopamine - -
'
N

(TCA cycle ) Vitamin C Dopamine

I |J-hydroxylase
Norepinephrine
-
Catechol O- methyl transferase
Revise
Phenylethanolamine W
SAM mclhyltransferase - - - - Cortisol Normetanephrine
Figure

i
Epinephrine - • Metanephrlne - Vanillytmandelic acid Homovamllic acid 0

80 SECTION II BIOCHEMISTRY BIOCHEMISTRY — METABOLISM

Phenylketonuria Due to I phenylalanine hydroxylase or Autosomal recessive. Incidence = 1:10,000.

I lelralivdrohiopterin I hi Hcohiclor Screening occurs 2-5 days after birth (normal at
(malignant PKU ). Tyrosine becomes essential birth because of maternal enzyme during fetal
—
,

t phenylalanine excess phenylkctones in life).

urine. —
Phenylkctones phcnylacetate, phenyllactatc,
Findings: intellectual disability, growth and phenylpyruvatc .
retardation, seizures, fair skin, eczema, musty Disorder of aromatic amino acid metabolism
body odor.
Treatment: t phenylalanine and f tyrosine in
—musty body odor.
PKU patients must avoid the artificial sweetener
diet, tetrahydrobiopterin supplementation. aspartame, which contains phenylalanine.
Maternal PKU — lack of proper dietary therapy
during pregnancy. Findings in infant:
microcephaly, intellectual disability, growth
retardation, congenital heart defects.
Alkaptonuria

—
Congenital deficiency ofhomogentisate oxidase in the degradative pathway of tyrosine to futnarate
pigment-forming homogentisic acid accumulates in tissue Q. Autosomal recessive. Usually
benign.
Findings: bluish - black connective tissue, ear cartilage, and sclcrac ( ochronosis ); urincj turns black on
! prolonged exposure to air. May have debilitating arthralgias ( homogentisic acid toxic to cartilage).
i l

Homocystinuria Types (all autosomal recessive ):
Cystathionine synthase deficiency
( treatment : t methionine , t cysteine, t B( ,
BJTJ and folate in diet)
i affinity of cystathionine synthase for
pyridoxal phosphate ( treatment: tt B6 and
t cysteine in diet )
Methionine synthase ( homocysteine
methyltransferase) deficiency ( treatment:
All forms result in excess homocysteine.
11( ) \ l ( K Astinuiia tt I lomocvstcinc in
) . .
mine Osteoporosis. M ntannid habitus .
Ocular changes ( downward and inward
.
—
lens subluxation ) Cardiovascular effects
thrombosis and atherosclerosis stroke and
Ml ), kYphosis, intellectual disability

t methionine in dictl
Methionine Cystathionine
synthase synthase
Methionine < Homocysteine > Cystathionine Cysteine
a / B,
Serine
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION II 1
Glycogen storage 12 types, all resulting in abnormal glycogen Very Poor Carbohydrate Metabolism ,

diseases metabolism and an accumulation of glycogen . and V arc autosomal recessive,

'lypes 1, 11, 111
within cells Periodic acid— Schiff stain
identifies glycogen and is useful in identifying
these diseases.
DISEASE FINDINGS DEFICIENT ENZYME COMMENTS
Von Gierke disease Severe fasting hypoglycemia, Glucose-6-phosphatase Treatment: frequent oral
(type 1) 11 Glycogen in liver, t blood glucose /cornstarch; avoidance
lactate, t triglycerides, of fructose and galactose
t uric acid (Gout), and Impaired gluconeogenesis and
hepatomegaly. glycogenolysis
Pompe disease Cardiomegaly, hypertrophic- Lysosomal acid a-1,4- Pomfje trashes the PumP(l,4 j
(type II) cardlomvopaths, hypotonia . glucosidase with a-1,6- ( heart, liver, and muscle)
cxcrcisrf intolerance, and glucosidase activity (acid
systemic findings lead to early maltase)
death.
Cori disease Milder form of von Gierke Debranching enzyme Gluconeogenesis is intact
(type III) ( type 11 with normal blood ( a-1,6-glucosidase)
lactate levels. Accumulation
of limit dextrin— like
structures in cytosol.
McArdle disease t glycogen in muscle, but Skeletal muscle glycogen Bl< x >d glucose levels typically

—
( type V ) muscle cannot break it down phosphorvlase unaffected
painful Muscle cramps, (Myophosphorylase) McArdle = Muscle
Myoglobinuria (red urine)
with strenuous exercise, and
arrhythmia from electrolyte
abnormalities. Second-wind
phenomenon noted during
exercise due to t muscular
blood flow.
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM

Lysosomal storage Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation
diseases of abnormal metabolic products.
DISEASE FINDINGS DEFICIENT ENZYME ACCUMULATED SUBSTRATE INHERITANCE
Sphingolipidoses
Fabry disease Early: Triad of episodic peripheral © a-galactosidase A Ceramide XR
neuropathy, angiokeratomas Q, trihexoside
hypohidrosis. Late: progressive renal
failure, cardiov ascular disease.

Gaucher disease Most common. 0 Glucocerebrosidase Glueocerebroside AR

m, A
Hepatosplenomegaly, pancytopenia,
osteoporosis, avascular necrosis of
femuj bone crises, Gaucher cells fl
( lipid-laden macrophages resembling
crumpled tissue paper ).
(P-glucosidase); treat
with recombinant
glucocerebrosidase

Niemann-Pick disease Progressive neurodegencration, © Sphingomyelinase Sphingomyelin AR

&
-*
rX•% * t:l
hepatosplenomegaly, foam cells
i lipid-laden macrophages) H,

“cherry-red” spot on macula Q.

'‘C
.
4
Tay-Sachs disease Progressiv e neurodegencration, O HeXosaminidase \ ,
GM ganglioside AR
developmental delay, “cherry-red” ( "TAv-SaX "!
spot on macula 0, lysosomes with
onion skin, no hepatosplenomegaly
( vs Niemann-Pick).

Krabbe disease Peripheral neuropathy, destruction of 0 Gaiactocerebrosi- Galactocerebroside, AR

oligodendrogliai, developmental delay, dasc psychosine
optic atrophy, globoid cells .
Metachromatic Central and peripheral demyelination © Arylsulfatase A Cerebroside sulfate AR
leukodystrophy with ataxia, dementia.
Mucopolysaccharidoses
Hurler syndrome Developmental delay, gargoylism, a-L-iduronidase 1Icparan sulfate, AR
airway obstruction, corneal clouding, dermatan sulfate
hepatosplenomegaly.
Hunter syndrome Mild Hurler + aggressive behavior, no Iduronate sulfatase 1 Icparan sulfate, XR
corneal clouding. dermatan sulfate

GM; Ceramide trihexoside No man picks ( Niemann-Pick) his nose with

o, his sphinger ( sphingomyelinase).
GM, 0 -
Tay SaX lacks heXosaminidase.
_
Sulfatides
Glueocerebroside
Ilunters sec clearly ( no corneal clouding) and
® aggressively aim for the X ( X-linked recessive),
o o
Gatactocerebroside Ceramide Sphingomyelin 119 t incidence ofTay-Sachs, Niemann-Pick and .
some forms of Gaucher disease in Ashkenazi
Jews.
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM II . ©

Fatty acid metabolism Fatty ac id synthesis requires transport of citrate

from mitochondria to cytosol. Predominantly
Synthesis Degradation occurs in liver, laetating mammary glands, and
Fatty acid synthesis
adipose tissue.
( palmitate, a 16C
FA ) Long-chain fatty acid I LCFAl degradation
Fatty acid * CoA requires carnitine-dependent transport into the
Malonyl-CoA mitochondrial matrix.
f--
Acetyl CoA
CO2 ( biotin )
Fatty acid CoA
synthase “ SYtrate ” SYnthesis.
=
Fatty Acyl-CoA CARnitine = CARnage of fatty acids.
ATP citrate
JK )"" Malonyl- CoA
—
—
Cell cytoplasm lyase Systemic 1° carnitine deficiency inherited
Mitochondrial Citrate Carnitine
defect in transport of LCFAs into the
membranes shuttle shuttle mitochondria toxic accumulation. Causes
weakness, hypotonia, and hvpoketotic
Mitochondrial hypoglycemia.
matrix

Citrate Fatty Acyl-CoA Medium -chain acyl -CoA dehydrogenase

-
[i oxidation
(Acyl CoA —
deficiency 1 ability to break down fatty
acids into acetvl-CoA • accumulation of lath
dehydrogenases)
acyl carnitines in the blood with hvpoketotic
Acetyl-CoA
hvpoglvcemica. Causes vomiting, lethargy,
/\ TCA
Ketone
seizures, coma, liver dysfunction. Can lead to
bodies cycle sudden death in infants or children . Treat bv
B
avoiding fasting.
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION II 87

Metabolic fuel use

4 kcal = lg GARB
100% -
7 kcal = lg ALCOHOL
9 kcal = lg FATTY ACID!
-
\ —
\ //
9 Stored ATP
2 — Creatme phosphate
a \f .\ —

j\ .
Anaerobic metabolism
i Y \ ^
-
-\ — — Aerobic metabolism
Overall performance
-z

-4-
V
1 1 r
2 sec 10 sec 1min 2 hr
Duration of exercise \a

Fasting and starvation Priorities are to supply sufficient glucose to the brain and RBGs and to preserve protein.
Fed state (after a Glycolysis and aerobic respiration, Insulin stimulates storage of lipids, proteins, and
meal) glycogen.
Fasting (between Ilepatic glycogenolysis (major); hepatic Glucagon and epinephrine stimulate use of fuel
meals) gluconeogenesis, adipose release of FFA reserves.
(minor ).
Starvation days 1- 3 Blood glucose levels maintained by: Glycogen reserves depleted after day 1.
Hepatic glycogenolysis RBGs lack mitochondria and therefore cannot
• Adipose release of FFA use ketones.
• Muscle and liver, which shift fuel use from
glucose to FFA
Hepatic gluconeogenesis from peripheral 10- Protein
tissue lactate and alanine, and from
S' F-
adipose tissue glycerol and propionyl- 5 Fat
CoA ( from odd-chain FFA — the only £ 6-
triacylglvcerol components that contribute L
to gluconeogenesis) 5 <-
Starvation after Adipose stores ( ketone bodies become the main
day 3 source of energy for the brain). After these arc Carbohydrate
1 I I I I I I
depleted, vital protein degradation accelerates, 2 3 4 5 6 7 8
Weeks of starvation ta
leading to organ failure and death.
Amount of excess stores determines surviv al
time.
 BIOCHEMISTRY BIOCHEMISTRY — METABOLISM SECTION II 89

Major apolipoproteins
Chylomicron
Apolipoproteln Function Chylomicron remnant VLDL IDL LDL HDL
E. Mediates remnant uptake / / /
Mediates remnant
uptake (Everythinq
Except LDU

AT Activates LCAT / /
Activates LCAT
C-ll. Lipoprotein lipase cofactor / /
Lipoprotein lipase
Cofactor that
Catalyzes Cleavaqe

B- 48 Mediates chylomicron S

B-100
secretion into lymphatic
Binds LDL receptor
^

Lipoprotein functions Lipoproteins are composed of varying

proportions of cholesterol, TGs, and
phospholipids. LDL and 1 IDL cart)' the
most cholesterol.
LDL transports cholesterol from liver to tissues. LDL is Lousy.
HDL transports cholesterol from periphery to 1 IDL is Healths ,

liver.
Cholesterol Needed to maintain cell membrane integrity and to synthesize bile acid, steroids, and vitamin Dj
Chylomicron Delivers dietarv TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron
remnants, which are mostly depleted of their TGs. Secreted bv intestinal epithelial cells
VLDL Delivers hepatic TGs to peripheral tissue. Secreted by liver.
IDL Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.
LDL Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in
the liver and peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.
HDL Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for
apolipoproteins C and E (which arc needed for chylomicron and VLDL metabolism). Secreted
from both liver and intestine. Alcohol t synthesis.

Abetalipoproteinemla Autosomal recessive. Chylomicrons. VLDL, LDL absent. Deficiency in ApoB48, ApoBlOO.
Affected infants present with severe fat malabsorption, steatorrhea, failure to thrive. Retinitis
pigmentosa and spinocerebellar degeneration due to vitamin F, deficiency. Progressive ataxia .
Acanthocvtosis.
Treatment: Restriction of long-chain fattv acids, large doses of oral vitamin E.
1 76 SECTION II IMMUNOLOGY IMMUNOLOGY — LYMPHOID STRUCTURES

IMMUNOLOGY — LYMPHOID STRUCTURES

Immune system 1° organs:

organs
Thymus
—
—
T cell maturation!
.
Bone marrow immune cell production B cell maturation!

2° organs:
Spleen, lymph nodes, tonsils, Peyer patches
Allow immune cells to interact with antigen

Lymph node A 2° lymphoid organ that has many afferents, 1 or more efferents. Encapsulated , with trabeculae.
Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune
response activation .
Follicle -
Site of B cell localization and
proliferation . In outer cortex. 1° follicles Afferent
lymphatic
are dense and dormant . 2° follicles have
pale central germinal centers and are Follicles IB celts) 1° follicle
active. Paracortex J 1
i .

(T cells)
Medulla Consists of medullary cords (closely
Germinal cente
packed lymphocytes and plasma cells) Mantle zone
and medullar)- sinuses. Medullary Medullary cord
sinuses communicate with efferent Postcapillary
( lymphocytes,
plasma cells)
lymphatics and contain reticular cells venule
Vein
and macrophages.
Capillary Artery
Paracortex Houses T cells. Region of cortex between supply
follicles and medulla. Contains high efferent
endothelial venules through which T SS0
and B cells enter from blood . Not well
developed in patients with DiGeorge Trabecula
6 Medullary sinus
lymphatic

syndrome. ( reticular cells,

Capsule macrophages)
Paracortex enlarges in an extreme cellular
immune response (eg, viral infection ).
 IMMUNOLOGY IMMUNOLOGY — LYMPHOID STRUCTURES

Spleen Located in LUQ of abdomen, anterior to left

kidney, protected bv th - llth ribs.
^
{sinuosoids are long, vascular channels in red
Splenic dysfunction ( eg, postsplcnectoiny, sickle

pulp ired arrow in Q ) with fenestrated "barrel

hoop” basement membrane.
—
cell disease): 1 IgM 1 complement activation
t C3b opsonization t susceptibility
to encapsulated organisms.
——
m T cells are found in the periarteriolar
Postsplenectomy:
Howell-Jolly bodies ( nuclear remnants )
is lymphatic sheath ( PALS ) within the white
pulp (white arrow in Q ).
Target cells
Thrombocytosis ( loss of sequestration and
B cells are found in follicles within the removal )
Revised white pulp. Ly mphocytosis ( loss of sequestration )
Fact
The marginal zone, in between the red pulp Vaccinate patients undergoing splenectomy
and white pulp, contains macrophages and against encapsulated organisms
specialized B cells, and is where antigen- ( pneumococcal , Hib. meningococcal ) .
presenting cells ( APCs) capture blood-borne
antigens for recognition by lymphocytes.
Macrophages found nearby in spleen remove
encapsulated bacteria.
Capsule
Germinal center laeoi a
Red pulp IRBCs)
Mantle zone Sinusoid

White pulp ( WBCs)

Marginal zone
-
f Reticular fibrous
framework

k
Follicle ( B cells)
Penartenolar
lymphoid sheath
( PALS) (T cells ) -s
Open
cifcu at on
osed
r '
I' I i'

% Pulp vein

Artery
Vein ILS

am
Thymus Located in the anterosuperior mediastinum . T cells = Thymus
Site of T-cell differentiation and maturation . B cells = Bone marrow
Encapsulated - Thymus is derived from the Hypoplastic in DiGeorge syndrome and severe
Third pharyngeal pouch. Lymphocytes of combined immunodeficiency ( SC1D ).
m £
mesenchymal origin . Cortex is dense with
immature T cells; medulla is pale with mature
—
Thymoma lienign neoplasm
mild association with
of thymus,
myasthenia gravis and
m T cells and Hassall corpuscles Q containing superior vena cava syndrome)
epithelial reticular cells.
 IMMUNOLOGY IMMUNOLOGY — LYMPHOCYTES
1 IMMUNOLOGY -- LYMPHOCYTES
innate vs adaptive immunity
Innate immunity
COMPONENTS Neutrophils, macrophages, monocytes,
dendritic cells, natural killer (NK | cells
(lymphoid origin), complement
MECHANISM Germline encoded
RESISTANCE Resistance persists through generations; does
not change within an organisms lifetime
RESPONSE TO PATHOGENS Nonspecific
Occurs rapidly (minutes to hours ]
No memory response!
PHYSICAL BARRIERS Epithelial tight junctions, mucus
SECRETED PROTEINS Lysozyme, complement, C-reactive protein
(CRP), defensins
KEY FEATURES IN PATHOGEN Toll-like receptors (TLRs): pattern recognition
RECOGNITION receptors that recognize pathogen-associated
molecular patterns (PAMPs). Examples of
PAMPs include LPS ( gram © bacteria),
flagcllin ( bacteria), nucleic acids (viruses).
SECTION II
Adaptive immunity
T cells, B cells, circulating antibodies
Variation through V( DiJ recombination during
lymphocyte development
Microbial resistance not heritable
Highly specific, refined over time
Develops over long periods; memory response is
faster and more robust
-
Immunoglobulins
Memory cells: activated B and T cells;
subsequent exposure to a previously
—
encountered antigen stronger, quicker
immune response
180 SECTION II IMMUNOLOGY IMMUNOLOGY — LYMPHOCYTES

Major MI IC encoded by HLA genes. Present antigen fragments to T cells and bind T-cell receptors
histocompatibility ( TCRs ).
complwjl and II
MHC I (1 letter ) MHC II (2 letters)
LOCI
BINDING
HLA-A, HLA- B. HLA C
TCR and CD8
- -
HLA DP, HLA-DQ. HLA-DR
TCR and CD4
STRUCTURE .
I long chain 1 short chain 2 equal-length chains
EXPRESSION All nucleated cells, APCs, platelets J \ PCs
Not on RBC 4
FUNCTION Present endogenously synthesized antigens leg . Present exogenously synthesized antigens ( eg,
viral or cytosolic proteins) to CD8+ cytotoxic bacterial proteins) to CD4+ helper T cells
T cells
ANTIGEN LOADING Antigen peptides loaded onto MHC I in RPR Antigen loaded following release of invariant
after delivery via TAP ( transporter associated chain in an acidified endosome
with antigen processing )
ASSOCIATED PROTEINS (5,- microglobulin Invariant chain
Peptide- binding
groove
Peptide binding
<
I '1 '
u
p, rracroglobutm

Cel ! membrane
iQOQOQQOOOOboOOOOQl
CeL membrane

HLA subtypes associated with diseases

A3 Hemochromatosis
B8
B27
Addison disease, myasthenia gravi
^
Psoriatic arthritis, Ankylosing spondylitis, PAIR . Also known as seronegative arthropathies.
IBD-associatcd arthritis, Reactive arthritis
( formerly Reiter syndrome!

DQ2 / DQ8 Celiac disease! I ate (8) too ( 2) much gluten at Dairy Queen.
DR 2 Multiple sclerosis, hav fever, SLE , Multiple has pastures have dirty
Goodpasture syndrome!
DR 3 Diabetes mcllitus type I , SI , I ',, Graves disease, 2-3, S- l .- K
Hashimoto thyroiditis, Addison diseasej
DR 4 Rheumatoid arthritis, diabetes mcllitus ri pe 1, There are 4 walls in a "rheum ” ( room ).

DR 5
Addison disease!

—
Pernicious anemia vitamin Bp deficiency,
Hashimoto thvroiditii
 IMMUNOLOGY IMMUNOLOGY — LYMPHOCYTES SECTION II 181

Natural killer cells
Use perforin and granzymes to induce apoptosis of vitally infected cells and tumor cells.
Lymphocyte member of innate immune system.
Activity enhanced by IL-2, IL-12, IFN-a, and IFN-P.
Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence
of class 1 Ml IC on target cell surface.
Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fe region of bound Ig,
activating the NK cell).

Major functions of B and T cells

B cells (humoral Recognize antigen — undergo somatic hypermutation to optimize antigen specificity .
immunity!
] Produce antibody — differentiate into plasma cells to secrete specific immunoglobulins.
Maintain immunologic memory — memory B cells persist and accelerate future response to antigen.
T cells (cell-mediated CD4+ 1 cells help B cells make antibodies and produce cytokines to recruit phagocytes and
immunity)! activate other leukocytes.
CD8+ T cells directly kill virus-infected cells.
Delayed cell-mcdiatcd hypersensitivity ( type IV ).
Acute and chronic cellular organ rejection.
Rule of 8: MHC II x CD-I = 8; MHC I x CDS = 8.

Differentiation of T cells
Bone marrow Thymus Lymph node

Cytotoxic T celt (kills virus-infected, ,

Th cell
CD8+ T cell neoplastic, and donor graft cells!

. .
( D t ( Dar
' .

Teel
-
T cell precursor
Th, cell

CD4 tT cell Helper T celt

ll - 4

-cell receptor ,
Y (Tbinds MHCI
rCf. Th , cell

or MHC III Cortex Medul i

CD8
k
| CD4
Positive selection Thymic cortex. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells
survive.
Negative selection Thymic medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis.
Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune
regulator (AIRE); deficiency leads to autoimmune polycndocrinc syndromc-1.
 1U <[']’ ! I ’ l lII MLliMaiMMWIillflSMBHMaaiailM

Helper T cells Thl cell Th 2 cell

Secretes IFX -yand 1L-2
Activates macrophages and cytotoxic I cells
Differentiation induced by IFN-yand IL-12
Inhibited bv IL-4 and IL-10 ( from Th2 cell )
Secretes IL-4. ILo, IL-fj IL-10, IL- B
Recruits eosinophils for parasite defense and
promotes IgF production by B cells
Differentiation induced by IL-4
Inhibited bv IFN - y ( from 1 hl cell )
'

—
Macrophage-lymphocyte interaction dendritic cells, macrophages, and other Al'Cs release IL-12 ,
whichjstimulates T cells to differentiate into Thl cells. Till cells release IFN-y to stimulate
macrophages.
I Iclpcr T cells have CD4, which binds to Ml 1C II on Al’Cs

Cytotoxic T cells Kill virus-infcctcd. neoplastic, and donor graft cells by inducing apoptosis.
Release cytotoxic granules containing preformed proteins ( eg, perforin , granzyme B).
Cytotoxic T cells have CD8, which binds to MHC 1 on virus-infected cells.

Help maintain specific immune tolerance bv suppressing CD4 and CD8 T-cell effector functions.
Regulatory T cells
Identified by expression of CD?, CD4, CD2S. and FOXl’L
_
Activated regulatory T cells ( Trees j produce anti-inflammatory cytokines (eg, IL-10, TGF-fJ).
—
IPEX syndrome Dysfunction of FOXP? -» autoimmunity. Characterized bv enteropathy ,
endocrinopatln , nail dystrophy, dermatitis, and /or other autoimmune dermatologic conditions.
 IMMUNOLOGY IMMUNOLOGY — LYMPHOCYTES SECTION II 183

T- and B- cell activation .

APCs: B cells, dendritic cells. Langerhans cells, macrophages T helper cell 4 -
Two signals are required for T-cell activation, B-cell activation, and class switching.
Naive T-cell activation 1. Dendritic cell (specialized APC) samples and processes antigen.
2. Dendritic cell migrates to the draining lymph node.
3. T-cell activation (signal 1): antigen is presented on MHC II and recognized by TCR on Th
(CD4+) cell. Kndogcnous or cross-prcsentec |antigen is presented on MHC I to Tc (CD8+) cell.
4. Proliferation and survival ( signal 2): costimulatory signal via interaction of B7 protein on
dendritic cell ( CDSO/86 ) and CD28 on naive T cell
5. Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus-
infected cell.
B -cell activation and 1. Th-cell activation as above.
class switching 2. B -cell receptor-mediated cndocytosis; foreign antigen is presented on Ml 1C !i and recognized
by TCR on Th cell.
3. CD40 receptor on B cell binds CD40 ligand ( CD40L) on Th cell.
4. I'll cell secretes cytokines that determine lg class switching of B cell. B cell activates and
undergoes class switching, affinity maturation, and antibody production.

m
g Dendritic cell Thcetl
ICD4+)

B7 (CD80/86)
1
i
Revised!
Figure [

Naive T cell

4
Bcell
 IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES SECTION II 187

Complement System of hepatieallv synthesized plasma proteins that play a role in innate immunity and
inflammation. Membrane attack complex (MAC) defends against gram © bacteria.
ACTIVATION Classic pathway — IgG or IgM mediated. GM makes classic cars.
Alternative pathway— microbe surface
molecules.
—
Lectin pathway mannose or other sugars on
microbe surface.
FUNCTIONS —
C3b opsonization. C3b binds bacteria.
CTa, C4a, C5 a — anaphylaxis.
C 5a neutrophil chemotaxis.
—
-—
C5b 9 cytolysis by MAC.
Opsonins — Csb and IgG are Ihe two 1° Opsonin (Greek) = to prepare for eating,
opsonins in bacterial defense; enhance
phagocytosis. Clb also helps clear immune
complexes.
Inhibitors — decay-accelerating factor ( DAF,
aka CD55 ) and Cl esterase inhibitor help
prevent complement activation on self cells
(eg, RBCs|.

HP1* Bb
C3
Alternative C3bBb C3bBb3b
C3 - >
- C3b -
(C3 conwrtase) IC5 convertasel
Spontaneous and
microbial surfaces
C a
* C5a C6-C9
Lectin
Cl-like
complex C3b
C5 . 4 fMACl - .
lysis
cytotoxicity
Microbial surfaces C4a
(CSb- 9)
leg. mannose)
C4 C 46 C5a
*
c
Classic C 4b2b C 4b2b3b
Cl • - a (C3 convertase) (C5 convertase)
Antigen antibody
complexes
C2 clb C3

* 'Historically, the larger fragment of C2 was

caked C2a but is now referred to as C2b.

Complement disorders
C1 esterase inhibitor
deficiency
Causes hereditary angioedema due to unregulated activation of kallikrein t bradykinin. ACE
inhibitors are contraindicated. Causes hereditary angioedema due to unregulated activation of
—
C3 deficiency
—
kallikrein t bradykinin. Characterized bv 1 C 4 levels. ACE inhibitors are contraindicated.
Increases risk of severe, recurrent pyogenic sinus and respiratory tract infections; t susceptibility to
type 111 hypersensitivity reactions.
C 5-C9 deficiencies Terminal complement deficiency increases susceptibility to recurrent Neisseria bacteremia.
CD55 deficiency! Also called decav-accelerating factor ( DAF) deficiency. Causes complement-mediated lysis of RBCs
and paroxysmal nocturnal hemoglobinuria
188 SECTION II IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES

Important cytokines
SECRETED BY MACROPHAGES
IL-1 pauses fever, acute inflammation. Activates “Hot T-bone stF.AK"
endothelium to express adhesion molecules. IL-1: fever ( hot).
Induces chemokiue secretion to recruit VVBCs. IL-2: stimulates T cells.
IL- s: stimulates bone marrow.
IL-4: stimulates IgE production.
-
IL 5: stimulates IgA production.
IL-6: stimulates aKute-phase protein
production.
IL- 6 Causes fever and stimulates production of acute-
phase proteins.
IL-8 Major chcmotactic factor for neutrophils. “Clean up on aisle 8.” Neutrophils are recruited
by IL-8 to clear infections.
IL-12 Induces differentiation ofT cells into Till cells.
Activates NK cells.
TNF- ot Activates endothelium. Causes VY'BC Causes cachexia in malignancy

SECRETED BY ALLTCELLS
recruitment, vascular leak. -
Maintains granuloma iin TR .
^

IL-2 Stimulates growth of helper, cytotoxic, and

regulatory Tcells, and NK cells.
IL-3 Supports growth and differentiation of bone
marrow stem cells. Functions like CM-CSF.
FROM Thl CELLS
Interferon-y Secreted by NK cells and T cells in response to Also activates NK cells to kill virus-infected
antigen or IL-12|from macrophages; stimulates cells. Increases MHC expression and antigen
macrophages to kill phagocytoscd pathogens. presentation by all cells.
Inhibits differentiation ofThl cells.
FROM Th2 CELLS
IL- 4 Induces differentiation of T cells into Th 2 cells.
Promotes growth of B cells. Enhances class
switching to IgE and IgG.
IL-5 Promotes growth and differentiation of B cells.
Enhances class switching to IgA. Stimulates
growth and differentiation of eosinophils.
IL-10 Attenuates inflammatory response. Decreases TGF-P and IL-10 both attenuate the immune
expression of MHC class II and Thl cytokines. response.
Inhibits activated macrophages and dendritic
cells. Also secreted bv regulators T cells.
Cell surface proteins MHC I present on all nucleated cells ( ie, not mature RBCs).
T cells -
TCR (binds antigen MHC complex)
CD? (associated with TCR for signal
transduction)
CD28 ( binds B7 on APC )
CXCR4/CCR 5 (co-receptors for HIV)
Helper T cells CD4, CD40L
Cytotoxic T cells CD8
CXCR4/CCR 5
Regulatory T cells CD4, CD25
B cells Ig ( binds antigen)
CD19, CD20, CD21 (receptor for EBV), CD40 You can drink Beer at the Bar when you’re 21:
MHC II, B7 B cells, Epstein-Barr virus, CD21.
Macrophages CD14 ( receptor for PAMPs, eg, LPS ), CD40
CCR5
.
MHC II B7 (CD80/86)
Fc and C?b receptors (enhanced phagocytosis)
NK cells ICD56 ( suggcstivdmarker for NK )
Hematopoietic stem CD34
cells

Anergy State during which a cell cannot become activated by exposure to its antigen. T and B cells
become anergic when exposed to their antigen without costimulatory signal (signal 2). Another
mechanism of self-tolerance.

Effects of bacterial
toxins
—
—
Superantigens (S pyogenes and S aureus ) cross link the p region of the T-cell receptor to the MHC
-
class II on APCs. Can activate any CD4+ T cell massive release of cytokines.
—
Endotoxins/lipopolysaccharide (gram @ bacteria ) directly stimulate macrophages by binding to
endotoxin receptor TLR4/CD14; Th cells are not involved.

Antigenic variation Classic examples: Some mechanisms for variation include DNA
—
Bacteria Salmonella ( 2 flagellar variants),
Borrelia recurrentis (relapsing fever).
rearrangement and RNA segment rcassortmer
(eg. influenza maior shift ) or protein mutation
N sionorrhoeae ( pilus protein ) (eg. influenza minor drift).
Viruses-influenza , HIV, HCV
—
Parasites trypanosomes
 IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES SECTION II

Passive vs active immunity

Passive Active
MEANS OF ACQUISITION Receiving preformed antibodies Exposure to foreign antigens
ONSET Rapid Slow
DURATION Short span of antibodies (half-life = s weeks) Long-lasting protection (memory)
EXAMPLES IgA in breast milk, maternal IgG crossing Natural infection, vaccines, toxoid
placenta, antitoxin, humanized monoclonal
antibody
NOTES After exposure to Tetanus toxin. Botulinum Combined passive and active immunizations
toxin, HBV, Varicella,fiabies virus, or _ can be given for hepatitis B or rabies exposure
diphtheria antitoxin, unvaccinated patients are
given preformed antibodies (passive) — “ To Be
Mealed Very Rapidly"

Vaccination Induces an active immune response ( humoral and/or cellular ) to specific pathogens.
VACCINE TYPE DESCRIPTION PROS /CONS EXAMPLES
Live attenuated Microorganism loses its pathogenicity but Pro: induces strong, BCC, influenza
vaccine retains capacity for transient growth within often lifelong ( intranasal ), measles,
inoculated host. Induces cellular and humoral immunity. mumps, polio (Sabin),
responses. MMR and varicella are live Con: mav revert to rotavirus, rubella!
vaccines that can be given to patients with 111V virulent form. Often varicella, yellow fever.
who have a CD4 cell count > 200/mmi contraindicated
in pregnancy and
immunodeficiency.
Inactivated or killed Pathogen is inactivated by heal or chemicals. Pro: safer than live Rabies, Influenza
vaccine Maintaining epitope structure on surface vaccines. .
(injection) Polio
antigens is important for immune response. Con: weaker immune (Salk ), hepatitis A
Mainly induces a humoral response. response; booster (“ R.l.P. Always” ).
shots usually
required.
 IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES SECTION II 193

Hypersensitivity types ( continued )

Type III —
Immune complex antigen-antibody ( IgG)
complexes activate complement , which attracts
In tv pc 111 reaction , imagine an immune
complex as 3 things stuck together: antigen -
l\ -it neutrophils; neutrophils release lysosomal
enzymes. Examples:
-
antibodv complement.

Can be associated with vasculitis and systemic Arthus reaction

A manifestations. SLE
• Polyarteritis nodosa
Poststreptococcal glomerulonephritis
Serum sickness
—
Serum sickness an immune complex disease
in which antibodies to foreign proteins are
Most serum sickness is now caused by drugs
( not serum ) acting as haptens. Fever, urticaria,
produced ( takes 5 days ). Immune complexes arthralgia, proteinuria, Ivmphadenopathy
form and are deposited in membranes, where occur 5-10 days after antigen exposure.
they fix complement ( leads to tissue damage ) .
More common than Arthus reaction .

—
Arthus reaction a local subacute antibody-
mediated hypersensitivity reaction .
Antigen-antibody complexes cause the Arthus
reaction .
Intradermal injection of antigen into a Test: immunofluorescent staining.
presensitized ( has circulating IgG ) individual
leads to immune complex formation in the
skin . Characterized by edema , necrosis, and
activ ation of complement.
Type IV —
Delayed (T-cell-mediated ) type sensitized
T cells encounter antigen and then release
Fourth ( type) and last ( delayed ).
Pell mediated; therefore, it is not transferable by
cytokines ( leads to macrophage activation ). serum .
.
4 T's = T cells Transplant rejections, TB skin
Response does not involve antibodies (vs types I , .
tests Touching (contact dermatitis).
II. and III ). Test: patch test , PPD.
Tl> cells Examples:
Contact dermatitis (eg, poison ivy, nickel
allergy )
a

Multiple sclerosis_
Graft-versus-host disease

* Pernicious anemia
Granulomatous inflammation
JA IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES
Blood transfusion reactions
TYPE PATHOGENESIS
Allergic reaction Type 1 hypersensitivity' reaction
against plasma proteins in
transfused blood.
Anaphylactic reaction Severe allergic reaction.
IgA-deficient individuals
must receive blood products
without IgA.
Febrile nonhemolytic Type II hypersensitivitv
transfusion reaction reaction. Host antibodies
against donor HLA antigens
and WBCs .
Acute hemolytic Tvpc II hvpcrsensitivitv
transfusion reaction reaction. Intravascular
hcmolvsis ( ABO blood
group incompatibility) or
cxtravascular hcmolvsis i host
antibodv reaction against
foreign antigen on donor
RBCs).
Transfusion-related Donor anti-leukocvte
acute lung injury! antibodies against recipient
neutrophils and pulmonary
endothelial cells!]
CLINICAL PRESENTATION TIMING
Urticaria, pruritus, (Within 2- hours
^
wheezing, fever. Treat with
antihistamines.
Dyspnea, bronehospasm, [Within minutes
hypotension, respiratory
arrest, shock. Treat with
epinephrine.
Fever, headaches, chills, [Within 1-6 hours
flushing.
Fever, hvpotcnsion, tachypnea, [V\ ’ithin 1 hour
tachycardia, flank pain,
hemoglobinuria ( intravascular
hemolysis), jaundice
( cxtravascular ).
Respiratory distress and [Within 6 hours
noneardiogenic pulmonary
edema]
 IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES SECTION II

Autoantibodies AUTOANTIBODY ASSOCIATED DISORDER

Anti-ACh reeeptoij Myasthenia gravii

Anti-glomerular basement mcmbrane| Goodpasture syndrome!

-
Anti-3 glycoproteiii Antiphospholipid syndrome!
Anticardiolipin, lupus anticoagulant SLE, antiphospholipid syndromtj
Anticentromerel Limited scleroderma ( CRPiST syndrome!
Anti-desmoglcin (anti-dcsniosomcil Pemphigus vulgaril
.
Anti-glutamic acid decarboxvlase islet cell Type 1 diabetes mellituij
cvtoplasmic antibodies
Antihemidesmosomej Bullous pemphigoid!
Antisvnthetase (eg. anti-lo-1). anti-SRP. anti- Poly myositis, dermatomyositii
'
lielicase (anti-Mi-2l
Antimicrosomal. antithy roglobulin. anti-thvroid Uashimoto thvroiditi'j
peroxidase!

1° biliars cirrhosi
Antimitochrondrialj
Antioarietal cell, anti-intrinsic factoil Pernicious anemia| ^
Antiphospholipasc A, receptoij 1 ' membranous nephropathsj
Anti-Scl-70 (anti-DNA topoisomerase l! Scleroderma (diffuse!
Anti-smooth muscle| Autoimmune hepatitis type lj
Anti-SSA , anti-SSB ( anti-Ro, anti-Lai Sjiigren syndromej
Anti-TSH receptoij Grases disease !
Anti-press naptic voltage-gated calcium channel Lambert-Eaton myasthenic syndrome!
- .
IgA anti endomvsial IgA anti-tissue Celiac disease!
transglutaminase!
MPO-ANCA/p-ANC.Ai .
Microscopic polyangiitis eosinophilic
granulomatosis with pohangiitis ( Churg-Straus >
syndrome), ulccrathc colitis!
PRVA \CA /c-ANC.\i Granulomatosis with pohangiitis ( Wegener!
Rheumatoid factor ( IgM antibody against IgG Rheumatoid arthritii
.
Fc region) anti-CCP ( more specific )!
Antinuclear (ANA! Nonspecific screening antibody, often associated
with Sl Fi.
Anti-dsDNA. anti- Smith! SLPl
Anti-histone Drug-induced lupus
Anti-Ul RNP ( ribonucleoprotein|| Mixed connectirc tissue disease!
196 SECTION I I IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES

Immunodeficiencies
DISEASE DEFECT PRESENTATION FINDINGS
B- cell disorders
X- linked (Bruton) Defect in BTK . a tyrosine Recurrent bacterial and Absent B cells in peripheral
agammaglobulinemia kinase gene no B-cell —
maturation. X-linkcd recessive
enteroviral infections after 6
months ( 1 maternal IgG).
blood, 1 Ig of all classes,
Absent /scanty lymph nodes
(t in Boys) . and tonsils. Live vaccines
contraindicate
Selective IgA Unknown. Most common 1° Majority Asymptomatic.
^
i IgA with normal IgG, IgM
deficiency immunodcficiencv. Can see Airway and GI levels, t suscentibilitv to
.
infections Autoimmune giardiasis. Common in
.
disease Atopy. Anaphylaxis to patients with celiac diseasii
IgA-containing products.
Common variable Defect in B-cell differentiation. Can be acquired in 20s — Alls; 1 plasma cells.
immunodeficiency Many causes. t risk of autoimmune disease, 1 immunoglobulins.
bronchiectasis, lymphoma,
sinopulmonary infections.
T- cell disorders
Thymic aplasia 22qll deletion; failure Tetany (hypocalcemia), i T cells, 1 PTH, 1 Ca -*.
(DiGeorge syndrome) to develop srd and 4th recurrent viral/fungal Absent thymic shadow on
pharyngeal pouches absent
thymus and parathyroids.
— infections (T-cell deficiency),
conotruncal abnormalities
CXRJ
(eg. tetralogy' of Fallot,
truncus arteriosus).
IL-12 receptor 1 Thl response. Autosomal Disseminated mycobacterial l IFN-y.
deficiency recessive. and fungal infections; may
present after administration of
BCG vaccine .
Autosomal dominant Deficiency of Thl7 cells due to FATED: coarse Facies, cold t IgF, i IFN-y _
hyper- lgE syndrome
( Job syndrome)
—
STAT5 mutation impaired
recruitment of neutrophils to
(noninflamed) staphylococcal
Abscesses, retained primary
t eosinophils,

sites of infection. Teeth, t IgE, Dermatologic

problems (eczema).
Chronic T-cell dysfunction. Many Noninvasive Candida albicans Absent in vitro T-cell
mucocutaneous causes. infections of skin and mucous proliferation in response to
candidiasis membranes. Candida antigens.
Absent cutaneous reaction to
Candida antigens.
 IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES SECTION II

Immunodeficiencies ( continued )
"

DISEASE DEFECT PRESENTATION FINDINGS

B - and T-cell disorders
Severe combined Several types including Failure to thrive, chronic -
1 T cell receptor excision
immunodeficiency defective II.-2 R gamma chaindiarrhea , thrush . Recurrent circles ( TRFCs). .
( most common , X-linkcd ), viral, bacterial , fungal, and Absence of thymic shadow
adenosine deaminase protozoal infections. (CXR), germinal centers
deficiency ( autosomal Treatment: bone marrow- ( lymph node biopsy), and
recessive). transplant ( no concern for T cells ( flow cytometry ).

Ataxia -telangiectasia
— rejection ).
Defects in ATM gene failure Triad : cerebellar defects

—
t AFP.

- _
to repair DNA double strand ( Ataxia ), spider Angiomas t IgA , IgG, and IgF.

/ *
V breaks cell cycle arrest . ( telangiectasia y ), IgA
deficiency.
Lymphopenia, cerebellar
atrophy.
t risk of Ivnrphoma and
* G leukemia .

—
Hyper- IgM syndrome Most commonly due to
defective CD40L on Th cells
class sw itching defect;
X-l inked recessive.
Wiskott-Aldrich Mutation in WAS gene;
Severe pyogenic infections
early in life; opportunistic
infection with Pneumocystis,
Cryptosporidium, CMV.
WATER: W iskott-Aldrich :
Normal or t IgM.
it IgG, IgA, IgF,.
Failure to make germinal
centers.
1 to normal IgG , IgM.

—
syndrome leukocytes and plateletj Thrombocytopenia, Eczema, t IgE, IgA.
unable to reorganize actin Recurrent ( pyogenic ) Fewer and smaller platelets.
cvtoskeleton defective infection
antigcn-presentatioiA X-linked ^
t risk of autoimmune disease
recessive. and malignancy.
Phagocyte dysfunction
Leukocyte adhesion Defect in LFA-1 integrin Recurrent bacterial skin and t neutrophils ,

deficiency (type 1 ) (GDIS) protein on mucosal infections, absent Absence of neutrophils at

phagocytes; impaired pus formation, impaired infection sites ,

migration and chemotaxis; wound healing, delayed

autosomal recessive.
Chediak- Higashi Defect in lysosomal trafficking
syndrome regulator gene ( LY'ST ).
Microtubule dysfunction in
separation of umbilical cord
(> 40 days).
Recurrent pyogenic
infections by staphylococci
and streptococci, partial
Giant granules [ Q, arrows) in
granulocytes and platelets.
Pancytopenia .

f phagosotne-lysosome fusion; albinism, peripheral Mild coagulation defects.

I autosomal recessive. neuropathy, progressive

neurodegeneration , infiltrat
lymphohistioevtosis.

Chronic
granulomatous
disease —
Defect ofNADPIl oxidase
I reactive oxygen
species (eg, superoxide )
and i respiratory burst
in neutrophils; X-liuked
t susceptibility to catalase ©
organisms
^
Abnormal dihydrorhodamine
(flow cytometry) test ( l green
fluorescence ).
Nitroblue tetrazolium dye
reduction test fails to turn
recessive most common . blue ( note, this test!is
obsolete!
198 SECTION II IMMUNOLOGY IMMUNOLOGY — IMMUNE RESPONSES

Infections in immunodeficiency
PATHOGEN J!CELLS JBCaLS i GRANULOCYTES l COMPLEMENT
Bacteria Sepsis F.neapsulated ( Please Staphylococcus, Encapsulated species
SHINE mvSKiSi Burkholderia cepacia. with early component
Pseudomonas Pseudomonas deficiencies
aeruginosa, aeruginosa , Serratia, Neisseria with late
Streptococcus Nocardia component { MAC )
pneumoniae , deficiencies
Haemophilus
Influenzae type B,
Neisseria
meningitidis ,
Escherichia coli ,
Salmonella ,
Klebsiella
pneumoniae, group B
Group B
Streptococcus
Viruses CMV, EBV, JC _ Entcroviral N /A N /A
viru.' j VZV, chronic encephalitis,
infection with poliovirus
respiratory/Gl viruses ( live vaccine
contraindicated )
Fungi / parasites Candida ( local ). PCP. G1 giardiasis (no IgA) Candida (systemic), N/A
Crvbtococcui Asberzillus. Mucoii
Note: B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-ccll deficiencies produce more fungal and
viral infections.

Grafts
Autograft From self.
Syngeneic graft From identical twin or clone.
( isograft )
Allograft From nonidentical individual of same species.
Xenograft From different species.
200 SECTION II IMMUNOLOGY IMMUNOLOGY — IMMUNOSUPPRESSANTS

IMMUNOLOGY — IMMUNOSUPPRESSANTS

Immunosuppressants Agents that block lymphocyte activation and proliferation. Reduce acute transplant rejection by
.
suppressing cellular immunity Frequently combined to achieve greater efficacy with i toxicity.
Chronic suppression t risk of infection and malignancy.
DRUG MECHANISM USE TOXICITY NOTES
Cyclosporine Calcincurin inhibitor; Psoriasii rheumatoid Nephrotoxicity ,

hinds cvclophilin. arthritis. hypertension,

Blocks T-cell
activation by
hyperlipidemia
neurotoxicity;
.
preventing IL-2 gingival hyperplasia,
transcription. hirsutism. Both calcineurin
inhibitors are highly
Tacrolimus (FK 506) Calcineurin inhibitor; Transplant rejection Similar to cyclosporine, nephrotoxic.
binds FKS06 binding prophylaxis. t risk of diabetes
protein (FKBP). and neurotoxicity;
Blocks T-cell activation nojgingival
b\ preventing IL-2 hy perplasia or
transcription. hirsutism.
Sirolimus (RapamycinU mTORjmhibitor; binds “ PanSirtopcnia” Kidney “sir -vives.”
FKBP. (pancytopenia ) . Synergistic with
Blocks T-cell insulin resistance, cyclosporine.
activation and B-cell Kidney transplant hyperlipidemia; Also used in drug-
differentiation by rejection prophy laxis not nephrotoxic. eluting stents.
preventing response specifically!
to IL-2
Daclizumab, Monoclonal antibodies; Edema, hy pertension .
basiliximab block 1L-2R. tremor.
Azathioprine Antimetabolite Rheumatoidarthritis. Pancytopenia 6-MP degraded by
precursor of Crohn disease . xanthine oxidase;
6-mercaptopurine. glomerulonephritis. toxicity t by
Inhibits Ivmphocvte other autoimmune allopurinol.
proliferation by conditions. Pronounce “azathio-
blocking nucleotide purine.”
synthesis.

Lupu nephritis.
Mycophenolate
mofetil
Reversibly inhibits
IMP dehy drogenase . ^ GJ upset,
pancytopenia .
Associated with
invasive CMV
preventing purine hypertension, infection.
synthesis of B and T hyperglycemia.
cells. Less nephrotoxic and
ncurotoxic.
Corticosteroid
^ -
Inhibit NF KB.
Suppress both B- and
\ lanv Autoimmune
and inflammatory
Cushing syndrome
osteoporosis.
. Mav experience
adrenal insufficiency
T-cell function by disorders, adrenal hyperglycemia . if stopped abruptly
i transcription of insufficiency, asthma. diabetes, amenorrhea, after chronic usdi
many cytokines. ('LL. non-!lodgkin adrenocortical
Induce apoptosis ofT lvmphonni atrophy , peptic ulcers .
celU psychosis, cataracts.
avascular necrosis
( femoral head ) ]
 IMMUNOLOGY IMMUNOLOGY — IMMUNOSUPPRESSANTS SECTION II

Immunosuppression targets

M Basiiiximab.
dadizumab

FKBP +
CD3 Tacrolimus FKBP + IL- 2R Azathioprine

Cydophilln +
/ Srolimus
(rapamycinl
6- MP
/
/
Mycophenolate
Cyclosporine - 1 Calcineurin N

NFAT-P ^ "
NFAT mTOR 7 r
i
IMP
/ PRPP
amidotransferase
t
dehydrogenase
rogenase /

Proliferation
Corticosteroids „ I genes
Purine
THELPER nucleotides
caL i *
W - KB > Denovo
Inflammatory purine
1 synthesis
V cytokine genes
DNA replication «

Revised
Figure
a

Recombinant AGENT CLINICAL USES

cytokines and clinical Aldesleukin (IL-2) Renal cell carcinoma, metastatic melanoma
uses
Epoetin alfa (erythropoietin) Anemias (especially in renal failure)
FilGRAstim iG CSFi GRAnulocvte - — Recovery of bone marrow
stimulating
SarGRAMOSTIMl(GM-CSF)1 GRAnulocvte and MOnocvte STIMkilation
Recovery of bone marrow
IFN-a Chronic hepatitis B and C, Kaposi sarcoma,
malignant melanoma, hairvcell leukemia,
condvloma acuminatum, renal cell eareinomal
IFN-P Multiple sclerosis
IFN Y - Chronic granulomatous disease
Romiplostim ( thrombopoictin analog), ' 1 h romhocy topenia

eltrombopag ithrombopoietin receptor agonist!

Oprelvekin ( IL-ll ) Thrombocy topenia
202 SECTION II IMMUNOLOGY IMMUNOLOGY — IMMUNOSUPPRESSANTS

Therapeutic antibodies
AGENT TARGET CLINICAL USE NOTES
Cancer therapy
Alemtuzumab CD52 CLL, MS "Alvmtuzumab” — chronic
lymphocytic leukemia
Bevacizumab VEGF Colorectal cancer, renal cell
carcinoma, non-small cell
lung canceij
Cetuximab .
ECFR Stage IVr colorectal cancer,
head and neck cancer
Rituximab CD20 B-cell non-Hodgkin
lymphoma, CLL, rheumatoid
arthritis, ITP
Trastuzumab HFR 2 /neu Breast cancer, gastric cancel HER:— •Iras2zumab”
Autoimmune disease therapy
Adalimumab, Soluble TNF-a IBD, rheumatoid arthritis, .
F tanercept is a decoy
certolizumab, ankylosing spondylitis, TNF- a receptor and not a
qolimumab, psoriasis monoclonal antibody
infliximab!
Eculizumab Complement protein C5 Paroxysmal nocturnal
hemoglobinuria
Natalizumab a4-integrin Multiple sclerosis, Crohn a4-integrin; YVBC adhesion
disease Risk of PML in patients with
JC virus
Ustekinumab IL-12 /IL-2? Psoriasis, psoriatic arthritis
Other applications
Abciximab Platelet glycoproteins llb/llla Antiplatelet agent for lib times Ilia equals
prevention of ischemic “absiximab"
complications in patients
undergoing percutaneous
coronary intervention
Denosumab RANKL Osteoporosis; inhibits osteoclast Denosumab affects osteoclast:
maturation (mimics
osteoprotegerin)
Digoxin immune Fab Digoxin Antidote for digoxin toxicity
Omalizumab IgE Refractory allergic asthma!
prevents IgE binding to FceRI
Palivizumab RSV F protein RSV prophylaxis for high-risk PaliVIzumab — Virus
infants
Ranibizumab, VEGF Neovascular age-related
bevacizumab macular degeneration;
proliferative diabetic
retinopathy and macular
edema!
 Abetalipoproteinemia Autosomal recessive. Chylomicrons, VLDL, LDL absent. Deficiency in ,\poB48, ApoBlOO.
Affected infants present with severe fat malabsorption, steatorrhea, failure to tliriu. Retinitis
1

.
pigmentosa and spinocerebellar degeneration due to vitamin F deficiency. Progressive ataxia.
Acanthocvtosis.
Treatment: Restriction of long- chain fattv ac ids, large doses of oral vitamin E .

90 SECTION I I BIOCHEMISTRY BIOCHEMISTRY — METABOLISM

Familial dyslipidemias
TYPE INHERITANCE PATHOGENESIS T BLOOD LEVEL CLINICAL
1— Hyper- AR Lipoprotein lipase or Chylomicrons, TC, Pancreatitis,
chylomicronemia apoUpoprotein C-ll cholesterol hepatosplenoinegaly, and
deficiency eruptive/pruritie xanthomas
( no t risk for atherosclerosis).
Creamy layer in supernatant.
l|— Familial hyper ¬
AD Absent or defective 1 la: LDL. cholesterol Ileterozygotes (1:500) have
cholesterolemia LDL receptors lib: 1.D1 cholesterol. cholesterol = TOOmg/dL;
VLDLJ homozygotes (sen rare| have
cholesterol » 700+ mg/dL.
Accelerated atherosclerosis (may
have Ml before age 20), tendon
(Achilles) xanthomas, and
cornea] arcus .
III — Dvsbetalipopro- AR Defective ApoE Chvlomicrons. VLDL Premature atherosclerosis.
teinemia tuberoeruptive xanthomas,
xanthoma striatum palmare
IV— Hyper ¬
AD Hepatic VLDL TC . . Hypertriglyceridemia (> 1000
triglyceridemia overproduction of mg/dL) can cause acute
VLDL pancreatitis .
.
Mu
:f;«i :f.T«n:inuntVi r.f

Bacterial structures
STRUCTURE CHEMICAL COMPOSITION FUNCTION
Appendages
Flagellum Proteins. Motility.
Pilus/fimbria Glycoprotein. Mediate adherence of bacteria to cell surface;
sex pilus forms during conjugation.
Specialized structures
Spore Keratin-like coat; dipicolinic acid; Gram © only.
peptidoglycan DNA.. Survival: resist dehydration, heat, chemicals.
Cell envelope
Capsule Organized, discrete polysaccharide layer ( except Protects against phagocytosis.
poly-D glutamate on B anthracis ).
Glycocalyx Loose network of polysaccharides. Mediates adherence to surfaces, especially
foreign surfaces (eg, indwelling catheters).
Outer membrane Outer leaflet: contains endotoxin ( LPS/LOS). Gram © only.
Embedded proteins: porins and other outer Endotoxin: lipid A induces TMF and IL-I;
membrane proteins (OMPs) antigenic O polysaccharide component
Inner leaflet: phospholipids. Most OMPs are antigenic.
Porins: transport across outer membrane.
Periplasm Space between cytoplasmic membrane (Accumulates components exiting gram
and outer membrane in gram © bacteria. © cells, including hydrolytic enzymes
(Peptidoglycan in middle.) (eg. (3-lactamases).
Cell wall Peptidoglycan is a sugar backbone with peptide Net-like structure gives rigtd support, protects
side chains cross-linked by transpeptidase. against osmotic pressure damage.
Cytoplasmic Phospholipid bilayer sac with embedded Site of oxidative and transport enzymes; PBPs
membrane .
proteins (eg penicillin-binding proteins involved in cell wall synthesis.
[ PBPs) ) and other enzymes. Lipoteichoic acids induce I NF and 1L- 1.
Lipoteichoic acids ( gram © only ) extend from
membrane to exterior.

Cell walls
Unique to Common to both Unique to
gram © gram 0
r— i 1

Flagellum — r
Lipoteichoic acid Pilus
jmsud

Endotoxin /LPS outer

''WWV —
Ponn membrane
Gfi i MNH
iRevis
V-iPeptidoglycan Periplasmic space Figu

Cytoplasmic
“membrane "
_ ((5- lactamase location)

Gram (?) Gram 0 a

>11 walls

Unique to Common to both Unique to

gram ® gram 0
r i (
f 1 — Flagellum —
Lipoteichoic acfd PH IS

IS
>
* T .
I - '-.
Endotoxin' /LPS outer
membrane
Ceil wall
Revised!

_—
Figure |
Peptidoglycan
i - Penplasmic
P e n p l a s m i c space
((5-lactamase location)
Cytoplasmic
"
^
membrane "
64kv. .
Gram ® Gram © <3
94 SECTION II MICROBIOLOGY MICROBIOLOGY — BASIC BACTERIOLOGY

Stains
Gram stain First-line lab test in bacterial identification . Bacteria with thick peptidoglycan layer retain crystal
v iolet dye ( gram ©); bacteria with thin peptidoglycan layer turn red or pink ( gram ©) with
counterstain .
The bugs below do not Gram stain well. These Microbes May Lack Real Color
.
Treponema Leptospira Too thin to be visualized.
Mycobacteria Cell wall has high lipid content.
Mycoplasma, Ureaplasma No cell wall.
Legionella, Rickettsia , Chlamydia , Bartonella , Primarily intracellular; also, Chlamydia lack
Ehrlichia , Anaplasma classic peptidoglycan because of i muranuc
acid.
Giemsa stain Chlamydia , Borrelia. Rickettsia. Certain Bugs Really Try my Patience.
Trypanosomes Q, Plasmodium
Periodic acid -Schiff Stains glvcogcn , mucopolysaccharides; used PaSs the sugar.
stain to diagnose Whipple disease ( Tropheryma
whipplei )
Ziehl - Neelsen stain Acid-fast bacteriajpg, Mycobacteria 0 . Alternative is auramine-rhodamiue stain for
*
(carbol fuchsin ) blocardia: stains mvcolic acid in cell wall ) ; screening ( inexpensive, more sensitive but less
protozoa ( eg, Cry0tos0oridium oocvstsj specific ).
India ink stain Cr) ptococcus neofomwns 0; mucicarmine
can also be used to stain thick polysaccharide
capsule red
Silver stain Fungi |cg, Coccidioides Q, Pneumocystis
jirovecii ), Legionella , Helicobacter pylori
Fluorescent antibody Used to identify many bacteria and viruses.
1
Example is FTA-ABS for confirming syphilis.
stain

s.*
aU
irv

Pf
\ , V
•V
' iD
o°

Properties of growth The same type of media can possess both (or neither) of these properties.
media
Selective media Favors the growth of particular organism while preventing growth of other organisms, eg, Thaycr-
Martin agar contains antibiotics that allow the selective growth of Neisseria bv inhibiting the
growth of other sensitive organisms.
Indicator (differential ) Yields a color change in response to the metabolism of certain organisms, eg, MaeConkey agar
media contains a pi I indicator; a lactose fermenter like E coli will convert lactose to acidic metabolites
-» color change.
 SECTION II MICROBIOLOGY MICROBIOLOGY — BASIC BACTERIOLOGY

Intracellular bugs
Obligate intracellular Rickettsia , CHlamydia, COxiella. Rely on host Stay inside (cells ) when it is Really Cl Lilly and
ATP. COld.
Facultative Salmonella , \eisseria , Brucella. Mycobacterium, Some Nasty Bugs May Five FacultativcLY.
intracellular Listeria, Francisella , Legionella, Yersinia pestis .

Encapsulated bacteria Examples are Pseudomonas aeruginosa . Please SHINE my SKiS.

Streptococcus pneumoniae Q Haemophilus
Influenzae type B, Neisseria meningitidis ,
Escherichia coli , Salmonella. Klebsiella
pneumoniae, and group B Strep. Their
capsules serve as an antiphagocytic virulence
Are opsonized, and then cleared by spleen.
Asplenics have l opsonizing ability and thus
t risk for severe infections. Give S pneumoniae .
11 influenzae , N meningitidis vaccines.

- ' n
factor.
Capsular polysaccharide + protein conjugate
serves as an antigen in vaccines.

Encapsulated bacteria Some vaccines containing polysaccharide
vaccines capsule antigens are conjugated to a carrier
protein, enhancing immunogenicity by
promoting T-cell activation and subsequent
class switching. A polysaccharide antigen
alone cannot be presented to T cells.
Pneumococcal vaccine: PCVls ( pneumococcal
.
conjugate vaccine ) PPSV ? s i pneumococcal
polysaccharide vaccine with no coniugatcd
protein)
|f I influenzae type B ( conjugate vaccine)
Meningococcal vaccine ( conjugate vaccine)

Urease-positive .
Proteus , Cryptococcus , II pylori , l reaplasma Pee Cl I LIN KSS.
organisms Socardia , Klebsiella, S epidermidis,
S saprophyticus Urease hydrolyzes urea to
-
release ammonia and CO • t pH. Potentiate
struvite ( ammonium magnesium phosphate)
stones. Proteus most likely to cause struvite
renal calculi]

Catalase- positive Catalase degrades I ECU into H,0 and Cats Need PLACESS to Belch their Hairballs.
organisms bubbles of O,Q before it can be converted
to microbicidal products by the enzyme
myeloperoxidase. People with chronic
granulomatous disease (NADPH oxidase
deficiency) have recurrent infections with
certain catalase © organisms.
Examples: Socardia, Pseudomonas , Listeria ,
Aspergillus, Candida, E coli , Staphylococci,
Serratia. B cepacia, H pylori.
Encapsulated bacteria Some vaccines containing polysaccharide
vaccines capsule antigens are conjugated to a carrier
protein , enhancing inununogcnicity by
promoting T-cell activation and subsequent
class switching. A polysaccharide antigen
alone cannot be presented to T cells.
Pneumococcal vaccine: PCVls ( pneumococcal
conjugate vaccine ). PPSV 2 s ( pneumococcal
polysaccharide vaccine with no conjugated
protein )
|f/ influenzae type B (conjugate vaccine)
Meningococcal vaccine ( conjugate vaccine)

-
Urease positive Proteus , Cryptococcus, H pylori , Ureaplasma , PeeCHUNKSS.
organisms iSocardia , Klebsiella , S epidermidis,

release ammonia and CO - —

S saprophyticus I ' l e a s e hvdrolv /.e.s urea to
t pH . Potentiate
struvite (ammonium magnesium phosphate )
stones. Proteus most likely to cause struvite
renal calculi!

Catalase- positive
organisms
-
Catalase degrades 11 O, into H ?0 and
bubbles of O, Q before it can be converted
Cats Need PLACESS to Belch their Hairballs.

to microbicidal products by the enzyme

.
V myeloperoxidase. People with chronic
granulomatous disease ( NADPH oxidase
A. V
deficiency) have recurrent infections with
certain catalase © organisms.
Examples: Kocardia , Pseudomonas , Listeria ,
• \
Aspergillus , Candida , E coli , Staphylococci,
Serratia , B cepacia , H pylori.

MICROBIOLOGY MICROBIOLOGY — BASIC BACTERIOLOGY SECTION II

-
Pigment producing
bacteria
—
Actinomyces israelii yellow "sulfur" granules,
w hich are composed of filaments of bacteria ,
Israel has yellow sand .

—
S aureus yellow pigment.
1’ aeruginosa — blue-green pigment ( pvoevanin
Aureus ( Latin) = gold.
Acrugula is green .
and .
p\ overdin )

—
Serratia marcescens red pigment . —
Serratia marcescens think red maraschino
cherries.

In vivo biofilm- S epidermidis Catheter and prosthetic device infections

producing bacteria Viridans streptococci ( S mutans, S sanguinis) Dental plaques, infective endocarditis
Paeruginosa Respirators tree colonization in patients
-
with evstic fibrosis, ventilator associated
pneumonia , contact lens-associated kcratitU

Nontypeable ( unencapsulated ) H influenza Otitis media

Bacterial virulence Tlipse nmmnte evadnn of IHKI inimiinp resnnnsp

 -
Spore forming Some bacteria can form spores Q at tire end Bacillus anthracis Anthrax
bacteria of the stationary phase when nutrients are Bacillus cereus Food poisoning
limited. Clostridium botulinum Botulism
Spores are highly resistant to heat and Clostridium difficile Pseudomembranous
£ jr j chemicals. Have dipicolinic acid in their core.
1 lave no metabolic activity. Must autoclave to
colitis
Clostridium perfringens Gas gangrene
MV potentially kill spores (as is done to surgical Clostridium tetani Tetanus
equipment ) by steaming at 121°C for 15 Be Cerious About ALL Clostridia .
minutes.

MICROBIOLOGY > MICROBIOLOGY — BASIC BACTERIOLOGY [l

Main features of exotoxins and endotoxins

PROPERTY Exotoxin Endotoxin
SOURCE Certain species of gram © and gram © bacteria Outer cell membrane of most gram © bacteria
SECRETED FROM CELL Yes No
CHEMISTRY Polypeptide Lipid A component of LPS (structural part of
bacteria; released when lysed )
LOCATION OF GENES Plasmid or bacteriophage Bacterial chromosome
ADVERSE EFFECTS High ( fatal dose on the order of 1 pg ) Low (fatal dose on the order of hundreds of
micrograms )
CLINICAL EFFECTS Various effects (see following pages ) Fever, shock ( hypotension ), DIC
MODE OF ACTION Various modes (see follow ing pages) Induces TNF, IL-1, and IL-6
ANTIGENICITY Induces high-titer antibodies called antitoxins Poorly antigenic
VACCINES Toxoids used as vaccines No toxoids formed and no vaccine available
HEAT STABILITY Destroyed rapidly at 60 <>C (except Stable at 1 ()0°C for 1 hr
.
staphvlococc il enterotoxin and E coli heat-
stable toxin!
TYPICAL DISEASES Tetanus, botulism, diphtheria Mcningococcemia; sepsis by gram © rods
 MICROBIOLOGY MICROBIOLOGY — BASIC BACTERIOLOGY SECTION II 101

Bugs with exotoxins (continued )

BACTERIA TOXIN MECHANISM MANIFESTATION
Lyse cell membranes
Clostridium
perfringens
Alpha toxin Phospholipase (Iccilhinase)
that degrades tissue and
—
Degradation of phospholipids myonecrosis
( "gas gangrene") and hemolysis ( “ double zone”
cell membranes of hemolysis on blood agar)
Streptococcus Streptolysin O Protein that degrades cell Lyses RBCs; contributes to fj-hemolysis;
pyogenes membrane host antibodies against toxin (ASO) used to
diagnose rheumatic fever ( do not confuse
with immune complexes of poststreptococcal
glomerulonephritis)
Superantigens causing shock
Staphylococcus Toxic shock Binds to MHC II and ICR Toxic shock syndrome: fever, rash, shock; other
aureus syndrome toxin outside of antigen binding toxins cause scalded skin syndrome (exfoliative
( TSST-1) site to cause overwhelming toxin) and food poisoning ( cntcrotoxin)
Streptococcus Exotoxin A release of IL-1, IL-2, Toxic shock-like svndromd fever, rash, shock
IFN-v, and TNF-a
pyogenes
— shock

Endotoxin LPS found in outer membrane of gram © .

FNDOTOXINS:
bacteria ( both cocci and rods). Composed of Edema
O antigen + core polysaccharide + lipid A itlie N itric oxide
toxic component). DIC/Death
Released upon cell lysis or by living cells by Outer membrane
blebs detaching from outer surface membrane TNF-a
(vs exotoxin, which is actively secreted ). O-antigen + core polysaccharide + lipid A
Three main effects: macrophage activation eXtrcmcly heat stable
( TLR4), complement activation, and tissue IL-1 and IL-6
factor activation. Neutrophil chcmotaxis
Shock

-
IL L IL-6 Fever

Macrophage activation
(TLR4)
TNF-a Fever and hypotension

Nitric oxide Hypotension

Endotoxin
(lipid A component) Complement activation rL Cfc

C5a
8 3
—
j
Histamine release
Hypotension and edema

Neutrophil chemotaxis

Coagulation
Tissue factor activation DIC
cascade a
104 SECTION II MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Staphylococcus Gram ©, catalase ©, coagulase ©, urease © cocci in clusters. Novobiocin resistant.

saprophyticus Normal flora of female genital tract and perineum .
Second most common cause of uncomplicated UTI in young women ( most common cause is
E coli ).

Streptococcus Gram ©. lancet-shaped diplococci Q Pneumococcus is associated with "rusts ”

pneumoniae Encapsulated. IgA protease. Optochin sputum , sepsis in patients with sickle cell
sensitive. Most common cause of: disease and splenectomy.

4 T
* Meningitis No sarulencc without capsule.
Otitis media ( in children )
Pneumonia
Sinusitis

t ' V

Viridans group Gram ©. a-hemolytic cocci. They arc normal
streptococci flora of the oropharynx that cause dental
caries ( Streptococcus mutam and S mitis)
and subacute bacterial endocarditis at
damaged heart valves (S sanguinis ) Resistant
to optochin. differentiating them from
-
Sjpneumoniae, which is a hemolytic hut is
optochin sensitise.
Sanguinis = blood. Think, "there is lots of
blood in the heart ” (endocarditis). S sanguinis
makes dextrans, which bind to fibrin -platelet
aggregates on damaged heart salves
Viridans group strep lise in the mouth because
- - --
they are not afraid of the chin (op to chin
resistant).

Streptococcus Gram © cocci. Group A strep Q cause: JvNF.S ( major criteria for acute rheumatic
pyogenes ( group A —
Pyogenic pharyngitis, cellulitis, impetigo fever):
streptococci ) ( " hones -crusted " lesions ) , ers sipelas

—
Toxigenic scarlet fever , toxic shock-like — —
Joints polyarthritis
v carditis
syndrome, necrotizing fasciitis Nodules (subcutaneous)
—
Immunologic rheumatic feser,
glomerulonephritis
Erythema marginatum
Sydenham chorea
Bacitracin sensitise, P-hemolytic, pvrrolidonyl Pharyngitis can result in rheumatic “ phever"
/ X arylamidase I PVRi ©. Hsaluronie acid capsule and glomerulonephritis.
inhibits phagocytosis. Antibodies to M protein Impetigo usually precedes glomerulonephritis.
enhance host defenses against S pyogenes but
can give rise to rheumatic feser.
—
Scarlet fever blanching, sandpaper-like body
rash , strawberry tongue, and circumoral
ASO titer or anti - PNasc B antibodies indicate pallor in the setting of group A streptococcal
recent S pyogenes infectioij pharyngitis (erythrogenic toxin © ).
Bacillus anthracis Gram ©. spore-forming rod that produces anthrax toxin . The only bacterium with a polypeptide

Cutaneous anthrax

r
—
capsule (contains D-glutamate ). Microscopy show ' s long chains resembling "medusa heads."

—
Painless papule surrounded hy vesicles ulcer with black eschar ( Q) ( painless, necrotic !
uncommonly progresses to bacteremia and death.

jp

Pulmonary anthrax
—
Inhalation of spores flu -like symptoms that rapidly progress to fever, pulmonary hemorrhage,
mediastinitis, and shock . Also known as woolsorter 's disease
106 SECTION II MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Bacillus cereus Gram © rod. Causes food poisoning. Reheated rice syndrome.
Spores survive cooking rice. Keeping rice
warm results in germination of spores and
enterotoxin formation.
Emetic type usually seen with rice and pasta.
Nausea and vomiting within 1-5 hr. Caused
by cereulide, a preformed toxin.
Diarrheal type causes watery, nonbloody
. -
diarrhea and C1 pain within 8 18 hr.

Clostridia ( with Gram ©, spore-forming, obligate anaerobic rods.

exotoxins)
C tetani Produces tetanospasmin, an exotoxin causing Tetanus is tetanic paralysis.
tetanus. Tetanus toxin (and botulinum toxin i
are proteases that cleave SNARE proteins for
neurotransmitters. Blocks release of inhibitory
neurotransmitters, GABA and glycine, from
Rcnshaw cells in spinal cord.
Causes spastic paralysis, trismus (lockjaw), risus
sardonicus (raised eyebrows and open grin ),
opisthotonos ( spasms of spinal extensorj).
Prevent with tetanus vaccine. Treat with
antitoxin +/- vaccine booster, diazepam ( for
muscle spasms), and wound debridement.
C botulinum Produces a heat-labile toxin that inhibits Symptoms of botulism ( the 4 D 'si: Diplopia .
ACh release at the neuromuscular junction, Dysarthria, Dvpshagia, Dyspnea .
causing botulism. In adults, disease is caused Botulinum is from bad bottles of food, juice, and
by ingestion of preformed toxin. In babies, honey (causes a descending flaccid paralysis).
ingestion of spores (eg, in honey) leads to Local botox injections used to treat focal
disease ( floppy baby syndrome ). Treat with dystonia, achalasia, and muscle spasms. Also
antitoxin. used for cosmetic reduction of facial wrinkles.
C perfringens Produces a toxin ( lecithinase, a phospholipase) Perfringens perforates a gangrenous leg.
that can cause myonecrosis ( gas gangrene Q)
and hemolysis.
Spores can survive in undercooked food:
when ingested, bacteria release heat-labile
—
enterotoxin food poisoning.

C difficile Produces 2 toxins. Toxin A, enterotoxin, binds to Difficile causes diarrhea. Treatment:
brush border of gut and alters fluid secretion. metronidazole or oral vancomycin. For
Toxin B. evtotoxin, causes cvtoskcletal recurrent cases, consider repeating prior
disruption via actin depolvmerization. Both regimen, fidaxomicin, or fecal microbiota
C difficile Produces 2 toxins. Toxin A. cntcrotoxin, binds to Difficile causes diarrhea. Treatment:
brush border of gut and alters fluid secretion. metronidazole or oral vancomycin. For
, .
Ihxin It cvlotoxin. (.Muses cvtoskclct il recurrent cases, consider repeating prior
disruption via actin depolv merization. Both regimen, fidaxomicin, or fecal microbiota
—
toxins lead to diarrhea pseudomembranous
|Often 2° to antibiotic use, especially
colitis Q
clindamycin or ampicilliu; associated with PP1
transplant.

use. Diagnosed bv detecting one or both toxins

in stool by PCR ,

MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY SECTION II

Corynebacterium Gram © rod; transmitted via respirators Coryne = club shaped.

diphtheriae droplets. Causes diphtheria via exotoxin Black colonies on cystine-tellurite agar.
encoded by Pprophage. Potent exotoxin ABCDEFG:
inhibits protein synthesis via ADP-ribosvIation ADP-ribosylation
ofEF-2. P-prophage
Symptoms include pseudomembranous Corynebacterium
phary ngitis ( grayish-white membrane Q) Diphtheriae

i A
with lymphadenopathy, myocarditis, and
arrhythmias.
Lab diagnosis based on gram © rods with
metaehromatic ( blue and red) granules and
Elongation Factor 2
Granules

© Elek test for toxin .

Toxoid vaccine prevents diphtheria.

Listeria Gram ©, facultativ e intracellular rod; acquired by ingestion of unpasteurized dairy products and
monocytogenes cold deli meats, via transplacental transmission, or by vaginal transmission during birth. Grows
well at refrigeration temperatures (4C-10°C; “ cold enrichment "!
Forms “rocket tails" (red in Q) via actin polymerization that allow intracellular movement and cell-
to-cell spread across cell membranes, thereby avoiding antibody. Characteristic tumbling motility'
in broth.
{
Can cause amnionitis, septicemia, and spontaneous abortion in pregnant women; granulomatosis
V infantiseptica; neonatal meningitis; meningitis in immunocompromised patients; mild, self-
limited gastroenteritis in healthy individuals.
Treatment: ampicillii)

Nocardia vs Both are gram 0 and form long, brandling filaments resembling fungi.
Actinomyces Nocardia Actinomyces
Aerobe Anaerobe
fV - Acid fast ( weak) Q Not acid fast Q

y
w T
Found in soil
Causes pulmonary infections in
immunocompromised (can mimic TB but
with © PPD ); cutaneous infections after
trauma ill immunocompetent
Normal oral, reproductive, and Gl flora
Causes oral/facial abscesses that drain through
sinus tracts, often associated with dental caries/
extraction; form jvcllovv “ sulfur granules;" can
also cause P1D with IUDs
Z Treat with sulfonamides (TMP-SMX ) Treat with penicillin
Treatment is a SNAP: Sulfonamides — Vocrmfia; Actinomyces — Penicillin
Primary and secondary tuberculosis
Mycobacterium
'*' * * tuberculosa
PPD © if current infection or past exposure.
i PPD © if no infection and in sarcoidosis or
i
HIV infection ( especially with low CD4+ cell
Ghon
com pie* Ghon locus -v - count!
(usually mid /
Interferon-y release assay ( IGRA) has fewer false
lower lobes!
__
Primary tuberculosis
1
positives from BCG vaccination .
> 90X | }< m Caseating granulomas with central necrosis
Healing by fibrosis Progressive primary tuberculosis ( upper left) and Langhan jgiant cells (arrow)
Calcification (AIDS malnutrition)
are characteristic of 2° tuberculosis.
,

(tuberculin ®)

Reactivation Progressive D
lung disease
2* tuberculosis
- Bacteremia
- M'
Fibrocaseous
cavitary lesion
1/ '
.vv -
( usually upper
lobes) V Milia
tubercu

!
rcrabne
i rt 1 . . v
; 1

'
-
.
amm & rJ

Localized destructive disease Lymph nodes

Cavity N ;
Caseation
Scar
-4 Lungs
V ’, ' I
Liver
--- 1
1 rin .l
'

V"” Joints and

long bones

Mycobacteria Mycobacterium tuberculosis ( TB, often resistant TB symptoms include fever, night sweats,
to multiple drugs). weight loss, cough ( nonproductive or
M avium— intmcellulare ( causes disseminated , productive ), hemoptysis.
non- I B disease in AIDS; often resistant to Cord factor creates a "serpentine cord ”
multiple drugs). Prophylaxis with azithromycin appearance in virulent M tuberculosis

m>A when CDT + count < 50 cclls/mm '.

M scrofulaceum (cervical lymphadenitis in
children ).
M marinum ( hand infection in aquarium
handlers).
All mycobacteria are acid-fast organisms ( pink
strains; inhibits macrophage maturation and
induces release ofT\ F-a. Sulfatides (surface
glycolipids ) inhibit phagolysosomal fusion.

rods; arrows in Q),

MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY SECTION II

Leprosy ( Hansen Caused by Mycobacterium leprae , an acid-fast bacillus that likes cool temperatures ( infects skin
disease)
—
and superficial nerves "glove and stocking” loss of sensation Q) and cannot be grown in vitro .
Diagnosed via skin biopsy or tissue FCHj Reservoir in United States: armadillos.
Hansen disease has 2 forms:
—
Lepromatous presents diffusely over the skin, with leonine ( lion-like) facies 0, and is
communicable; characterized by low cell-medialcd immunity with a humoral Th 2 response.
Lepromatous form can be lethal .
Tuberculoid — limited to a few hypocsthetic, hairless skin plaques; characterized by high cell-
mediated immunity with a largely Th 1-type immune response.
Treatment: dapsone and rifampin for tuberculoid form ; clofazimine is added for lepromatous form .
Neisseria Gram © diplococci. Metabolize glucose MemnGococci ferment Maltose and Glucose.
and produce IgA proteases. Contain Gonococci ferment Glucose.
lipooligosacclraridcs ( LOS ) with endotoxin -
like cytotoxic capabilities. N gonorrhoeae is
often intracellular (within neutrophils ) Q.
Gonococci Meningococci
No polysaccharide capsule Polysaccharide capsule
No maltose metabolized Maltose fermentation

, No vaccine due to antigenic variation of pilus

proteins
Vaccine ( type B vaccine not widely available)

Sexually or perinatally transmitted Transmitted via respiratory and oral secretions

Causes gonorrhea, septic arthritis, neonatal
—
conjunctivitis ( 2 5 days after birth!pelvic
inflammatory disease ( PID), and Fitz- Hugh-
Curtis syndrome
Condoms i sexual transmission , erythromycin
eye ointment prevents neonatal blindness
Treatment: ceftriaxone + ( azithromycin
or doxycycline ) for possible chlamydial
coinfection
Causes mcningococcemia w ith petechial
hemorrhages and gangrene of toes ,
-
meningitis, Waterhouse Friderichsen
syndrome (adrenal insufficiency, fever, DIC,
shock1
Rifampin , ciprofloxacin, or ceftriaxone
prophylaxis in close contacts
Treatment: ceftriaxone or penicillin G

Haemophilus Small gram © (coccobacillary ) rod . Aerosol Vaccine contains tvpc b capsular polysaccharide
influenzae transmission . Nontypeable ( uncncapsulated ) ( pol \ ribosvlrihitol phosphatei conjugated
strains are the most common cause of mucosal ttjdiphthcria toxoid or other protein . Given
infections iotitis media , conjunctivitis, between 2 and 18 months of age.
bronchitis ) as well as invasive infections since Does not cause the flu (influenza virus docsl.
the vaccine for capsular type b as introduced.
w
Produces IgA protease. Culture on chocolate
agar, which contains factors V ( NAD*) and X
( hematin ) for growth ; can also be grown with
S aureus , which provides factor V through the
hemolysis of RBCs. HaEMOPhilus causes
Fpiglottitis ( endoscopic appearance in JJ .
can be “ cherry red" in children; “ thumb sigrf
-
on x ray Q ) , Meningitis, Otitis media , and
Pneumonia.
Treatment: amoxicillin +/- clavulanate for
mucosal infections; ceftriaxone for meningitis;
rifampin prophylaxis for close contacts.
 MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY SECTION II

Bordetella pertussis Gram ©, aerobic coccobacillus. Virulence factors include pertussis toxin (disables Gj and tracheal
cytotoxin. Three clinical stages:
—
Catarrhal low -grade fevers, corvza .
Paroxysmal — paroxysms of intense cough followed In inspirator! "w hoop" ( ''whooping cough " ) ,
posttussive vomiting.

—
Convalescent gradual recovery of chronic eouglj
Prevented by Tdap. DTaP vaccines. May be mistaken as viral infection due to lymphocytic
fr/ tni iinmnnn rpcnrtnco
• Ecthyma gangrenosum piperacillin , ticarcillin )
UTIs
• Diabetes, drug use
—
Aeruginosa aerobic.
Mucoid polysaccharide capsule max contribute
Osteomyelitis (eg. puncture wounds) to chronic pneumonia in cystic fibrosis patients
Mucoid polysaccharide capsule due to biofilm formation.
• Otitis externa (swimmer’s car ) Can cause wound infection in burn victims.
• Nosocomial infections (catheters, Corneal ulcers /keralitis in contact lens wearers/
equipment) minor cxc trauma .
• exotoxin A Frequently found in water -* hot tub folliculitis.
Skin infections ( hot tub folliculitis) —
Ecthyma gangrenosum rapidly progressive,
necrotic cutaneous lesion Q caused by
Pseudomonas bacteremia , ' typically seen in
immunocompromised patients.
 SECTION II MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Escherichitjcoli Cram © rod. £ coli virulence factors: fimbriae cystitis and pyelonephritis ( P-pili ); K capsule-
—
.
pneumonia neonatal meningitis; LPS endotoxin — septic shock.
STRAIN TOXIN ANO MECHANISM PRESENTATION
EIEC Microbe invades intestinal mucosa and causes Invasive; dysentery. Clinical manifestations
necrosis and inflammation. similar to Shigella.
ETEC Produces heat-labile and heat-stable Travelers' diarrhea ( watery).
enteroToxins. No inflammation or invasion.
EPEC No toxin produced. Adheres to apical surface, Diarrhea, usually in children ( Pediatrics).
flattens villi, prevents absorption.
EHEC 0157:H7 is most common serotype in US. Often Dysentery ( toxin alone causes necrosis and
transmitted via undercooked meat, raw leafs inflammation).
vegetables. Does not ferment sorbitol or produce
Shiga-like toxin causes hemolytic- uremic glucuronidase ( vs othciit' coli ).
syndrome: triad of anemia, thrombocytopenia, Hemorrhagic, Hamburgers, Hemolytic-uremic
and acute renal failure due to microthrombi syndrome.
forming on damaged endothelium
— mechanical hemolysis (with schistocytes on
peripheral blood smear), platelet consumption,
and l renal blood flow.

Klebsiella Gram © rod; intestinal flora that causes lobar |A’s of KlebsiellA:
s

pneumonia in alcoholics and diabetics when Aspiration pneumonia

aspirated. Very mucoid colonics [J caused by Abscess in lungs and liver
abundant polysaccharide capsules. Dark red Alcoholics
"currant jelly" sputum ( blood/mucus). di-A-betics_
“ Curr-A -nt jelly ’ sputum
1

Also cause of nosocomial UTIs.

 liusc spms UII d i i u o i i i c u ,

constipation, abdominal sources

pain , fever ); treat Antibiotics not S flexneri , S boydii, S sannei
with ceftriaxone or indicated Invasion of M cells is kev to
fluoroquinolone - Gastroenteritis is pathogenicity; organisms that
Carrier state with usually caused by non - -
produce little toxin can cause disease
gallbladder colonization typhoidal Salmonella due to invasioij

Vibrio choierae Gram ©, flagellated , comma shaped 0, oxidase ©, grows in alkaline media. Endemic to
developing countries. Produces profuse rice-water diarrhea via enterotoxin that permanently
activates Gs, t cAMP. Sensitive to stomach acid ( acid labile ); requires large inoculum ( high ID- ( I )
unless host has l gastric acidity Associated with contaminated water and sealood . Prompt oral
rehydration is necessary.

Yersinia enterocolitica Gram © rod . Usually transmitted from pet feces (eg, puppies), contaminated milk , or pork . Causes
acute diarrhea or pseudoappendicitis ( right lower abdominal pain due to mesenteric adenitis and /
or terminal ileitis).
 4 11 MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Helicobacter pylori Curved , terminally flagellated ( motile ), gram ) ) rod [|that is triple ®: catalase ®, oxidase ®, and
-

urease ® ( can use urea breath test or fecal antigen test for diagnosis). Urease produces ammonia ,
creating an alkaline environment, which helps H pylori survive in acidic mucosa. Colonizes
mainly antrum of stomach ; causes gastritis and peptic ulcers (especially duodenal i . Risk factor for
peptic ulcer disease, gastric adenocarcinoma , and M ALI ' lymphoma .
Most common initial treatment is triple therapy: Amoxicillin ( metronidazole if penicillin allergy )
+ Clarithromycin + Proton pump inhibitor; Antibiotics Cure Pylori .

Spirochetes Spiral-shaped bacteria Q with axial filaments. BLT.

Includes Horrelia ( bigsize), Leptospira, and llorrelia is Big.
Treponema. Only Horrelia can be visualized
using aniline dyes ( Wright or Gicmsa stain )
in light microscopy due to size. Treponema is
visualized by dark-field microscopy or direct
fluorescent antibods ( DFA ) microscopy.

Leptospira interrogans Spirochete with hook-shaped ends found in water contaminated with animal urinejCausc 4
leptospirosis — flu-like symptoms, myalgias (classically of calves), jaundice, photophobia with
conjunctival suffusion (erythema without exudate). Prevalent among surfers and in tropics ( eg,
Hawaii ).

—
Weil disease ( ictcrohemorrhagic leptospirosis) severe form with jaundice and azotemia from liver
and kidney dysfunction, fever, hemorrhage, and anemia .

Lyme disease Caused by Horrelia burgdorferi , which is
transmitted by the Ixodes deer tick ^3 (also
vector for Anaplasma spp. and protozoa
Habesia ). Natural reservoir is the mouse.
Mice are important to tick life cycle.
Common in northeastern United States.
—
Stage 1 early localized: erythema migrans Q,
flu -like symptoms.
A Key Lyme pie to the PACK:
Facial nerve palsy ( ty pically bilateral )
Arthritis
Cardiac block
Erythema migrans.
Treatment: doxvcvline ( 1st line ); amoxicillin and
cefuroxime in pregnant women and children .

—
Stage 2 early disseminated: secondary lesions,
carditis, AV block , facial nerve ( Bell ) palsy,
migratory myalgias/transient arthritis.
—
Stage s late disseminated: encephalopathies,
chronic arthritis.
 MICROBIOLOGY MTUUJDTUTUGT UJNIIAL DALI tKiULUUY 1HIL 1i L I

Rickettsial diseases Treatment for all: doxvcvclinc [ except during pregnancvil

and vector-borne
illnesses
RASH COMMON
Rocky Mountain Rickettsia rickettsii. vector is tick. Despite its Classic triad— headache, fever, rash (vasculitis).
spotted fever name, disease occurs primarily in the South Palms and soles rash is seen in Coxsackievirus
Atlantic states, especially North Carolina. A infection ( hand, foot, and mouth disease),
Rash ty pically starts at wrists and ankles and Roekv Mountain spotted fever, and 2° Syphilis
then spreads to trunk, palms, and soles. ( you drive CARS using your palms and soles).
Typhus Endemic ( fleas) — R txplii. Rickettsii on the wRists, Typhus on the Trunk.
Epidemic ( human body louse) — R prowazekii .
Rash starts centrally and spreads out, sparing
palms and soles.
RASH RARE

Ehrlichiosis Ehrlichia, vector is tick. Monocytes with MEGA berry —

morulae £J (mulberry-like inclusions ! in
cytoplasm.
Anaplasmosis Anaplasma, vector is tick. Granulocytes with
morulae Q in cytoplasm.
Q fever Coxiella burnetii , no arthropod vector. Spores
inhaled as aerosols from cattle/sheep amniotic
fluid. Presents as pneumonia. Common cause
of culture © Endocarditis.
Monocytes = Ehrlichiosis
Granulocytes = Anaplasmosis
y fever is Queer because it has no rash or vector
and its causative organism can survive outside
in its endospore form. Not in the Rickettsia
genus, but closely related.
B, *'
i

4 l /

1#
118 SECTION II MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Chlamydiae Chlamydiae cannot make their own ATP. They Chlamys = cloak (intracellular).
are obligate intracellular organisms that cause C psittaci — has an avian reservoir (parrots),
mucosal infections. 2 fomis: causes atypical pneumonia.
Elementary body (small, dense) Lab diagnosis: PCR, nucleic acid amplification
is "Knfectious" and Enters cell via test. Cvtoplasmiclinclusions seen on Giemsa or
Endocytosis; transforms into reticulate body. fluorescent antibody— stained smear.
Reticulate body Replicates in cell by fission; The chlamydial cell wall lacks classic
Reorganizes into elementary bodies. peptidoglvcan ( due to reduced muramic acid ),
Chlamydia trachomatis causes reactive arthritis rendering (5-lactam antibiotics less effective.
(Reiter syndrome ), follicular conjunctivitis Q,
nongonococcal urethritis, and I’ll )
Chlamydophila pneumoniae and Chlamxdophila
psittaci cause atypical pneumonia; transmitted
by aerosol.
Treatment ' azithromycin ( favored because one
, ¬

time treatment ) or doxvcvclinc; (+ ceftriaxone

C rul ;i- _i t i
118 SECTION II MICROBIOLOGY MICROBIOLOGY — CLINICAL BACTERIOLOGY

Chlamydiae Chlamydiac cannot make their own ATP. They
are obligate intracellular organisms that cause
mucosal infections. 2 forms:
• Elementary body (small, dense)
is "Knfectious" and Enters cell via
Endocvtosis; transforms into reticulate body.
Reticulate body Replicates in cell by fission;
Reorganizes into elementary bodies.
Chlamydia trachomatis causes reactive arthritis
( Reiter syndrome ), follicular conjunctivitis ,
nongonococcal urethritis, and I’ll)
Chlamydophila pneumoniae and Chlamxdopliila
psittaei cause atypical pneumonia; transmitted
by aerosol.
Treatment : azithromycin ( favored because one
Chlamys = cloak ( intracellular).
C psittaei — has an avian reservoir ( parrots),
causes atypical pneumonia.
Lab diagnosis: PCR, nucleic acid amplification
test . Cytoplasmic!inclusions seen on Giemsa or
fluorescent antibody-stained smear.
The chlamydial cell wall lacks classic
peptidoglycan (due to reduced muramic acid),
rendering P-lactam antibiotics less effective.
¬

time treatment ) or doxvcyclinc; ( + ceftriaxone

for possible concomitant gonorrheal

Chlamydia trachomatis serotypes

Types A, B, and C Chronic infection, cause blindness due to ABC = Africa, Blindness, Chronic infection.
follicular conjunctivitis in Africa.
Types D- K Urethritis/PID, ectopic pregnancy, neonatal D-K = everything else.
pneumonia (staccato cough) with eosinophilia, Neonatal disease can be acquired during
neonatal conjunctivitis ( 1— 2 weeks after birthj passage through infected birth canal.
Types LI, L2, and L3 Lymphogranuloma venereum — small, painless
ulcers on genitals -* swollen, painful inguinal
lymph nodes that ulcerate ( buboes). Treat with
doxycycline.

Mycoplasma Classic cause of atypical “ walking” pneumonia
pneumoniae ( insidious onset, headache, nonproductive
cough, patchy or diffuse interstitial infiltrate ).
X-ray looks worse than patient. High titer of
s' cold agglutinins (IgM), which can agglutinate
or lyse RBCs. Crown on Eaton agar.
Treatment: macrolides, doxycycline, or
fluoroquinolone (penicillin ineffective since
Mycoplasma have no cell wall).
No cell wall. Not seen on Gram stain.
Pleomorphic Q.
Bacterial membrane contains sterols for stability.
Mycoplasmal pneumonia is more common in
patients < 30 years old.
Erequcnt outbreaks in military recruits and
prisons.
Mycoplasma gets cold w ithout a coat (cell wall).
 MICROBIOLOGY MICROBIOLOGY — MYCOLOGY

MICROBIOLOGY — MYCOLOGY

ystemic mycoses All of the following can cause pneumonia and can disseminate. _
All are caused bv dimorphic fungi: cold (20°C ) = mold; heat ( 37 ) = veast. The only exception is
Qiccidioidoe which is a spherule (not yeast) in tissue. _ ^
^
Svstemic mycoses can form granulomas i like TB ); cannot be transmitted person-to-person (unlike
TB ).
Treatment: fluconazole or itraconazole for local infection; amphotericin B for systemic infection !
DISEASE ENDEMIC lOCATIOIi| PATHOtOGIC FEATURES UNIQUE SIGNS/S VMPTOM NOTES
Histoplasmosis Mississippi and Ohio Macrophage filled
^
Palatal /tonguc ulcers. Ilisto hides ( w ithin
River \Jillev4 with Histoplasnia splenomegaly] macrophages ) Bird

m I ( smaller than (eg, starlings ) or bat

RBC ) Q droppings.
Diagnosis made via
•«. determination of
urme /scruni antigen.

Blastomycosis Kastern and Broad-base budding Inflammatory Blasto Inids hroadlv.

n Central US of Blastomyces ( same lung disease, can

M
1 size as RBC) fj. disseminate to skin /
bone. Verrucous skin
lesions can simulate
SCC. Forms
granulomatous
nodules]
Coccidioidomycosis Southwestern US! Spherule ( much larger Disseminates Coccidio crowds
California than RBC ) filled to skin/bone. endospores.
I with endospores of .
Frslhema nodosum
Coccidioides H. ( desert bumpsl
or multifonne.
Arthralgias (desert
rheumatism ). Can
*”w #
cause meningitis!
Para ¬
Latin America! Budding veast of Similar to Paracoccidio parasails
coccidioidomycosis I’artjcoccidiodtrs with coccidiomvcosis . w ith the captain 's
“ captain's wheel’’ males > females] wheel all the was to
jiW
'

Latin America.
• .
formation (much
larger than RBC j [ A .
120 SECTION II MICROBIOLOGY MICROBIOLOGY — MYCOLOGY

Cutaneous mycoses
Tinea Tinea is the clinical name given to dermatophyte ( cutaneous fungal ) infections. Dermatophytes
(dermatophytes) include Mictmporum, Trichophyton , and Epidermophyton. Branching septate hvphae visible on
KOH preparation with blue fungal stain . Associated with pruritu ' j
Tinea capitis Occurs on head , scalp. Associated with lymphadenopathy, alopecia, scaling 0.
Tinea corporis Occurs on torso. Characterized by erythematous scaling rings ( “ ringworm’’ ) and central
clearing Q. Can be acquired from contact with an infected cat or dog.
Tinea cruris Occurs in inguinal area | ]. Often does not show the central clearing seen in tinea corporis.
Tinea pedis Three varieties:
Interdigital Q; most common
Moccasin distribution Q
Vesicular type
Tinea unguium Onychomycosis; occurs on nails.
Tinea ( pityriasis) Caused by Alalassesia spp. ( Pityrosporum spp.), a yeast-like fungus ( not a dermatophyte despite
versicolor being called tinea ). Degradation of lipids produces acids Ibat damage melanocytes and cause
hvpopigmcntcd 3. hvperpigmcnted , and /or pink patches. Weaker association with pruritu 4
Can occur any time of year, but more common in summer ( hot , humid weather). “ Spaghetti and
meatballs" appearance on microscopy Q.
Treatment: selenium sulfide, topical and/or oral antifungal medications.
r

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 MICROBIOLOGY MICROBIOLOGY — MYCOLOGY SECTION I I

Opportunistic fungal infections

Candida albicans alba = white. Dimorphic; forms pseudohyphae and budding yeasts at 20°C , germ tubes at
T7°C O
Systemic or superficial fungal infection. Causes oral 0 and esophageal thrush in
immunocompromised (neonates, steroids, diabetes, AIDS), vulvovaginitis (diabetes, use of
antibiotics), diaper rash, endocarditis ( IV drug userst. disseminated candidiasis ( to any organ),
chronic mucocutaneous candidiasis.
Treatment; oral fluconazole/topical azole for vaginal nystatin, fluconazole, or caspofungin for oral /
esophageal; fluconazole, caspofungin, or amphotericin B for systemic,
Aspergillus Septate hvphae that branch at 45° Acute Angle [3- Produces conidia in radiating chains at end of
fumigatus conidiophore 0.
Causes invasive aspergillosis in immunocompromised, patients with chronic granulomatous discascj
Can cause aspergillomas in pre-existing lung cavities, especially after TB infection.
Some species of Aspergillus produce Aflatoxin
^
Allergic bronchopulmonary aspergillosis ( ABPA): hypersensitivity response associated with
asthma and cystic fibrosis; may cause bronchiectasis and cosinophilia.
Cryptococcus 5-10 pm with narrow budding. Heavily encapsulated yeast. Not dimorphic.
neoformans Found in soil, pigeon droppings. Acquired through inhalation with hematogenous dissemination
to meninges. Culture on Sabouraud agar Highlighted with India ink ( clear halo Q) and
mucicarmine ( red inner capsule 0). Latex agglutination test detects polysaccharide capsular
antigen and is more specific.
Causes cryptococcosis, cryptococcal meningitis, cryptococcal encephalitis (“ soap bubble" lesions
in brain), primarily in immunocompromised.
Treatment : amphotericin B + flucytosine followed bv fluconazole for cryptococcal meningitis.
Mucor and Rhizopus Irregular, broad, nonseptate hvphae branching at w ide angles Q.
spp. Mucormycosis. Causes disease mostly in ketoacidotic diabetic and/or neutropenic patients (eg .
leukemia). Fungi proliferate in blood vessel walls, penetrate cribriform plate, and enter brain.
Rhinocerebral, frontal lobe abscess; cavernous sinus thrombosis Headache, facial pain, black
necrotic eschar on face; may have cranial nerve involvement.
Treatment: surgical debridement, amphotericin B.
. IV?
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 MICROBIOLOGY MICROBIOLOGY — PARASITOLOGY

MICROBIOLOGY -PARASITOLOGY

rotozoa — gastrointestinal infections

“ORGANISM DISEASE TRANSMISSION DIAGNOSIS TREATMENT
Giardia lamblia Giardiasis — bloating, flatulence, Cysts in water Multinucleated Metronidazole
foul-smelling, fatty diarrhea trophozoites Q or
(often seen in campers/hikers) — cysts Q in stool
think fat-rich Ghirardelli
chocolates for fatty stools of
Giardia
Entamoeba Amebiasis — bloody diarrhea Cysts in water Serology and /or Metronidazole;
histolytica (dysentery), liver abscess trophozoites (with paromomycin or
(“anchovy paste” exudate ), engulfed RBCs iodoquino! for
RUQ pain; histology shows in the cytoplasm) asymptomatic cyst
flask-shaped ulcer or cysts with up to passerj
T nuclei in stool 1
Entamoeba Eats
Erythrocyte
^
Cryptosporidium Severe diarrhea in AIDS Oocysts in water Oocysts on acid-fast Prevention i by
Mild disease (watery diarrhea) in stain Q filtering city
immunocompetent hosts water supplies);
nitazoxanide in
immunocompetent
hosts
3 0 0 0

> i 0
124 SECTION II MICROBIOLOGY MICROBIOLOGY — PARASITOLOGY

Protozoa — CNS infections

ORGANISM DISEASE TRANSMISSION DIAGNOSIS TREATMENT
Toxoplasma Congenital toxoplasmosis = Cysts in meat (most Serology, biopsy Sulfadiazine +
gondii classic triad of chorioretinitis, common); oocysts ( tachyzoite) Q pyrimethamine
hydrocephalus, and intracranial in cat feces; crosses
calcifications; reactivation in placenta ( pregnant
AIDS -* brain abscesses usually women should
seen as multiple ring- enhancing avoid cats)
lesions on MRtfl
Naegleria fowleri Rapidly fatal meningoencephalitis Swimming in Amoebas in spinal Amphotericin B has
freshwater lakes fluid Q been effective for a
( think Nalgene few survivors
bottle filled
with fresh water
containing
Naegleria ); enters
via cribriform plate
Trypanosoma African sleeping sickness- .
Tsetse flv a painful Trypomastigotc in Suramin for blood-
brucei enlarged lymph nodes, recurring bite blood smear El borne disease or
fever (due to antigenic variation), mi larsoprol for

somnolence, coma CNS penetration

Two subspecies: Trypanosoma ( "I sure am
.
brucei rhodesiense Trypanosoma mellow when
brucei gambiense I'm sleeping’’;
remember
melatonin helps
with sleep!
cr 4 . I*
\
f C>
k
V.
>1 r
 MICROBIOLOGY MICROBIOLOGY — PARASITOLOGY SECTION II 1 27

Nematodes (roundworms)
ORGANISM DISEASE TRANSMISSION TREATMENT
Intestinal
Enterobius vermicularis Caused anal pruritus ( diagnosed bv seeing Fecal- oral Pvrantcl pamoate or
(pinworml| egg Q ia the tape test)
' bendazoles ( because
worms are bendy)
Ascaris lumbricoides May cause!obstruction at ileocecal valve Fecal-oral; knobbv -coated, Bendazoles
(giant roundworm) oval eggs seen in feces
under microscope!
Strongyloides Caused vomiting, diarrhea, epigastric Larvae in soil penetrate skin; Ivermectin or
stercoralis pain (may mimic peptic ulcer) rhabditiform larvae seen in bendazoles
(threadworm) feces under microscope!
Ancylostoma Causedanemia bv sucking blood from Larvae penetrate skin Bendazoles or pvrantel
duodenale, Necator intestinal \val| pamoate
americanus Cutaneous larva migrans — pruritic,
( hookworms) serpiginous rash from walking barefoot
on contaminated beach !
Trichinella spiralis Larvae enter bloodstream and enevst in Undercooked meat ( cspeciallv Bendazoles

muscle
—
striated muscle cells inflammation of pork ); fecal-oral ( less likely )

Trichinosis — fever, vomiting, nausea.

periorbital edema, myalgia
Trichuris trichiura Often asymptomatic; can cause loose Fecal-ora! Bendazole!
( whipworm! stool and anemia, rectal prolapse in
children with heavy infection!
Tissue
Toxocara canis Visceral larva migrans — nematodes Fecal-oral Bendazoles
migrate to blood through intestinal wall
causing inflammation and damage.
Freuuentlv affects heart ( myocarditis) .
liver, eves (visual impairment,
blindness), and CNS (seizures, coma |]
Onchocerca volvulus Skin changes, loss of clastic fibers, and Female blackfly Ivermectin ( ivermectin
river blindness ( black flies, black skin for river blindness)
nodules, “ black sight ” ); allergic reaction
to microfilaria possible
Loa loa ^
Swelling in skin, worm in conjunctiva .
Deer fly. horse fly mango fly Dicthylcarbamazinc
Wuchereria bancrofti Lymphatic filariasis (elephantiasis!— Female mosquito Diethylcarbamazine
worms invade lymph nodes and
cause inflammation, which can block
lymphatic vessels H, takes 9 nro-1 yr
after bite to become symptomatic!

Long page — please

edit to fit
; l ''m
128 SECTION II MICROBIOLOGY MICROBIOLOGY — PARASITOLOGY

Cestodes ( tapeworms )
ORGANISM DISEASE TRANSMISSION TREATMENT
Taenia solium El Intestinal tapeworm Ingestion ol larvae encysted in Praziquantel
undercooked pork
Cvsticercosis, Ingestion of eggs in food Praziquantel; albendazole for
neurocysticcrcosis Q contaminated with human neurocysticcrcosis

Diphyllobothrium Vitamin Bp deficiency

-
fece j
Ingestion of larvae from raw- Praziquantel
latum

Echinococcus
granulosus Q
—
(tapeworm competes for Bp
in intestine) megaloblastic
anemia
Hvdatid evsts |"eggshell
calcification" ) in liver H,
freshwater fish

Ingestion of eggs from dog

feces
Albendazole

causing anaphylaxis Sheep arc an intermediate host

\
mm
.
t

0 : V

Trematodes (flukes )
ORGANISM DISEASE TRANSMISSION TREATMENT
Schistosoma User and spleen enlargement Snails arc host; cercariac Praziquantel
( S mansoni , egg with lateral penetrate skin of humans
Jt spine El), fibrosis, and

f! inflammation
Chronic infection with
S haematobium ( egg with
O ;o terminal spine O ) can lead
c to squamous cell carcinoma
of the bladder ( painless
hematuria ) and pulmonary
, •
hypertension
Clonorchis sinensis

—
Biliary tract inflammation
pigmented gallstones
Associated with
cholangiocarcinoma
Undercooked fish Praziquantel
 MICROBIOLOGY MICROBIOLOGY — PARASITOLOGY SECTION II

Ectoparasites
jSarcoptes scabie ( Mite burrow into stratum comcrum and Common in children , crowded populations
cause scabies: pruritus ( worse at night ) and ( jails, nursing homes); transmission through
m serpiginous burrows ilincsl in webspacc of skin -lo-skin contact ( most common ) or via
hands and feetO - foniite4
Treatment: permethrin cream , washing/drying
// all clothing / bedding, treat close contacts.

fediculus humanus/ Blood-sucking insects that cause intense Can transmit Rickettsia prowazekii ( epidemic
Phthirus pubis( pruritus with associated excoriations, t \ plinj). Barrelia recurrentis ( relapsing fever),
commonly on scalp and neck ( head lice ) or Bartonella quintana ( trench fever ).
waistband and axilla ( body lice!
) Treatment includes pyrethroids, malathion , or
ivermectin lotion , and nit Q combing. Children
with head lice can be treated at home w ithout
interrupting school .

Parasite hints ASSOCIATIONS ORGANISM

Biliary tract disease , chol.iugiocarcinoma Clonorchis sinensis
Brain cysts, seizures Taenia solium ( neurocvsticercosis )
I leniaturia , squamous cell bladder cancer Schistosoma haematobium
Liver ( hydatid ) evsts Echinococcus granulosus
Microcytic anemia .\nc\lostoma ,\ecator
Mvalgias, periorbital edema Tnchinella spiralis
Perianal pruritus Enterohius
Portal hypertension .
Schistosoma mansoni Schistosoma japonicum
Vitamin Bn deficiency I 'iiplixllobothrium latum
130 SECTION II MICROBIOLOGY MICROBIOLOGY — VIROLOGY

MICROBIOLOGY — VIROLOGY

Viral structure — Naked virus with Enveloped virus with Enveloped virus with
icosahedra! capsid icosahedra! capsid helical capsid
general features
- protein
Surface

m Capsid
tjgS /TV*
<:::
- Lipid
iZ bilayer

^—
Nucleic acid
XK
^ - Upid bilayer
Lipid blU
V , “ Capsid
CapS d
V
V / ”
, ' s^— Nucleic'
\ - Helical mnucleocapsid
acid with into
integrated RNA ia

Viral genetics
Recombination Exchange of genes between 2 chromosomes by crossing over within regions of significant base
sequence homology.
Reassortment When viruses with segmented genomes ( eg, influenza virus) exchange genetic material. For
example, the 2009 novel H1N1 influenza A pandemic emerged via complex viral reassortment of
genes from human, swine, and avian viruses. lias potential to cause antigenic shift.
Complementation When I of 2 viruses that infect the cell has a mutation that results in a nonfunctional protein, the
nonnrutated virus “complements” the mutated one bv making a functional protein that serves
both v iruses. For example, hepatitis D virus requires the presence of replicating hepatitis B virus
to supply IIBsAg, the envelope protein for HDV.
Phenotypic mixing Occurs with simultaneous infection of a cell with 2 v iruses. Genome of virus A can be partially or
completely coated (forming pseudovirion) with the surface proteins of virus B. Type B protein coat
determines the tropism (infectivity) of the hybrid virus. However, the progeny from this infection
have a type A coat that is encoded by its type A genetic material .

Viral vaccines
Live attenuated MMR. Yellow fever. Rotavirus, Influenza “ Music andI.YRICSS are best enioved Live.’
vaccines ( intranasal i. Chickcnpox VCV ). Smallpox. |MMR = measles, mumps, rubella; live
Sabin polio virus. attenuated vaccine that can he given to
11IV © patients who do not show' signs of
I immunodeficiency.
Killed Rabies, Influenza ( injected), Salk Folio, and SalK = Killed.
HAV vaccines. Killed/inactivated vaccines RIP Always.
induce only humoral immunity but arc stable.
Subunit HBV ( antigen = HBsAg), HPV ( types 6, 11, 16,
and 18).
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION I I

RNA viral genomes All RNA viruses except Rcoviridae are ssRNA. All are ssRNA ( like our mRNA), except
© stranded RNA viruses: 1 went to a retro “repeato-virus” (reovirus) is dsRNA.
( retrovirus) toga ( togas irus| parts;svhcrc
I drank flavored (flavivirus) Corona
( coronavirus ) and ate hippie ( hepevirus)
California (calicivirus) pickles (picornavirus).

Naked viral genome Purified nucleic acids of most dsDNA (except poxviruses and HBV) and © strand ssRNA
infectivity ( = mRNA) viruses are infectious. Naked nucleic acids of © strand ssRNA and dsRNA viruses are
not infectious. They require polymerases contained in the complete virion.

Viral replication
DNA viruses All replicate in the nucleus ( except poxvirus ). "Pox is out of the box (nucleus).”
RNA viruses All replicate in the cytoplasm (except influenza virus and retroviruses ).

Viral envelopes Naked (nonenveloped ) viruses include Give PAPP smears and CPR to a naked hippie
Papillomavirus, Adenovirus, Parvovirus, ( hepevirus).
Polyomavirus, Calicivirus, Picornavirus, DNA = PAPP; RNA = CPR and hepevirus .
Reovirus, and 1 lepevirus.
Generally, enveloped viruses acquire their
envelopes from plasma membrane when
they exit from cell. Exceptions include
herpesviruses, which acquire envelopes from
nuclear membrane.

DNA virus Some general rules — all DNA viruses:

characteristics
GENERAL RULE COMMENTS
Are HHAPPPPy viruses Hepadna, Herpes, Adeno, Pox, Parvo,
Papilloma, Polyoma.
Are double stranded Except parvo (single stranded).
Have linear genomes Except papilloma and polyoma (circular,
supercoiled ) and hepadna (circular,
incomplete).
Are icosahedral Except pox (complex).
Replicate in the nucleus Except pox (carries own DNA-dependent RNA
polymerase).
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION II 133
Long page — please
edit to fit
Herpesviruses Enveloped, DS, and linear viruses
VIRUS ROUTE OF TRANSMISSION CUNICAL SIGNIFICANCE NOTES
Herpes Respirators '
Gingivostomatitis, keratoconjunctivitis Q, Most common cause of sporadic
simplex secretions, saliva herpes labialis HI herpetic whitlow on finger . encephalitis, can present as altered
virus-1 temporal lobe encephalitis, esophagitis, mental status, seizures, and/or

Herpes Sexual contact,

erythema multiform
^
Herpes genitalis Q, neonatal herpes.
aphasia.
Latent in sacral ganglia. Viral
simplex perinatal meningitis more common with
virus-2 HSV 2 than with IISV-1.
-
Varicella - Respiratory Varicella-zoster (chickenpox 0, shingles Q ), Latent in dorsal root or trigeminal
Zoster virus secretions encephalitis, pneumonia. ganglia; CN V, branch
(HHV-3) Most common complication of shingles is post ¬ involvement can cause herpes
herpetic neuralgia. -
zoster ophthalmic mi
Epstein- Barr Respiratory Mononucleosis — fever, hcpatosplenomegaly, Infects B cells through CD21.
virus (HHV- 4) secretions, pharyngitis, and lvmphadenopathv Atypical lymphocytes on peripheral
saliva; aka l especially posterior cervical nodes bi. Often blood smear 0— not infected B
"kissing disease," misdiagnosed as strep throat: can differentiate cells but reactive cytotoxic T cells.
(common in because amoxicillin in HHV-4 infection causes © Monospot test — heterophile
teens, young maeulopapular rasli Avoid contact sports until antibodies detected by agglutination
adults ) resolution due to risk of splenic rupture. of sheep or horse RBCs.
Associated with lymphomas (eg, endemic
Burkitt lymphoma), nasopharyngeal
carcinoma (especially Asian adults!
Cytomegalo ¬
Congenital Mononucleosis ( © Monospot ) in Infected cells have characteristic
virus (HHV-5 ) transfusion, immunocompetent patients; infection in "owl eve" inclusions Q.
sexual contact, immunocompromised! especially pneumonia Latent in mononuclear cells.
saliva, urine, in transplant patients; esophagitis; AIDS

transplant Retinitis (“ sightomcgalovirus"): hemorrhage,

cotton-wool exudates, vision loss.
Congenital CMV
Human Saliva Roseola infantum (exanthem subitum); high Roseola; fever first, Rosie (cheeks)
herpes ¬
fevers for several days that can cause seizures, later.
viruses 6 followed by diffuse macular rash Q. IIIIV-7— less common cause of
and 7 1 roseola.
Human Sexual contact Kaposi sarcoma (neoplasm of endothelial cells). Can also affect Gl tract and lungs.
herpesvirus Seen in HIV/AIDS and transplant patients.
8 Dark /violaceous plaques or nodules Q
representing vascular proliferations.

SLtfl I
* Sri

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-
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SECTION II MICROBIOLOGY MICROBIOLOGY — VIROLOGY

HSV identification Viral culture for skin/genitalia.

CSF PCR for herpes encephalitis.

h\
Tzanck test— a smear of an opened skin vesicle to detect multinuclcatcd giant cells Q commonly
seen in HSV-1, HSV-2, and YZV infection.
Intranuclear eosinophilic Cowdrv A inclusions also seen with IISV-I. IISV-2, WAj
Tzanck heavens I do not have herpes.

* «c rID
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION I I

RNA viruses
VIRALFAMILY ENVELOP RNA STRUCTURE CAPSIOSYMMETRV MEDICAL IMPORTANCE
Reoviruses No DS linear leosahedral Coltivirus3 — Colorado tick fever
10-12 segments (double) Rotavirus— cause of fatal diarrhea in childrcnl
Picornaviruses No SS © linear leosahedral Poliovirus — polio-Salk /Sabin vaccines — IPV/OPV
Echovirus — aseptic meningitis
Rhinovirus — "common cold”
Coxsackievirus — aseptic meningitis; herpangina
( mouth blisters, fever); hand, foot, and mouth
disease; myocarditis; pericarditis
11AY — acute viral hepatitis
PERCH
Hepevirus No SS © linear leosahedral HEV
Caliciviruses No SS © linear leosahedral Norovirus — viral gastroenteritis
Flaviviruses Yes SS © linear leosahedral HCV
Yellow fever1
Dengue3
St. Louis encephalitis3
West Nile virus'1 ( meningoencephalitis)
Zika virus
Togaviruses Yes SS © linear leosahedral Rubella
Western and Eastern euuine encephalitis^
Chikungunva viru4

Retroviruses Yes SS © linear leosahedral 1 lave reverse transcriptase

2 copies (HTLV), HTLV— T-cell leukemia
complex
and conical
—
HIV AIDS

(HIV )
Coronaviruses Yes SS © linear Helical "Common cold," SARS, MERS

Orthomyxoviruses Yes SS © linear Helical Influenza virus

8 segments
Paramyxoviruses Yes SS © linear Helical PaRaMyxovirus:
Nonsegmented Parainfluenza— croup
RSV— bronchiolitis in babies; Rx — ribavirin
Measles, Mumps
Rhabdoviruses Yes SS © linear Helical Rabies
Filoviruses Yes SS © linear Helical Ebola /Marburg hemorrhagic fever — often fatal!
Arenaviruses Yes SS © or © 1 lelical LCMV— lymphocytic choriomeningitis virus
circular Lassa fever encephalitis — spread by rodents
2 segments
Bunyaviruses Yes SS © circular Helical California encephalitis3
s segments Sandfly/Rift Valley fevers'1
Crimean-Congo hemorrhagic fever 3
Hantavirus — hemorrhagic fever, pneumonia
Delta virus Yes SS © circular Uncertain 11DV is a "defective" virus that requires the
presence of HBV to replicate
'll tmaU-itritvlMl- rlruiKl<*.i:lrjnrlwl' (?) n/ wiHvp CPIIW A upoifii 'p cpncP1
-
. a — lrlutt inic lrfltrnnn/l In >riu>
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fm/EcrinilruAc Hr l'cl
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION II

Influenza viruses Orthomyxoviruses. Enveloped, © ssRNA
viruses with 8-segment genome. Contain
hemagglutinin ( binds sialic acid and promotes
viral cntrvt) and neuraminidase promotes
progeny virion release) antigens. Patients at
risk for fatal bacterial supcrinfection , most
commonly S aureus , S pneumoniae , and
11 jjn /luenzae.
Genetic shift/ Causes pandemics. Reassortment of viral
Reformulated vaccine (“ the flu shot ” ) contains
viral strains most likely to appear during the flu
season , due to the virus' rapid genetic change.
Killed viral vaccine is most frequently used.
Live attenuated vaccine contains temperature-
sensitive mutant that replicates in the nose but
not in the lung; administered ilitranasally.
Sudden shift is more deadlv than gradual drift ,

antigenic shift genome segments, such as when segments of

human flu A virus rcassort with swine flu A
virus.

Reassortment

Genetic drift/ Causes epidemics. Minor (antigenic drift )

antigenic drift changes based on random mutation in
hemagglutinin or neuraminidase genes.
Random
v:
mutations '
va

Rubella virus A togasirus. Causes rubella, once known as German ( s-dav i measles. Fever, postauricular and
other lymphadcnopathy. arthralgias, and fine, confluent rash that starts on face and spreads
centrifugally to involve trunk and extremities Q. Causes mild disease in children but serious
congenital disease (a ToRCHeS infection). Congenital rubella findings include “ blueberry
muffin" appearance due to dermal extramedullary hematopoiesis.

Cl

Paramyxoviruses Paramyxov iruses cause disease in children. They include those that cause parainfluenza (croup;
seal-like barking cough ), mumps, and measles as well as RSV, which causes respiratory tract
infection ( bronchiolitis, pneumonia ) in infants. All contain surface F ( fusion ) protein , which
causes respiratory epithelial cells to fuse and form multinuclcatcd cells. Palivizumab ( monoclonal
antibody against F protein ) prevents pneumonia caused by RSV infection in premature infants.
Palivizumab for Parainvxovirus ( RSV ) Prophvlaxis in Premies.
h 38 SECTION II MICROBIOLOGY MICROBIOLOGY — VIROLOGY

Croup ( acute laryngo- Caused In parainfluenza viruses i paramyxovirus ), Virus mcmhranc contains hemagglutinin
tracheobronchitis) ( binds sialic acid and promotes viral entry ) and neuraminidase ( promotes progeny virion release )
antigens. Results in a "seal-like” barking cough and inspiratory stridoj Narrowing of upper trachea
and subglottis leads to characteristic steeple sign on x-ray Severe croup can result in pulsus
paradoxus 2° to upper airway obstruction.

Measles (rubeola ) A paramyxovirus that causes measles. Usual T C’s of measles:

virus presentation involves prodromal fever with Cough
cough, coryza, and conjunctivitis, then Coryza
eventually Koplik spots ( bright red spots with Conjunctivitis
blue-white center on buccal mucosa ), Vitamin A supplementation can reduce
followed 1-2 days later by a tnaculopapular morbidity and mortality from measles,
rash that starts at the head/neck and spreads particularly in malnourished children.
downward. Lymphadenitis with Warthin-
Finkeldey giant cells ( fused lymphocytes ) in
a background of paracortical hyperplasia.
SSPE (subacute sclerosing pancnccphalitis,
occurring years later ), encephalitis ( 1:2000),
and giant cell pneumonia (rarely, in
immunosuppressed ) are possible sequelae.

Mumps virus A paramyxovirus that causes mumps, Mumps makes your parotid glands and testes as
uncommon due to effectiveness of MMR big as POM-Poms .
vaccine.
Symptoms: Parotitis d, Orchitis (inflammation
of testes), aseptic Meningitis, and Pancreatitis.
Can cause sterilitv (especially after pubertv).
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION II

Rabies virus Bullet-shaped virus Q. Negri bodies
( cytoplasmic inclusions Qi commonly
found in Purkinje cells of cerebellum and
in hippocampal neurons. Rabies has long
incubation period (weeks to months) before
Infection more commonly from bat, raccoon, and
skunk bites than from dog bites in the United
Stales; aerosol transmission leg, bat caves) also
possible.

* symptom onset. Postexposurc prophylaxis

is wound cleaning plus immunization with
killed vaccine and rabies immunoglobulin.
r: Example of passive-active immunity.
Travels to the CNS by migrating in a retrograde
fashion ( via dvnein motorsjiup nerve axons
after binding to ACh receptors.
Progression of disease: fever, malaise
- agitation, photophobia, hydrophobia,
*

—
hypersalivation -* paralysis, coma death.

Ebola virus A filovirus Q that targets endothelial cells,
phagocytes, hepatocytes. Following an
incubation period of up to 21 days, presents
with abrupt onset of flu-like symptoms,
diarrhea/vomitiug, high fever, myalgia. Can
progress to DIG, diffuse hemorrhage, shock .
Diagnosed w itli RT-PCR within 48 hr ol
symptom onset. High mortality rate.
Transmission requires direct contact with bodily
fluids, fonntes (including dead bodies), infected
bats or primates (apes/monkeys); high incidence
of nosocomial infection.
Supportive care, no definitive treatment . Strict
isolation of infected individuals and barrier
practices for health care workers are kev to
preventing transmission.

Zika virus

tor Zika virus

ito come .
 MICROBIOLOGY MICROBIOLOGY — VIROLOGY SECTION II 141

Hepatitis serologic markers

Anti-HAV (IgM) IgM antibody to HAV; best test to detect acute hepatitis A.
Anti-HAV (IgG) IgG antibody indicates prior HAV infection and/or prior vaccination; protects against reinfection.
HBsAg Antigen found on surface of HBV; indicates hepatitis B infection.
Anti-HBs Antibody to IIBsAg; indicates immunity to hepatitis B due to vaccination or recovery from
infection.
HBcAg Antigen associated with core of HBV.
Anti- HBc Antibody to HBcAg; IgM = acute/rcccnt infection; IgG = prior exposure or chronic infection. IgM
anti-HBc may be the sole ® marker of infection during window period.
HBeAg Secreted by infected hepatocyte into circulation. Not part of mature HBV virion. Indicates active
viral replication and therefore high transmissibility.
Anti- HBe Antibody to HBcAg; indicates low transmissibility.

Important Incubation Prodrome, Convalescence

diagnostic period acute disease Early Late
tests
HBsAg Anti- Anti-HBs
HBsAg Coat protein
-HBc)
(anti HBc land-HBc )
IHBsAg)
DNA Anti- HBc
Relative polymerase Core (HBcAg)
concentration ^ HBV particles^
of reactants « 3
DNA genome
i- .
HBsAg

Window period Anti - HBs % DNA polymerase

HBeAg Anti-HBe
Level of Virus particle
detection V "7

1 2 3 4 5 6 7 8
Symptoms Months after
exposure
tALT a

HBsAg Anti-HBs HBeAg Anti- HBe Anti-HBc

Acute HBV / IgM
Window IgM
Chronic HBV (high infectivity) / IgG
Chronic HBV (low infectivity) IgC
Recovery IgG
Immunized
142 SECTION I I MICROBIOLOGY MICROBIOLOGY — VIROLOGY

HIV
Envelope proteins Diploid genome ( 2 molecules of RNA).
acquired through budding from
host cell plasma membrane
The 5 structural genes ( protein coded for):
1 p!7: Matrix protein " env (gpl 20 and gp 41):
gpl20 Formed from cleavage of gpl60 to form
Docking
glycoprotein
Lipid envelope envelope glycoproteins.
gp 41 gpl20 — attachment to host CD4+ T cell.
Transmembrane
/ gp4l — fusion and entry.
: reopt m apsid protein
gag (p24 and pl7]— capsid and matrix
• • . A
transcriptase
proteins, respectively.

£
wts
po/ — reverse transcriptase, aspartate protease,
integrase.
i Reverse transcriptase synthesizes dsDNA from
genomic RNA; dsDNA integrates into host
V genome.
Virus binds CD4 as well as a coreceptor, either
CCR 5 on macrophages (carls' infection ) or
CXCR4 on T cells (late infection ).
Homozygous CCR 5 mutation = immunity.
Heterozygous CCR 5 mutation = slower course.

HIV diagnosis Presumptive diagnosis made w ith ELISA ELISAAVestern blot tests look for antibodies to
(sensitive, high false © rate and low threshold, viral proteins; these tests often are falsely ©
rule out test ); © results jeonfirmed with in the first 1-2 months of HIV infection and
Western blot assay ( specific, low false © rate falsely © initially in babies bom to infected
and high threshold, rule in test). mothers (anti-gpl 20 crosses placenta ). Use
Viral load tests determine the amount of viral .
I'CK m neon lies to detect viral load.
RNA in the plasma. High viral load associated
with poor prognosis. Also use viral load to
monitor effect of drug therapy.
AIDS diagnosis 200 CD4+ cells/innV
(normal: 500-1500 cclls/mm’l. HIV© with
AlDS-defining condition (eg, Pneumocystis
pneumonial orCD4+ percentage < 14%.
 MICROBIOLOGY MICROBIOLOGY — SYSTEMS SECTION II 145

Prions Prion diseases are caused by the conversion of a normal ( predominantly a-helical) protein termed
| prion protein ( PrI*) to a (i-pleated form ( PrPsc ), which is transmissible via CNS- rclated tissue
( iatrogenic CJD ) or food contaminated bv BSE -infected animal products ( variant CJD). PrP'1
resists protease degradation and facilitates the conversion of still more PrP1 to PrP*c, Resistant to
standard sterilizing procedures, including standard autoclaving. Accumulation of PrP* results in
spongiform encephalopatlnjand dementia , ataxia , and death.
—
Creutzfeldt-Jakob disease rapidlv progressive dementia , typically sporadic (some familial forms).

— —
Bovine spongiform encephalopathy ( BSE) also known as “ mad cow disease."
Kuru acquired prion disease noted in tribal populations practicing human cannibalism .

1 MICROBIOLOGY- SYSTEMS

Normal flora: LOCATION MICROORGANISM

dominant Skin S epidermidis
Nose S epidermidis; colonized by S aureus
Oropharynx Viridans group streptococci
Dental plaque S mutans
Colon B fragilis > E coli
Vagina Lactobacillus , colonized by E coli and group
B strep
Neonates delivered by C-section have no flora but are rapidly colonized after birth.

Bugs causing food S aureus and B cereus food poisoning starts quickly and ends quickly.
poisoning
MICROORGANISM SOURC£ OF INFECTION
B cereus Reheated rice. " Food poisoning from reheated
rice? Be serious!” ( B cereus )
C botulinum Improperly canned foods ( toxins ), raw honey
(spores)
C perfringens Reheated meat
Ecoli 0157:117 Undercooked meat
L monocytogenes Deli meats, soft cheeses
Salmonella Poultry, meat , and eggs
S aureus Meats, mayonnaise, custard; preformed toxin
V parahaemolyticus and V vulnificus? Contaminated seafood
“ V vulnificus can also cause w ound infections from contact with contaminated water or shellfish.
 MICROBIOLOGY MICROBIOLOGY — SYSTEMS SECTION II 145

Prions Prion diseases are caused by the conversion of a normal (predominantly a-helical ) protein termed
| prion protein ( Prlx ) to a 3-pleated form ( PrP51), which is transmissible via CNS-related tissue
( iatrogenic CJD) or food contaminated bv BSE -infected animal products ( variant CJD ) . PrP't
resists protease degradation and facilitates the conversion of still more PrP to PrPc. Resistant to
standard sterilizing procedures, including standard autoclaving. Accumulation of PrPc results in
spongiform enccphalopathsjand dementia, ataxia, and death.
Creutzfeldt-Jakob disease — rapidly progressive dementia, typically sporadic isome familial forms).
—
Bovine spongiform encephalopathy ( BSE) also known as "mad cow disease."
Kuru — acquired prion disease noted in tribal populations practicing human cannibalism.

MICROBIOLOGY — SYSTEMS

Normal flora: lOCAtlON MICROORGANISM

dominant Skin S epidermidis
Nose S epidermidis; colonized by S aureus
Oropharynx Viridans group streptococci
Dental plaque S mutant
Colon B fragilis > E coli
Vagina Lactobacillus, colonized by E coli and group
B strep
Neonates delivered by C-section have no flora but are rapidly colonized after birth

Bugs causing food S aureus and B ccreus food poisoning starts quicklv and ends quickly.
poisoning
MICROORGANISM SOURCE OF INFECTION

B cereus Reheated rice. "Food poisoning from reheated

rice? Be serious!" (B cereus)
C botulinum Improperly canned foods ( toxins ), raw hones
(spores)
C perfringens Reheated meat
Eco/i 0157:117 Undercooked meat
L monocytogenes Deli meats, soft cheeses
Salmonella Poultry, meat, and eggs
S aureus Meats, mayonnaise, custard; preformed toxin I
V parahaemolyticus and V vulnificusa Contaminated seafood
aVvulnificus can also cause wound infections from contact with contaminated water or shellfish.
148 SECTION I I MICROBIOLOGY MICROBIOLOGY — SYSTEMS

Urinary tract Cystitis presents with dysuria, frequency, urgency, suprapubic pain, and WBCs ( but not WBC
infections casts) in urine. Primarily caused by ascension of microbes from urethra to bladder. Males —
infants with congenital defects, vesicoureteral reflux. Elderlv — enlarged prostate. Ascension to
kidney results in pyelonephritis, which presents with fever, chills, flank pain, costovertebral angle
tenderness, hematuria, and WBC casts.
Ten times more common in women (shorter urethras colonized by fecal flora). Other predisposing
factors: obstruction, kidney surgery, catheterization, GU malformation, diabetes, pregnancy.

UTI bugs
SPECIES FEATURES COMMENTS
Escherichia coli Leading cause of UTI. Colonies show green Diagnostic markers:
metallic sheen on EMB agar. © Leukocyte esterase = evidence of WBC
Staphylococcus 2nd leading cause of UTI in sexually active activity.
saprophyticus women. © Nitrite test = reduction of urinary nitrates
by bacterial species (eg, E coli ),
Klebsiella pneumoniae srd leading cause of UTI.Iairge mucoid capsule
© Urease test = urease-producing bugs ( eg.
and v iscous colonies.
S saproplivticus. Proleus, Klebsiellct ).
Serratia marcescens Some strains produce a red pigment; often
nosocomial and drug resistant.
Enterococcus Often nosocomial and drug resistant.
Proteus mirabilis Motility causes “ swarming" on agar; produces
urease; associated with struvite stones.
Pseudomonas Blue-green pigment and fruity odor; usually
aeruginosa nosocomial and drug resistant.

Common vaginal infections

Bacterial vaginosis Trichomonas vaginitis Candida vulvovaginitis
SIONS AND SYMPTOMS No inflammation Inflammation ( “ strawberry Inflammation
Thin, white discharge Q with cervix”) Thick, white, “cottage cheese"
fishy odor Frothy, yellow-green, foul ¬
discharge Q
smelling discharge
LAB FINDINGS Clue cells Motile trichomonads Q Pscudohyphae
pH > 4.5 pH > 4.5 pH normal (4.0-4.5)
TREATMENT Metronidazole Metronidazole -azoles
Treat sexual partner(s)

.
fv k

I £ :

- '
\ t
 SECTION II I MICROBIOLOGY MICROBIOLOGY — SYSTEMS

Red rashes of childhood

AGENT ASSOCIATED SYNDROME / DISEASE CLINICAL PRESENTATION
Coxsackievirus type A Hand-foot-mouth disease Oval-shaped vesicles on palms and soles Q;
vesicles and ulcers in oral mucosa
Human herpesvirus 6 Roseola (exanthem subitum ) Asymptomatic rose-colored macules appear
on body after several days of high fever; can
present with febrile seizures; usually affects
infants
Measles virus Measles (rubeola) Confluent rash beeinning at head and moving
down; rash precededlbv cough, con / a,
conjunctivitis, and blue-white ( Koplik ) spots
on buccal mucosa
Parvovirus B19 Erythema infectiosum ( fifth disease) “ Slapped cheek" rash on face (can cause
hydrops fetalis in pregnant women)
Rubella virus Rubella (German measles) Pink macules and papules begin at head
and move down, remain discrete -* fine
desquamating truncal rash; postauricular
lymphadenopathx
Streptococcus pyogenes Scarlet fever Erythematous, sandpaper-like rash Q with fever
and sore throat
Varicella - Zoster virus Chickenpox Vesicular rash begins on trunk; spreads to face
and extremities with lesions of different stages

«
150 SECTION I I MICROBIOLOGY MICROBIOLOGY — SYSTEMS

Red rashes of childhood

AGENT ASSOCIATED SYNDROME/DISUSE CLINICAL PRESENTATION
Coxsackievirus type A Hand-foot-nioutli disease Oval-shaped vesicles on palms and soles ;
vesicles and ulcers in oral mucosa
Human herpesvirus 6 Roseola (exanthem subitum ) Asymptomatic rose-colored macules appear
on body after several days of high fever; can
present with febrile seizures; usually affects
infants
Measles virus Measles Irubeola i Confluent rash beginning at head and moving
down; rash precedec|hy cough, coryza,
conjunctivitis, and blue-w hite i KLoplik ) spots
on buccal mucosa
Parvovirus B19 Erythema infectiosum ( fifth disease ) “ Slapped cheek" rash on face Q] ( can cause
hydrops fetalis in pregnant women)
Rubella virus Rubella (German measles ) Fink macules and papules begin at head
and move down, remain discrete fine
^ —
desquamating truncal rash; postauricular
lymphadenopathy
Streptococcus pyogenes Scarlet fever Erythematous, sandpaper-like rash Q with few
and sore throat
Varicella-Zoster virus Chickcnpox Y'esicular rash begins on trunk; spreads to face
and extremities with lesions of different stage
 MICROBIOLOGY MICROBIOLOGY — SYSTEMS SECTION II 151

Sexually transmitted infections

DISEASE CLINICAL FEATURES ORGANISM

AIDS Opportunistic infections, Kaposi sarcoma, HIV

lymphoma
Chancroid Painful genital ulcer with exudate, inguinal Haemophilus ducreyi (it’s so painful, vou "do
adenopathy cry” )
Chlamydia Urethritis, cervicitis, epididymitis, Chlamydia trachomatis ( D-K )
conjunctivitis, reactive arthritis, PID
Condylomata Genital warts, koilocytes HPV-6 and - 11
acuminata
Genital herpes Painful penile, vulvar, or cervical vesicles and HSV-2, less commonly HSV-1
ulcers; can cause systemic symptoms such as
fever, headache, myalgia
Gonorrhea Urethritis, cervicitis, PID. prostatitis, Neisseria gonorrhoeae
epididymitis, arthritis, creamy purulent
discharge
Granuloma inguinale Painless, beefv red ulcer that bleeds rcadilv on Klebsiella (Calvmmatobacterium ) granulomatis:
(donovanosis) contact cytoplasmic donovan bodies ( bipolar staining)
Not common in US seen on microscopy

Hepatitis B Jaundice HBV

Lymphogranuloma Infection of lymphatics; painless genital ulcers, C trachomatis ( LI— LA )
venereum painful lymphadenopathy ( ie, buboes)
Primary syphilis Painless chancre Treponema pallidum
Secondary syphilis Fever, lymphadenopathy, skin rashes,
condylomata lata
Tertiary syphilis Gummas, tabes dorsalis, general paresis, aortitis,
Argyll Robertson pupil
Trichomoniasis Vaginitis, strawberry cervix, motile in wet prep Trichomonas vaginalis
 MICROBIOLOGY MICROBIOLOGY — SYSTEMS SECTION II 153

Bugs affecting unvaccinated children

CLINICAL PRESENTATION FINDINGS/LABS PATHOGEN
Dermatologic
Rash Beginning at head and moving down with Rubella yirus
postauricular lymphadenopathy
Beginning at head and moving down; rash Measles virus
preceded by cough, conza. conjunctivitis, and
blue-white ( Koplik) spots on buccal mucosa
Neurologic
Meningitis Microbe colonizes nasopharynx 11 influenzae type B
Can also lead to myalgia and paralysis Poliovirus
Respiratory
Epiglottitis Fever with dysphagia, drooling, and difficulty H influenzae type B (also capable of causing
breathing due to edematous “cherry red" epiglottitis in fully immunized children)
epiglottis; " thumbprint sign" on x-ray
Pharyngitis Grayish oropharyngeal exudate Corynebaclerium diplitheriae (elaborates toxin
( “ pseudomembranes" may obstruct airway); that causes necrosis in pharynx, cardiac, and
painful throat CNS tissue)

Bug hints (if all else CHARACTERISTIC ORGANISM

fails) Asplcnic patient ( due to surgical splenectomy Encapsulated microbes, especially SHiN
or autosplenectomy, eg, chronic sickle cell (S pneumoniae » H influenzae type B >
disease ) N meningitidis )
Branching rods in oral infection, sulfur granules Actinomyces israelii
Chronic granulomatous disease Catalase © microbes, especially S aureus
“ Currant jelly" sputum Klebsiella
Dog or cat hite Vasteurella multocida
Facial nerve palsv (typically bilateral 1 Borrelia burgdorferi ( Lyme disease)
Fungal infection in diabetic or A lucor or Rbizopus spp.
immunocompromised patient
1 lealth care provider HBV (from needlestick )
Neutropenic patients Candida albicans ( systemic), Aspergillus
Organ transplant recipient CMV
PAS © Trophenma whipplei ( Whipple disease)
Pediatric infection Haemophilus influenzae ( including epiglottitis)
Pneumonia in cystic fibrosis, burn infection Pseudomonas aeruginosa
Pus, empyema, abscess S aureus
Rash on hands and feet Coxsackie A virus, Treponema pallidum,
Rickettsia rickettsii
Sepsis/mcnmgitis in newborn Group B strep
Surgical wound S aureus
Traumatic open wound Clostridium perfringens
 MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS SECTION II 155

Penicillinase-sensitive Amoxicillin , ampicillin ; aminopenicillms.

penicillins
MECHANISM Same as penicillin . Wider spectrum; Wlinol’enicillins are AMPed-up penicillin .
penicillinase sensitive. Also combine with AmOxicillin has greater Oral bioavailability
clavulanic acid to protect against destruction than ampicillin .
by P -lactamase.
CLINICAL USE
.
—
Kxtended-spectrum penicillin II influenzae,
H pylori , E coli Listeria monocytogenes ,
Coverage: ampicillin /amoxicillin 1 IIIEEPSS
kill enterococci.
Proteus mirabilis , Salmonella , Shigella ,
enterococci.
ADVERSE EFFECTS 1 Is persensitivily reactions; rash ;
pseudomembranous colitis.
MECHANISM OF RESISTANCE Penicillinase in bacteria (a type of p-lactamase )
cleaves p-lactam ring.

Penicillinase- resistant Dieloxacillin , nafcillin , oxacillin.

penicillins
MECHANISM Same as penicillin . Narrow spectrum;
penicillinase resistant because bulky R group
blocks access of p-lactamase to P-lactam ring.
CLINICAL USE S aureus (except MRSA; resistant because of “ Use naf ( nafcillin ) for staph ."
altered penicillin-binding protein target site ).
ADVERSE EFFECTS Hypersensitivity reactions, interstitial nephritis.

Antipseudomonal Piperacillin, ticarcillin.

penicillins
MECHANISM Same as penicillin . Extended spectrum .
CLINICAL USE Pseudomonas spp. and gram © rods; susceptible to penicillinase; use with P-lactamase inhibitors.
ADVERSE EFFECTS Hypersensitivity reactions.

^- lactamase inhibitors Include Clavulanic acid , Avibactanr ,

Sulbactam. Tazobactani Often added
CAST.

to penicillin antibiotics to protect the

antibiotic from destruction by P-lactamase
56 SECTION II MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS
Cephalosporins (generations i-V )
MECHANISM P-lactam drugs that inhibit cell wall synthesis
but are less susceptible to penicillinases. generation cephalosporins are LAME:
—
Organisms typically not covered by 1st 4th

Bactericidal. Listeria , Atypicals (Chlamydia, Mycoplasma ),

MRSA, and Enterococci. Exception:
ceftaroline ( 5th generation cephalosporin )
covers MRSA.
CLINICAL USE —
1st generation (cefazolin, cephalexin) gram ®
cocci, Proteus mirabilis, E coli , Klebsiella
—
1st generation PEcK.

pneumoniae. Cefazolin used prior to surgery to

prevent S aureus wound infections.
2nd generation (cefaclor, cefoxitin, Fake fox fur.
—
cefuroximc) gram © cocci, H influenzae,
Enterobacter aerogenes, Seisseria spp., Serratia
—
2nd generation HENS PEcK.

marcescens , Proteus mirabilis , E coli , Klebsiella

pneumoniae.
3rd generation (ceftriaxone, cefotaxime, Can cross blood-brain barrier.
—
cefDodoxime. ceftazidimdl serious gram ©
infections resistant to other JJ-lactams.
—
Ceftriaxone meningitis. gonorrhea.
disseminated Lvme disease.

—
4th generation (cefepime) gram © organisms,
—
Ceftazidime Pseudomonas

with t activity against Pseudomonas and gram

© organisms.
—
5th generation (ceftaroline) broad gram © and
grant © organism coverage, including MRSA;
does not cover Pseudomonas.
ADVERSE EFFECTS Hypersensitivity reactions, autoimmune
hemolytic anemia, disulfiram-likc reaction,
vitamin K deficiency. Exhibit cross-reactivity
with penicillins, t nephrotoxicity of
aminoglycosides.
MECHANISM Of RESISTANCE Structural change in penicillin -binding proteins
( transpeptidases ).
 MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS SECTION II 1 59

Tetracyclines Tetracycline, doxycycline, minocycline.

MECHANISM Bacteriostatic; bind to sOS and prevent attachment of aminoacyl - tRNA; limited CNS penetration .
Doxycycline is fecally eliminated and can be used in patients with renal failure. Do not take
- -
tetracyclines with milk ( Ca ~ ), antacids ( Ca -~ or Mg * ), or iron -containing preparations because
divalent cations inhibit drugs' absorption in the gut.
CLINICAL USE Bonelia burgdorferi , M pneumoniae. Drugs' ability to accumulate intraccllularly makes them very
effective against Rickettsia and Chlamydia. Also used to treat acne. Doxvcveline effective against
MRSAt
ADVERSE EFFECTS GI distress, discoloration of teeth and inhibition of bone growth in children , photosensitivity.
Contraindicated in pregnancy.
MECHANISM OF RESISTANCE 1 uptake or t efflux out of bacterial cells by plasmid -encoded transport pumps.

Chloramphenicol
MECHANISM Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic.
CLINICAL USE .
Meningitis ( Haemophilus influenzae , Neisseria meningitidis Streptococcus pneumoniae ) and Rocky
Mountain spotted fever ( Rickettsia rickettsii ).
.
1 imiled use owing to toxicities but often still used in developing countries because of low cost.
ADVERSE EFFECTS Anemia ( dose dependent ), aplastic anemia (dose independent ), gray baby syndrome ( in premature
infants because they lack liver UDP-glucuronyl transferase).
MECHANISM OF RESISTANCE Plasmid-encoded acetyltransferase inactivates the drug.

Clindamycin
MECHANISM Blocks peptide transfer (translocation ) at 50S
ribosomal subunit . Bacteriostatic.
CLINICAL USE Anaerobic infections (eg, Bacteroides spp.. Treats anaerobic infections above the diaphragm
Clostridium perfringens ) in aspiration vs metronidazole (anaerobic infections below
pneumonia, lung abscesses, and oral diaphragm ),
infections. Also effective against invasive
group A streptococcal infection .
ADVERSE EFFECTS Pseudomembranous colitis (C difficile
overgrow th ), fever, diarrhea .
162 SECTION II MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS

Fluoroquinolones Ciprofloxacin, norfloxacin, levofloxacin. ofloxacin , moxifloxacin , gemifloxacin, enoxacin .

MECHANISM Inhibit prokaryotic enzymes topoisomerasc
II ( DNAgyrase) and topoisomerase IV.
Bactericidal. Must not be taken with antacids.
CLINICAL USE Gram © rods of urinary and Gl tracts ( including
Pseudomonas ), Neisseria , some gram ©
organisms, otitis externa.
ADVERSE EFFECTS GI upset , superinfections, skin rashes, headache, Fluoroquinolones hurl attachments to vour
dizziness. Less commonly, can cause leg bones.
cramps and myalgias. Contraindicated in
pregnant women , nursing mothers, and
children < 18 years old due to possible damage
to cartilage. Some may prolong QT interval.
May cause tendonitis or tendon rupture in
people > 60 years old and in patients taking
prednisone.
MECHANISM OF RESISTANCE Chromosome-encoded mutation in DNA
gyrase, plasmid-mediated resistance, efflux
pumps.

Daptomycin
MECHANISM l .ipopeptide that disrupts cell membrane of
gram © cocci.
CLINICAL USE S aureus skin infections (especial!) MRSA ), Not used for pneumonia (avidly binds to and is
bacteremia, endocarditis, VRE. inactivated by surfactant ).
ADVERSE EFFECTS Myopathy, rhabdomvolysis.

Metronidazole
MECHANISM Forms toxic free radical metabolites in the
bacterial cell that damage DNA. Bactericidal ,
antiprotozoal.
CLINICAL USE Treats Uiardia , Entamoeba , trichomonas . GET GAP on the Metro with metronidazole!
.
Gardnerella vaginalis Anaerobes ( Baeleroides ,
C difficile ). Used with a proton pump inhibitor
Treats anaerobic infection below the diaphragm
vs clindamycin ( anaerobic infections above
and clarithromycin for " triple therapy" against diaphragm ).
H Pylori.
ADVERSE EFFECTS Disulfiram-like reaction (severe flushing,
tachycardia , hypotension ) with alcohol;
headache, metallic taste .
i
164 SECTION I I MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS

Isoniazid
MECHANISM . Bacterial catalase-
1 synthesis of mycolic acids
peroxidase (encoded by KatG) needed to
convert INI 1 to active metabolite.
CLINICAL USE Mycobacterium tuberculosis . The only agent Different 1NH half-lives in fast vs slow
used as solo prophylaxis against TB. Also used acetylators.
as monotherapy for latent TB.
ADVERSE EFFECTS Hepatotoxicitv, P-450 inhibition, drug-induced INH Injures Neurons and Hepatocvtes.
SLE. anion gap metabolic acidosis, vitamin
B„deficiencvi ( peripheral neuropaths ,
sideroblastic anemia). Administer svith
pyridoxine ( Bh ).
MECHANISM OF RESISTANCE Mutations leading to undcrcxpression of KatC.

Pyrazinamide
MECHANISM Mechanism uncertain. Pyrazinamide is a prodrug that is converted to the active compounc
pyrazinoic acid. Works best at acidic pH ( eg, in host phagolysosomes).
CLINICAL USE lycobacterium tuberculosis.
i\

ADVERSE EFFECTS Hyperuricemia, hepatotoxicitv.

Ethambutol
MECHANISM i carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferas
CLINICAL USE A lycobacterium tuberculosis.
ADVERSE EFFECTS Optic neuropathy (red-green color blindness). Pronounce “evethambutol.”

Streptomycin
MECHANISM Interferes with 50S component of ribosome.
CLINICAL USE Mycobacterium tuberculosis ( 2nd line).
ADVERSE EFFECTS Tinnitus, vertigo, ataxia, nephrotoxicity.
 MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS SECTION II 167

Echinocandins Anidulafungin, caspofungin, micafungin.

MECHANISM Inhibit cell wall synthesis by inhibiting synthesis of P-gluean.
CLINICAL USE Invasive aspergillosis, Candida.
ADVERSE EFFECTS GI upset, flushing (by histamine release).

Griseofulvin
MECHANISM Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (eg,
nails).
CLINICAL USE Oral treatment of superficial infections; inhibits growth of dermatophytes ( tinea, ringworm).
ADVERSE EFFECTS Teratogenic, carcinogenic, confusion, headaches, disulfiram-like reaction! t cytochrome P-450 and
warfarin metabolism.

Antiprotozoan therapy Pyrimethamine (toxoplasmosis), suramin atrd melarsoprol (Trypanosoma brucei ), nifurtimox
( Tcruzi ). sodium stibogluconate ( leishmaniasis).

Anti-mite/louse Pcrmethrin ( blocks Na* channels .

Treat PML ( Pests Mites and I ice) with PML
therapy -* neurotoxicity), malathion .
( Permethrin, Malathion Lindane), because
(acetylcholinesterase inhibitor), lindane they N \G you ( Na, AChE, GABA blockade ) ,
( blocks GABA channels
— neurotoxicity).
Used to treat scabies ( Sarcoptes scabiei ) and
lice lPediculus and Pthirus ).

Chloroquine
MECHANISM Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia.
CLINICAL USE Treatment of plasmodial species other than P falciparum (frequency of resistance in P falciparum
is too high ). Resistance due to membrane pump that l intracellular concentration of drug. Treat
P falciparum with artemether/lumefantrine or atovaquone/proguanil. For life-threatening malaria,
use quinidine in US ( quinine elsewhere) or artcsunatc.
ADVERSE EFFECTS Retinopathy; pruritus (especially in dark-skinned individuals ).

Antihelminthic Mebendazole (microtubule inhibitor), pyrantel pamoate, ivermectin, diethylcarbamazine,

therapy praziquantel.
168 SECTION II MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS

Antiviral therapy

HIV ANTIVIRAL OTHER ANTIVIRAL

FUSION
THERAPY THERAPY
.- w a s
ATTA< HMENI
Ml IV ' K - REVERSE
TRANSCRIPTASE
PRO
SYNTHESIS
Receptor
binding
PENETRATION
Interferon -a
UMMM IHBV. HCV)
\ NRTIs
Abacavir IABCI
Endo
cytosis
y
Didanosine (ddl) r
transcription Emtncrtabine IFTC]
Lamivudme (3TQ
Stavudine (d4T)
m
^ -V/x DNA
integration
Tenofovir (TDF)
Zidovudine (ZDV, UNCOATING
NUCLEIC ACID
SYNTHESIS
INTEGRASE formerly AZT )

NNR1 - n .
Rimantadine
J
/ ^ ^1
Amarudlne 1LtorlBItefWdM
!l 0 yefuse !
. ..
LL
vr.
Guanosine analogs
.
Acyclovir, etc IHSV VZV)
Dolutegravif Transcription
J Detavirdme .

tfavirenz Ganciclovir (CMV)

Elviiegravir
Ncv m me Viral DNA polymerase
.
4
V v /x Virion
assembly 3 inhibitors
Cidolovir 1 HSV* .
Foscarnet / CMV

PROTEASE
ftMMWII

Proteolytic
n MAMMALIAN
CELL
Guanmcle nucleotide
synthesis
Ribavirin IRSv, HCVI

—
CD 4 + T CELL
Atazanavir •Acyclovir resistant
Darunavir
’ AS
Fosamprenavir
Indnavir
Loplnavir
Ritonavir
Saquinavir
Packaging
and assombly
' RELEASE OF PROGENY VIRUS

Neuraminidase inhibitors
Budding Oseltarmvirl Inllucn
. ..
.
/ aA B
Release Zanamivit

Oseltamivir, zanamivir
MECHANISM

CLINICAL USE
Inhibit influenza neuraminidase
— I release of progeny virus.
Treatment and prevention of both influenza A and B . Start within 4S hours of influenza symptom
onset.

Acyclovir, famciclovir, valacydovir

MECHANISM Guanosinc analogs. Monophospliorylated by HSV/VZV thymidine kinase and not phosphorylatcd
in uninfected cells -» few adverse effects. Triphosphate formed by cellular enzymes. Preferentially
inhibit viral DNA polymerase by chain termination.
CLINICAL USE .
HSV and VZV. Weak activity against EBV No activity against CMV. Used for HSV-
mduced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in
immunocompromised patients. No effect on latent forms of HSV and VZV. Valacyclovir, a
prodrug of acyclovir, has better oral bioavailability .
For herpes zoster, use famciclovir.
ADVERSE EFFECTS Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated.
MECHANISM OF RESISTANCE Mutated viral thymidine kinase.
170 SECTION II MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS

HIV therapy Highly active antiretroviral therapy (HAART): often initiated at the time of HIV diagnosis.
-
Strongest indication for patients presenting with AIDS defining illness, low CD4+ cell counts
(< 50( 1 cclls/nnn?), or high viral load. Regimen consists of 5 drugs to prevent resistance:
2 NRTIs and preferrablv an integrase inhibitor.
DRUG MECHANISM TOXICITY
NRTIs
Abacavir ( ABC) Competitively inhibit nucleotide binding to Bone marrow suppression lean be reversed
Didanosine (ddl) reverse transcriptase and terminate the DNA with granulocyte colons -stimulating factor
Emtricitabine (FTC) chain (lack a V Ol 1 group). Tenofovir is a [G-CSF] and erythropoietin ), peripheral
Lamivudine ( 3TC) nucleoTide; the others arc nucleosides and neuropaths’, lactic acidosis ( nucleosides ),
Stavudine (d4T) need to be phosphorylated to be active. anemia ( ZDV ), pancreatitis (didanosine).
'
Tenofovir (TDF) ZDV' can be used for general prophslaxis Abacavir contraindicated if patient has
Zidovudine (ZDV, and during pregnane) to t risk of fetal 1ILV-B” 5701 mutation due to t risk of
formerly AZT) transmission. hvperscnsitivitsl
1 lave vou dined ( vudinei w ith my nuclear
(nucleosides ) family?
NNRTIs
Delavirdine Bind to reverse transcriptase at site different Rash and hcpatotoxicity are common to all
Efavirenz from NRTIs. Do not require phosphorylation NNRTIs. Vivid dreams and CNS symptoms
Nevirapine to be active or compete w ith nucleotides. are common with efavirenz. Delavirdine and
efavirenz are contraindicated in pregnancy.
Protease inhibitors
Atazanavir Assembly of virions depends on HIV-1 protease Hyperglycemia, GI intolerance (nausea,
Darunavir { pot gene ), which cleaves the polypeptide diarrhea), lipodystrophy (Cushing-like
Fosamprenavir products of HIV mRNA into their functional syndrome).
Indinavir parts. Thus, protease inhibitors prevent Nephropathv. hematuria! thrombocytopenia
Lopinavir maturation of new viruses. (indinavm
Ritonavir Ritonavir can “ boost ” other drug concentrations Rifampin (potent CYI’/UCT inducer )
Saquinavir by inhibiting cytochrome P-450. contraindicated with protease inhibitors
All 111V protease inhibitors end iii-navir. because it can decrease prolease inhibitor
Navir (never ) tease a protease.
Integrase inhibitors ^
concentration; instead use rifabutii

Raltegravir Inhibits HIV genome integration into host cell T creatine kinase.
Elvitegravir
'
chromosome by reversibly inhibiting HTV
Dolutegravir integrase.
Fusion inhibitors
Enfuvirtide .
Binds gp41 inhibiting viral entry. Skin reaction at injection sites.
Maraviroc Binds CCR-5 on surface of T cells/monocytes,
inhibiting interaction w ith gpl 20.
 MICROBIOLOGY MICROBIOLOGY — ANTIMICROBIALS I SECTION I I T7T

Interferons
MECHANISM Glycoproteins normally synthesized by virus-infected cells, exhibiting a w ide range of antiviral and
antitumoral properties.
CLINICAL USt IFN-ot; chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum,
renal cell carcinoma, malignant melanoma.
IK \ P: multiple sclerosis.
IFN-y: chronic granulomatous disease.
ADVERSE EFFECTS Flu-like symptoms, depression, neutropenia, myopathy.

Hepatitis C therapy
DRUG MECHANISM CUNICAL USE
Ribavirin Inhibits synthesis of guanine nucleotides Chronic IICV; also used in RSV (palivizumab
by competitively inhibiting inosine preferred in children)
monophosphate dehydrogenase. Adverse effects: hemolytic anemia; severe
teratogen.
Sofosbuvir Inhibits IICV RNA-dependent RNA polymerase Chronic IICV' in combination with ribavirin.
acting as a chain terminator. simeprevir. ledipasvir (NS5A inhibitor ).
+/— peginterferon alfi
Do not use as monotherapy.
Adverse effects; fatigue, headache, nausea.
Simeprevir HCY' protease inhibitor; prevents viral Chronic HCY' in combination with ledipasvir
replication. (NS5A inhibitor).
Do not use as monotherapy.
Adverse effects: photosensitivity reactions, rash.

Infection control Goals include the reduction of pathogenic organism counts to safe levels (disinfection ) and the
techniques .
inactiv ation of self-propagating biological entities ( sterilization)
Autoclave Pressurized steam at > 120°C. May be sporicidal.
Alcohols Denature proteins and disrupt cell membranes. Not sporicidal.
Chlorhexidine Denatures proteins and disrupts cell membranes. Not sporicidal.
Hydrogen peroxide Free radical oxidation. Sporicidal.
Iodine and iodophors Halogcnation of DNA, RNA. and proteins. May be sporicidal.

Antimicrobials to ANTIMICROBIAL AOVERSE EFFECT

avoid in pregnancy Sulfonamides Kernicterus
Aminoglycosides Ototoxicity
Fluoroquinolones Cartilage damage
Clarithromycin Einbryotoxic
Tetracyclines Discolored teeth, inhibition of bone grow th
Ribavirin Teratogenic
Griseofulvin Teratogenic
Chloramphenicol Gray baby syndrome
SAFe Children Take Really Good Care.
I Pathology

HIGH- YIELD PRINCIPLES IN

Pathology

“ Digressions , objections, delight in mockery, carefree mistrust are signs of Inflammation 204
health; everything unconditional belongs in pathology."
— Friedrich Nietzsche Neoplasia 214

“ You cannot separate passion from pathology any more than you can
separate a person's stririt from his body."
— Richard Sclzer

The fundamental principles of pathology are key to understanding

diseases in all organ systems. Major topics such as inflammation and
neoplasia appear frequently in questions across different organ systems,
and such topics are definitely high yield. For example, the concepts of
cell injury and inflammation are key to understanding the inflammatory
response that follows myocardial infarction, a very' common subject of
board questions. Similarly, a familiarity with the early cellular changes
that culminate in the development of neoplasias for example,
—
esophageal or colon cancer is critical. Finally, make sure you
—
recognize the major tumor-associated genes and are comfortable with
key cancer concepts such as tumor staging and metastasis.
204 SECTION II PATHOLOGY PATHOLOGY — INFLAMMATION

PATHOLOGY — INFLAMMATION

Apoptosis ATP-dependent programmed cell death -

intrinsic andicxtrinsic pathway both pathways activate caspascs (cytosolic proteases) cellular
^
breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and
—
formation of apoptotic bodies, w hich arc then ph igocvtoscd .
Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pvknosis muelear
shrinkage ), and karvorrbexis ( fragmentation caused hv cndonuclease-mcdi,itct|cleavagc).
Cell membrane typically remains intact without significant inflammation ( unlike necrosis ).
ONA laddering ( fragments in multiples of 180 bp) is a sensitive indicator of apoptosis ]
Intrinsic Involved in tissue remodeling in embryogenesis. Occurs when a regulating factor is withdrawn
(mitochondrial ) -
from a proliferating cell population (eg. 1 IL 2 after a completed immunologic reaction
pathway
—apoptosis of proliferating effector cells ). Also occurs after exposure to injurious stimuli (eg,
radiation, toxins, hypoxia) .
Regulated by Bc]-2 family of proteins such as BAX and BAK (proapoptotic ) and Bcl-2
(antiapoptotic).
Bcl-2 prevents cytochrome c release by binding to and inhibiting APAF 1. APAF-1 normally -
binds cytochrome c and induces activation of caspase 9, initiating caspase cascade. If Bcl-2 is
overexpressed (eg, follicular lymphoma t[ 14;18] ), then APAF-1 is overly inhibited, t caspase
activation and tumorigenesis.
—
Extrinsic (death 2 pathways:
receptor) pathway Ligand receptor interactions ( FasL binding to Fas [CD95 ] or TNF-ot binding to its receptoj)
Immune cell (cytotoxic T-cell release of perforin and granzyme B)
Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas
t numbers of circulating self-reacting lymphocytes due to failure of clonal deletion.
Defective Fas-FasL interactions cause autoimmune lymphoproliferative syndrome.
Intrinsic Extrinsic
(mitochondrial) pathway (death receptor ) pathway
Cytotoxic T cell

•
Fa$L /}
^ TNFu
J
i
DNA damage
Radiation, ROS, toxins
Misfolded proteins
Granzyme
•
Hypoxia r t , i efforin
ospasa
pS 5 activation
. -
ytoctirome C Execu m KM
BAXTBAK _ .r • ••

be caspases
. APAF-1
Macrophage
Initiator Ligands for
caspases
ft / 2
‘
‘
macrophage cell
Wj/tefetal dispersion
rsion V receptors

_
,
Cytoplasmic
b eb
,/

Apoptotic IA i[
11 > ‘1
body
H I Figure
 PATHOLOGY PATHOLOGY — INFLAMMATION SECTION II 205

Necrosis

TYPE
Coagulative
Enzymatic degradation and protein denaturation of cell due to exogenous injury
components leak. Inflammatory process ( unlike apoptosis ).
SEEN IN
Ischemia/infarcts in
DUE TO
Ischemia or infarction ;
HISTOLOGY
— intracellular

Cell outlines preserved but nuclei disappear

most tissues (except proteins denature, then t cytoplasmic binding of eosinjdyes Q
brain) enzymatic degradation
Liquefactive Bacterial abscesses, Neutrophils release
brain infarcti lysosomal enzymes
that digest the
tissue H: enzymatic
degradation first , then
proteins denature
Caseous TB, systemic fungi Macrophages wall
( eg. Histoplasma off the infecting
Early: cellular debris and macrophages
Late: cystic spaces and cavitation ( brain )
Neutrophils and cell dehris seen with
bacterial infection
Fragmented cells and debris surrounded by
lymphocytes and macrophages

Fat
capsulation ), Nocardia

Enzymatic: acute
pancreatitis
(saponification of
—
microorganism
granular debris Q
Damaged cells release
lipase to break
down triglycerides.
Outlines of dead fat cells without peripheral
nuclei ; saponification of fat ( combined with
C;r ' i appears dark blue on I I & E stain 0
'

peripancreatic fat ) liberating fatty acids

Nonenzymatic: to bind calcium
traumatic (eg, breast -* saponification
injury )
Fibrinoid Immune reactions in Immune complexes Vessel walls are thick and pink 0
vessels ( eg. polvartcritis combine with
nodosa ) , preedampsia . fibrin -» vessel wall
malignant damage ( type III
hypertension! hypersensitivity
reaction!
Gangrenous Distal extremity and Dry: ischemia Q Coagulative
Cl tractL after chronic Wet: superinfection Liquefactive superimposed on coagulative
ischemia

48» - . '
-
w* v
—
.
K >

/
v : SW
-- - ' 6

.**
w r
K i
\
*
-
Uv
K r,
YVI
j

-
 PATHOLOGY PATHOLOGY — INFLAMMATION
*

Cell injury REVERSIBLE WITH 02 IRREVERSIBLE

Cellular /mitoehondrial swelling (1 ATP
-* 1 activity of VC/ICL ami Ca — niinml
Nuclear chromatin clumping
Membrane blebbing
1 glycogen
Fatty change
Kibosomal/polysomal detachment Ii protein
Mitochondrial permeability /v acuolization;
phospholipid-containing amorphous densities
within mitochondria (swelling alone is
reversible)
Nuclear pvknosis ( condensation), karvorrhexis
( fragmentation ), karyolysis ( fading)
Plasma membrane damage (degradation of
membrane phospholipid)
Lysosomal rupture
—
Cali influx easpase activation -» apoptosis

synthesis)

Ischemia Inadequate blood supply to meet demand.

Regions most vulnerable to hypoxia /ischemia and subsequent infarction:
ORGAN REGION
Brain ACA/MCA /PCA boundary areasjb
Heart Subendocardium ( LV )
Kidney Straight segment of proximal tubule (medulla )
Thick ascending limb (medulla)
Liver Area around central vein (zone III)
I New I Colon Splenic flexure,3 rectum'1
llmaael Watershed areas ( border zones) receive blood supply from most distal branches of 2 arteries with
limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion ( blue
area in Ql
^Neurons most vulnerable to hypoxic-ischemic insults include Purkinje cells of the cerebellum and
pyramidal cells of the hippocampus and neocortex ( zones 3, 5 , 6|
 PATHOLOGY PATHOLOGY — INFLAMMATION SECTION II 207

Types of Infarct j

Red Infarct! Red ( hemorrhagic ) infarcts Q occur in venous occlusion and tissues with multiple blood supplies,
such as liver, lung, intestine, testes; reperfusion ( eg, after angioplasty ). Reperfusion injury is due to

i damage by free radicals.

Red = reperfusion.

Pale Infarcti Pale (anemic) infarcts Q occur in solid organs with a single (end-arterial ) blood supply, such as
heart, kidney, and spleen.

L-
m
'

L L
Inflammation Characterized by rubor (redness), dolor (pain ), color ( heat), tumor ( swelling), and
functio luesa ( loss of function).
Vascular component t vascular permeability, vasodilation, endothelial injury.
Cellular component Neutrophils extravasate from circulation to injured tissue to participate in inflammation through
phagocytosis, degranulation, and inflammatory mediator release.
Acute Neutrophil, eosinophil, and antibody ( pre-existing), mast cell, and basophil mediatecj
Acute inflammation is rapid onset ( seconds to minutesl and of short duration (minutes to
days). Outcomes include complete resolution, abscess formation, or progression to chronic
inflammation.
Chronic Mononuclear cell (monocytes/macrophages, lymphocytes, plasma cells) and fibroblast mediated.
.
Characterized by persistent destruction and repair. Associated with blood vessel proliferation,
fibrosis. Granuloma: nodular collections of epithelioid macrophages and giant cells. Outcomes
include scarring and amyloidosis.
208 SECTION II PATHOLOGY PATHOLOGY — INFLAMMATION
Types of calcification
Dystrophic Ca -+ deposition in abnormal tissues 2° to injury or necrosis.
lends to be localized (eg, calcific aortic stenosis ). 3 shows dystrophic calcification ( yellow star),
calcification
^
m
small bony tissue ( yellow arrow's), and thick fibrotic wall (red arrows).
Seen in I B ( lung and pericardium ) and other granulomatous infectionj liquefactive necrosis
of chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis, congenital CMV
+ toxoplasmosis + rubellij psammoma bodies. CREST svndronnj

i -
Is not directly associated with scrum Ca + levels ( patients arc usually nomiocalccmic ).
&

Metastatic Widespread ( ie, diffuse, metastatic) deposition of Ca-4 in normal tissue 2° to hypercalcemia (eg,
calcification 1° hyperparathyroidism, sarcoidosis, hvpervitaminosis D) or high calcium -phosphate product
levels (eg, chronic renal failure with 2° hyperparathyroidism, long-temi dialysis, calciphvlaxis,
multiple mvclom 4) .

1u.
shows metastatic calcifications of alveolar walls in acute pneumonitis rrows).
- ^
Ca + deposits predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues
lose acid quickly; t pH favors deposition ). Nephrocalcinosis of collecting ducts may lead to
nephrogenic diabetes insipidujand renal failurcj
Patients are usually not normocalcemic.
 i PATHOLOGY PATHOLOGY — INFLAMMATION

Inhalationlinjury and Pulmonary complication associated with smoke

sequelae and fire. Caused by heat , particulates (< 1 |im
diameter), or irritants (eg. NIK ) -* chemical
tracheobronchitis, edema , pneumonia,
ARDS. Many patients present 2° to burns, 7
‘
r
COjjnhalation, or arsenic poisoning.
Bronchoscopy shows severe edema, congestion
of bronchus, and soot deposition (Q, 18 hours
after inhalation injury; Q, resolution at 11 days
after injury).
*
Scar formation 70-807c of tensile strength regained at T months iwhcn type I collagen is replaced with type III
collagent little additional tensile strength will be regained afterward.
SCAR TYPE Hypertrophic Q Keloid
COLLAGEN SYNTHESIS t ftvne I collagen! ttt ( type III collagen )
COLLAGEN ORGANIZATION Parallel Disorganized
EXTENT OF SCAR Confined to borders of original wound Extends beyond borders of original wound with
“clawlike” projections typically on earlobes,
face, upper extremities
SCAR EVOLUTION OVER YEARS Possible spontaneous regression Possible progressive grow'th
RECURRENCE Infrequent Frequent
PREDISPOSITION None t incidence in ethnic groups with darker skin

\" \
k

*YS
 PATHOLOGY PATHOLOGY — INFLAMMATION SECTION II

Wound healing
Tissue mediators MEDIATOR ROLE
PDGF Secreted by activ ated platelets and macrophages
Induces vascular remodeling and smooth muscle
cell migration
Stimulates fibroblast growth for collagen synthesis
FCF Stimulates angiogenesis
EGF Stimulates cell growth via tyrosine kinases (eg,
EGFR /ErbBi )
.
TC F-P
Metalloproteinases
Angiogenesis, fibrosi .
Tissue remodeling ^
VEGF Stimulates angiogenesis
PHASE OF WOUND HEAUNG EFFECTOR CELLS CHARACTERISTICS
Inflammatory (up to Platelets, neutrophils, macrophages Clot formation, t vessel permeability and
3 days after wound) neutrophil migration into tissue; macrophages
clear debris 2 days later
Proliferative Fibroblasts, myofibroblasts, endothelial cells, Deposition of granulation tissue and type
(day 3-weeks after keratinocytes, macrophages III collagen, angiogenesis, epithelial cell
wound ) proliferation, dissolution of clot , and wound
contraction ( mediated by myofibroblasts)^
Delayed wound healing in vitamin C deficiency
and copper deficiency
Remodeling
( 1 week -6+ months
Fibroblasts
t tensile strength of tissue _
Type III collagen replaced by ty pe 1 collagen ,

after wound ) Delayed wound healing in zinc deficiency

Granulomatous Bacterial : Granulomas arc composed of epitheloid cells

diseases Mycobacteria (tuberculosis, leprosy) { macrophages w ith abundant pink cytoplasm I

mmma 1
Bartonella henselae (cat scratch disease)
Listeria monocytogenes ( granulomatosis
infantiseptica )
Treponema pallidum ( 3° syphilis)
Fungal: endemic mycoses ( eg, histoplasmosis)
••
• Parasitic: schistosomiasis
Chronic granulomatous disease
Autoinflammatory:
Sarcoidosis Q
Crohn disease
* Primary biliary cirrhosis
Subacute (de Quervain/granulomatous )
thyroiditis
Granulomatosis with polyangiitis ( Wegener)
Eosinophilic granulomatosis with
polyangiitis ( Churg-Strauss)
Giant cell ( temporal ) arteritis
Takayasu arteritis
Foreign material : berylliosis, talcosis,
hypersensitivity pneumonitis
with surrounding multinucleated giant
cells and lymphocytes. ITiJcclls secrete
IFN-y, activating macrophages. TNF-a
from macrophages induces and maintains
granuloma formation . Anti-TNF drugs can , as
a side effect , cause sequestering granulomas to
break down , leading to disseminated disease.
Always test for latent TB before starting anti-
TNF therapy.
Associated with hypercalcemia due to caleitriol
( ],25-[OH], vitamin D?) production .
Caseating necrosis more common with
infectious causes (eg, TB). Diagnosing
sarcoidosis requires noncaseating granulomas
on biopsy.
 Transudatgl
Exudate vs transudate Exudate
^
Cellular (cloudy) Hypocellular (clear)
t protein ( > 2.9 e/dl .i
f LDH ( vs scrum )
Due to:
i protein (< 2.5 g/dl
t LDH (vs serum )
Due to:
^
• Lymphatic obstruction (chylous) t hydrostatic pressure (eg, IIF, Na +
• Inflammation /infection retention )
- Malignancy * i oncotic pressure ( eg, cirrhosis, nephrotic
syndrome )

Diagnostic analysis comparing serum and pleural fluid protein and LDII levels.

—
Light’s criteria
-
If > 1 criterion is met * effusion is likelv exudative.
IfO criteria are met by definition , effusion is transudative.
1 . Pleural protein /seruin protein ratio > 0.5
2. Pleural LDH /scrum LDH ratio > 0.6
r Pleural LDH > of Hie upper limit of normal for serum LDH

Erythrocyte Products of inflammation ( eg, fibrinogen ) coat RBCs and cause aggregation . The denser RBC
sedimentation rate aggregates fall at a faster rale within a pipette tube. Often co-tested with CRP levels.
t ESR i ESR
Most anemias Sickle cell anemia (altered shape )
Infections Polycythemia ( t RBCs "dilute ” aggregation
Inflammation (eg, giant cell [temporal] arteritis, factors)
polymyalgia rheumatica ) I IF
Cancer (eg, metastases, multiple myeloma ) Microcytosis
Renal disease (end-stage or nephrotic syndrome ) Hvpofibrinogenemia
Pregnancy
 PATHOLOGY PATHOLOGY — INFLAMMATION SECTION II 209

kocyte Extravasation predominantlv occurs at postcapillary venules.

avasation WBCs exit from blood vessels at sites of tissue injur)’ and inflammation in 4 steps:
VASCULATURE/STROMA LEUKOCYTE

O Margination and rolling— defective in K-sclectin ( from WeibcT - Sialyl-Lewisx

leukocyte adhesion deficiency type 2 Palade bodies! Sialyl-Lewisx
( J Sialyl-Lewisx) P-selectin L-selectin
GlyCAM-1, CD54
© Tight binding (adhesion) — defectivjin ICAM-1 (CD54) COll /18 integrins
leukocyte adhesion deficiency type 1 -
(LFA 1, Mac-1)
(I CD18 integrin subunit) VCAM-1 (CD106) VLA-4 integrin

© Diapedesis — WBC travels between PECAM-1 (CD31) PECAM-1 (CD31)

endothelial cells and exits blood vessel
© Migration— WBC travels through Chemotactic products Various
interstitium to site of injury or infection released in response
guided by chemotactic signals to bacteria: C5a, IL-8,
LTB4, kallikrein,
platelet-activating factor

I MN

O Margination 6 rolling © Tight binding © Diapedesis — © Migration

Sialyl-Lewis'

PMN
Vesse
umet
’ E- - ei 1
PMN
LFA -1
^
PMN

JJ Ijg ~ ICAM-1 /
Endothelium ^^
Interstitium Ml

PMN

> radical injury Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA
breakage.
Initiated via radiation exposure (eg, cancer therapy), metabolism of drugs ( phaseI), redox reactions,
.
nitric oxide (eg inflammation)!transition metals, WBC (eg, neutrophils, macrophages) oxidative
burst.
Free radicals can be eliminated by scavenging enzymes (eg, catalase, superoxide dismutase,
glutathione peroxidase), spontaneous decay’, antioxidants (eg, vitamins A, C,E), and certain metal
carrier proteins (eg, transferrin, ceruloplasmin) .
Examples:
Oxygen toxicity: retinopathy of prematurity ( abnormal vascularization), bronchopulmonary
dysplasia, reperfusion injury after thrombolytic thcrapsl
* Drug/chemical toxicity: carbon tetrachloride and acetaminophen overdose (hepatotoxicitv)
Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper)
 PATHOLOGY PATHOLOGY — INFLAMMATION SECTION II 213

Amyloidosis _
—
Abnormal aggregation of protcins (or their fragments ) into (3-plcatcd linear sheets damage
and apoptosis. Amyloid deposits visualized by Congo red stain Q, polarized light ( apple green
birefringence) Q, and I l&E stain (Q shows deposits in glomerular mesangial areas [white arrows],
tubular basement membranes [ black arrows] ).
COMMON TYPES DESCRIPTION
AL ( primary ) Due to deposition of proteins from Ig Light chains. Can occur as a plasma cell disorder or
associated with multiple myeloma. Often affects multiple organ systems, including renal
( nephrotic syndrome), cardiac ( restrictive cardiomyopathy, arrhythmia), hematologic (easy
bruising, splenomegaly). G1 ( hepatomegaly), and neurologic ( neuropathy).
AA (secondary) Seen with chronic inflammatory conditions such as rheumatoid arthritis, IBD,
spondyloarthropathy, familial Mediterranean fever, protracted infection . Fibrils composed of
serum Amyloid A. Often multisystem like AL amyloidosis.
Dialysis- related Fibrils composed of [A -inicroglobulni in patients with FSRD and /or on long-term dialysis. May
present as carpal tunnel syndrome.
Heritable Heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthyretin
gene mutation.
Age - related (senile) Due to deposition of normal ( wild- type) transthyretin (TTR ) predominantly in cardiac ventricles.
systemic Slower progression of cardiac dysfunction relative to AL amyloidosis.
Organ - specific Amyloid deposition localized to a single organ . Most important form is amyloidosis in Alzheimer
disease due to deposition of fT-amyloid protein cleaved from amyloid precursor protein ( APP).
Islet amyloid polypeptide ( IAPP ) is commonly seen in diabetes mcllitus type 2 and is caused by
deposition of amylin in pancreatic islets.
Isolated atrial amyloidosis due to atrial natriuretic peptide is common in normal aging, which can
predispose to t risk of atrial fibrillatiorj
Amyloid deposition lo ventricular eiidinmocardiinii in restrictive cardiomyopathy

mm
Calcitonin deposition in tumor cells in medullary carcinoma of the thvroid.

v a \w \
"
•’ -• •• •

-6 • '
. i
-V\ .
n
? .
A
'
tv * „. . . rN
£ *

rf s
'
* * 1‘ j
i. '-t h

Lipofuscin A yellow -brown "wear and tear * pigment associated w ith normal aging.
Formed by oxidation and polymerization of autophagoevtosed organellar membranes.

im /. t
Autopsy of elderly person will reveal deposits in heart , colon Cl, liv er, kidney, eye, and other organs.

mm fa
214 SECTION II PATHOLOGY PATHOLOGY — NEOPLASIA

PATHOLOGY — NEOPLASIA

Cjellular changes
Hyperplasia! t in number of cells. May be a risk factor for future malignancy (eg, endometrial hyperplasia | but
not considered premalignanl!
Hypertrophy f in size of cells.
Atrophy iin tissue mass due to l in size and/or number of cells. Causes inc lude disuse, denervation, loss of
blood supply, loss of hormonal stimulation, poor nutrition.
Dysplasia Disordered, non-neoplastic cell growth Term used only with epithelial cells. Mild dysplasia is
usually reversible: severe dysplasia usually progresses to carcinoma in situ.
Metaplasial Replacement of one cell type by another. Usually due to exposure to an irritant, such as gastric
acid or cigarette smoke. Reversible if the irritant is removed but may undergo malignant

Neoplasial Uncontrolled, clonal proliferation of cells. Can be benign or malignant!

—
transformation with persistent insult leg, Barrett esophagus esophageal adenocarcinoma )!

Anaplasia Complete lack of differentiation of cells in a malignant neoplasm.

Differentiation! The degree to which a malignant tumor resembles its tissue of origin;
Well-differentiated tumors ( often less aggressive) closely resemble t heir tissue of origin
Poorly differentiated tumors ( often more aggrcssivel look almost nothing like their tissue of
origiij

Hyperplasia
f * r>*\i
Change in cell size Change in cell type Dysplasia
and number and structure
Reversible
• •• • Reversible
Normal cells
Hypertrophy
• • • •
Metaplasia
Change in
Atrophy Irreversible cell type
and structure

ntfffy i '
Neoplasia Anaplasia

I New I
[Figure ]
 PATHOLOGY PATHOLOGY — NEOPLASIA SECTION II 215

Neoplastic Hallmarks of cancer: evasion of apoptosis, growth signal self-sufficiency, anti-growth signal
progression insensitivity, sustained angiogenesis, limitless replicative potential, tissue invasion, and metastasis.
Normal cells
— .
Normal cells w ith hasal apical pol rritvi See cervical example Q, which shows normal cells and
spectrum of dysplasia, as discussed below

OMOIOM o; MM

Dysplasia Abnormal proliferation of cells with loss of si/c, shape, and orientation (eg, koilocvtic change, arrow
in ijComparc vs hyperplasia l cells t in number ).

' o

Carcinoma in situ/ Neoplastic cells have not invaded the intact basement membrane,
preinvasive t Ikiuclearcvtoplasmid ratio and clumped chromatin.
Neoplastic cells encompass entire thickness.
m
sst

Invasive carcinoma Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases).
.
Cell-cell contacts lost by inactivation of f -cadhcrin.

Metastasis Spread to distant organ via lymphatics or bloodt

"Seed and soil” theory of metastasis:
- * Seed = tumor embolus.
• Soil = target organ is often the first-encountered capillary bed ( eg, liver, lungs, bone, brain, etc ).
1
l J
Blood Of
tympfutic

Normal Mild dysplasia Moderate dysplasia Severe dysplasia/

carcinoma in situ
216 SECTION II PATHOLOGY PATHOLOGY — NEOPLASIA

Tumor grade vs stage

Grade Degree of cellular differentiation and mitotic
activity on histology. Range from low grade
(well differentiated ) to high grade ( poorly
differentiated, undifferentiated or anaplastic).
Stage almost always has more prognostic value
than grade.
TNM staging system is used with mam
cancers ; exceptions include brain tumors and
leukemia jj

Stage Degree of localization/spread based on site and
size of 1° lesion, spread to regional lymph
nodes, presence of metastases. Based on
clinical (c) or pathology (p) findings. Example:
cTsNlMO
TNM staging system ( Stage = Spread ):
T = Tumor size/local invasion!
N = Node involvement
M = Metastases
Each TNM factor has independent prognostic-
value; M factor often most important.

Tumor nomenclature Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms
imply malignancy.
Terms for non-neoplastic malformations include hamartoma (disorganized overgrowth of tissues in
their native location, eg, Peutz -Jeghers polyps) and choristoma (normal tissue in a foreign location,
eg, gastric tissue located in distal ileum in Meckel diverticulum).
Benign tumor is usually well differentiated, well demarcated, low mitotic activity, no metastasis, no
necrosis.
Malignant tumor may show poor differentiation, erratic growth, local invasion, metastasis, and
1 apoptosis. Upregulation of telomerase prevents chromosome shortening and cell death.
CELL TYPE BENIGN MALIGNANT
Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma
Mesenchyme
Blood cells Leukemia, lymphoma
Blood vessels Hemangioma Angiosarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Connective tissue Fibroma Fibrosarcoma
Bone Osteoma Osteosarcoma
Fat Lipoma Liposarcoma
Melanocyte Nevus/mole Melanoma

Cancer epidemiology Skin cancer ( basal > squamous »melanoma) is the most common cancer ( not included in list).
MEM .
WQME'A NOTES
Cancer incidencel 1. Pros! |Lung cancer incidence has
Coll Copied to clipboard.
: i .iitil dropped in men, but has
r not changed significantly in
women .
Cancer mortality 1. Lung l. Lung 1. Leukemia Cancer is the 2nd leading cause
2. Prostate 2. Breast 2. Brain and CNS of death in the United States
v Colon /rectum 3. Colon /rectum 3, Neuroblastoma (heart disease is 1st).
 PATHOLOGY PATHOLOGY — NEOPLASIA

Tumor grade vs stage

Grade Degree of cellular differentiation and mitotic
activity on histology. Range from low grade
(well differentiated) to high grade (poorly
differentiated, undifferentiated or anaplastic).
Stage almost alw ays has more prognostic v alue
than grade.
TNM staging system is used with many
cancers; exceptions include brain tumors and
leukemias!!

Stage Degree of localization/spread based on site and
size of 1° lesion, spread to regional lymph
nodes, presence of metastases. Based on
clinical (c ) or pathology ip ) findings. Example:
CT3N1M0
TNM staging system ( Stage = Spread):
1 = Tumor sizc /local invasion!
N = Node involvement
M = Metastases
Each TNM factor has independent prognostic
value; M factor often most important.

Tumor nomenclature Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms
imply malignancy.
Terms for non-neoplastic malformations include hamartoma ( disorganized overgrow th of tissues in
their native location, eg, Peutz-Jeghers polyps) and choristoma (normal tissue in a foreign location,
eg, gastric tissue located in distal ileum in Meckel diverticulum ).
Benign tumor is usually well differentiated, well demarcated, low mitotic activity, no metastasis, no
necrosis.
.
Malignant tumor may show poor differentiation erratic grow th, local invasion, metastasis, and
t apoptosis. Uprcgulation of telomcrasc prevents chromosome shortening and cell death.
CELL TYPE BENIGN MALIGNANT
Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma
Mesenchyme
Blood cells Leukemia, lymphoma
Blood vessels Hemangioma Angiosarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Connective tissue Fibroma Fibrosarcoma
Bone Osteoma Osteosarcoma
Fat Lipoma Liposarcoma
Melanocyte Nevus/mole Melanoma

Cancer epidemiology Skin cancer ( basal > squamous» melanoma) is the most common cancer (not included in list ).
MEty WOMEU CHILDREN (AGE 0-14) NOTES
Cancer incidence! I. Prostate 1. Breast 1. Leukemia Lung cancer incidence has
2. Lung 2. Lung 2. Brain and CNS dropped in men, but has
3. Colon /rcctum '
5. Colon/rectum ’. Neuroblastoma not changed significantly ii
women .
Cancer mortality 1. Lung 1. Lung 1. Leukemia Cancer is the 2nd leading cause
2. Prostate 2. Breast 2. Brain and CNS of death in the United States
3. Colon /rcctum 3. Colon /rcctum v Neuroblastoma ( heart disease is 1st ).
 PATHOLOGY PATHOLOGY — NEOPLASIA SECTION II 217

Paraneoplastic syndromes
MANIFESTATION DESCRIPTION /MECHANISM MOST COMMONLY ASSOCIATED CANCER (S)
Cutaneous
Acanthosis nigricans 1lyperpigmented velvety plagues in axilla and Gastric adenocarcinoma and other visceral
neck malignancies |but more commonly associated
with obesity and insulin resistance)
Sign of Leser-Trelat Sudden onset of multiple seborrheic keratoses GI adenocarcinomas and other visceral
malignancies
Endocrine
Hypercalcemia PTHrP Squamous cell carcinomas of lung, head, and
neck; renal, bladder, breast, and ovarian
carcinomas
,
t 1,25 -( OHN vitamin D (calcitriol ) Lymphoma
Cushing syndrome t ACTH Small cell lung cancer
Hyponatremia (SIADH) t ADH Small cell lung cancer
Hematologic
Polycythemia T Krythropoietin Renal cell carcinoma, hepatocellular
carcinoma, hemangioblastoma,
pheochroinocytoina, leiomyoma
Pure red cell aplasia Anemia with low reticulocytes Thymoma
Good syndrome 1 lypogammaglobulinemia Thymoma
Trousseau syndrome Migrators superficial thrombophlebitis Adenocarcinomas, especially pancreatic
Nonbacterial Deposition of sterile platelet thrombi on heart Adenocarcinomas, especially pancreatic
thrombotic (marantic) valves
endocarditis
Neuromuscular
Anti-NMDA receptor Psychiatric disturbance, memory deficits, Ovarian teratoma
encephalitis seizures, dyskinesias, autonomic instability,
language dysfunction
Opsoclonus- “ Dancing eyes, dancing feet ” Neuroblastoma (children), small cell lung
myoclonus ataxia cancer (adults)
syndrome
Paraneoplastic Antibodies against antigens in Purkinjtlcells Small cell lung cancer (anti-1lu ), gvnecologic
cerebellar .
and breast cancers (anti-Yo) and Hodgkin
degeneration lymphoma ianti-Tri
Paraneoplastic Antibodies against Hu antigens in neurons Small cell lung cancer
encephalomyelitis
Lambert-Eaton -
Antibodies against prcsynaptic (P/Q type) Ca’+ Small cell lung cancer
myasthenic syndrome channels at NMJ
Myasthenia gravis Antibodies against postsvnaptic ACh receptor
at NMJ ^ Thymoma
218 SECTION II PATHOLOGY PATHOLOGY — NEOPLASIA

Oncogenes Gain of function -» t cancer risk. Need damage to only one allele of an oncogens
GENE GENE PRODUCT ASSOCIATED NEOPLASM
ALK Receptor tyrosine kinase Lung adenocarcinoma
BCR- ABL Tyrosine kinase CML, ALL
BCL-2 Anliapoptotic molecule (inhibits apoptosis! Follicular and diffuse large B cell lymphomas
BRAF Serinc /threonine kinase Melanoma. non-Hodgkin lvmphoma, papillary
thy roid carcinoma!

c- KIT Cytokine receptor Gastrointestinal stromal tumor (GIST )

c-MYC Transcription factor Burkitt lymphoma
HER2 / neu (c- erbB2 ) Receptor ty rosine kinasel Breast and gastric carcinomas
JAK2 Tyrosine kinase Chronic myeloproliferative disorders
KRAS GTPase Colon cancer, lung cancer, pancreatic cancer
mat Transcription factor Lung tumor
MYCN Transcription factor Neuroblastoma
RET Receptor tyrosine kinasa MEN 2 A and 2B, medullary thyroid cancer

Tumor suppressor
genes
Loss of function
—
expression of disease
t cancer risk; both ( trvni alleles of a tumor suppressor gene must be lost for

GENE GENE PRODUCT ASSOCIATED CONDITION

APC Negative regulator of B-catenin/WNT pathway Colorectal cancer (associated rvith FAP)
BRCA1/BRCA2 DNA repair protein Breast, ovarian, and pancreatic canceil
CDKN2 A . blocks G, -* S phase
pi 6 Melanoma, pancreatic cancer
DCC DCC — Deleted in Colon Cancer Colon cancer
DPC4/SMAD4 DPC — Deleted in Pancreatic Cancer Pancreatic cancer
MEN! Menin MEN 1
NF1 Ras C 1 Pa sc activating protein (neurofibromin ) Neurofibromatosis type 1 Columns
NF2 Merlin ischwannomin) protein Neurofibromatosis type 2 2 & 3 were

PTEN
B lAKTl activation)
- .
Tyrosine phosphatase of PIP (eg protein kinase Breast cancer, prostate cancer, endometrial
cancer
Rb Inhibits E2F; blocks G] -* S phase Retinoblastoma, osteosarcoma
TPS3 .
p53 activates p21 . blocks Gi — S phase -
Most human cancers, Li Fraumeni syndrome
.
(multiple malignancies at early age aka, SBI ,A
cancer sy ndrome: Sarcoma, Breast, Leukemia,
Adrenal gland!)

TSC1 Hamartin protein Tuberous sclerosis

TSC2 Tuberin protein Tuberous sclerosis
VHL Inhibits hypoxia inducible factor la von Hippel-Lindau discasej
WT 1{ Transcription factor that regulates urogenital Wilms Tumor (nephroblastoma)
development
220 SECTION II PATHOLOGY PATHOLOGY — NEOPLASIA

Psammoma bodies Laminated, concentric spherules with dystrophic calcification Q, PSaMMoma bodies arc seen in:
. Papillary carcinoma of thyroid
Serous papillary cystadenocarcinoma of ovary
• Meningioma
T
Malignant mesothelioma

-
Serum tumor markers Tumor markers should not be used as the 1° tool for cancer diagnosis or screening. T hey may be
used to monitor tumor recurrence and response to therapy, but definitive diagnosis is usually made
via biopsy.
MARKER ASSOCIATED CANCER NOTES
Alkaline phosphatase .
Mctastascs to bone or liver Paget disease of Must exclude hepatic origin bv checking LKTs
bone, seminoma ( placental ALP). ..
and CCT levels.
a- fetoprotein Hepatocellular carcinoma, hepatoblastoma, yolk Normally made by fetus. Transiently elevated in
sac (endodermal sinus) tumor, mixed germ pregnancy. High levels associated with neural
cell tumor. tube and abdominal wall defects, low levels
associated with Down syndrome.
PhCG I lydatidiform moles and Choriocarcinomas Produced by syncyTiotrophoblasts of the
(Gestational trophoblastic disease), testicular placenta.
cancer, mixed germ cell tumor.
CA 15-3/CA 27-29 Breast cancer.
CA 19- 9 Pancreatic adenocarcinoma.
CA 125 Ovarian cancer.
Calcitonin Medullary thvroid carcinoma lalone and in
.
MEN2 A MEN2B ) ]
CEA Major associations: colorectal and pancreatic Carcinoembrvonic antigen. Very nonspecific.
cancers.
Minor associations: gastric, breast, and
medullary thvroid carcinomas]

Chromoaranin Neuroendocrine tumors.

PSA Prostate cancer. Prostate-specific antigen
Can also be elevated in BPH and prostatitis.
Questionable risk /benefit for screening.
Surveillance marker for recurrent disease after
prostatectonn]

P-glycoprotein Also known as multidrug resistance protein 1 MDR 1). Classically seen in adrenocortical
i

.
carcinom hut also expressed bv other cancer cells ( eg colon, liver). Used to pump out toxins .
^
including chemotherapeutic agents ( one mechanism of l responsiveness or resistance to
chemotherapy over time).
 PATHOLOGY PATHOLOGY — NEOPLASIA SECTION II 221

Cachexia Weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg, cancer, AIDS, heart
failure, COPD). Mediated by TNF, IFN-y, IL-1, and IL-6.

Common metastases Most sarcomas spread hematogenously; most carcinomas spread via lymphatics. However, four
carcinomas route hcmatogcnouslv: follicular thyroid carcinoma, choriocarcinoma, renal cell
carcinoma, and hepatocellular carcinoma!
SITE OF METASTASIS 1° TUMOR NOTES
Brain Lung > breas||> melanoma, colon, kidneii 50% of brain tumors are from metastases Q 0.
Commonly seen as multiple well- circumscribed
tumors at gray/white matter junction .
Liver Colon» stomach > pancreas. _
Livcr Q 0 and lung are the most common sites
of metastasis after the regional lymph nodes.
Bone Prostate, breast > lung, thyroid, kidney. Bone metastasis Q Q» 1° bone tumors (eg,
multiple myeloma, lytic). Common mets to
bone: breast (mixed),lung (mixed), thyroid
( lytic), kidney ( lytic), prostate ( blastic).
Predilection for axial skeleton 0
“

m
b.

'
m< t

' w
226 SECTION II PHARMACOLOGY PHARMACOLOGY — PHARMACOKINETICS & PHARMACODYNAMICS

Elimination of drugs
Zero- order Rate of elimination is constant regardless of Cp Capacity-limited elimination.
elimination ( ie, constant amount of drug eliminated per PEA . (A pea is round, shaped like the “ 0” in
unit time ). C i linearly with time. Examples zero-order.)
of drugs — Phcnytoin, Ethanol, and Aspirin ( at
high or toxic concentrations) .
First- order elimination Rate of elimination is directly proportional Flow -dependent elimination.
to the drug concentration (ie, constant
fraction of drug eliminated per unit time).
Cp i exponentially with time. Applies to most
drugs.
-
Zero order elimination -
First order elimination
Elimination rate
Elimination rate
4 U/ h
- 2 U/h !
.
2 Time of tj/ j is constant
Time of tw J,as as concentration l

:ui
concentration J.
i 2 U /h devisee

-
Firjl lUj > i First ty2
- Figure
I \ 2 U/ h lU/h
i Second tl/2 >
*v Second
^ = TYlirdti
/j
Q 5 U/h

Time (h) Time (h) S3

Urine pH and drug Ionized species are trapped in urine and cleared quickly. Neutral forms can be reabsorbed.
elimination
Weak acids Examples: phenobarbital, methotrexate, aspirin. Trapped in basic environments. Treat overdose
with bicarbonate to alkalinizc urincj
RCOOI 1 RCOO- + IP
(lipid soluble )
^ (trapped )

Weak bases Example: amphetamines, TCAs. Trapped in acidic environments. Treat overdose with ammonium
chloride to acidify urincj
RNH * , RNH:+ H+
( trapped ) (lipid soluble )

Drug metabolism
Phase 1 Reduction, oxidation, hydrolysis with Geriatric patients lose phase I first.
cytochrome P-450 usually yield slightly polar,
water- soluble metabolites (often still active).
Phase II Conjugation ( Mcthvlation, Glucuronidation, Ccriatric patients have More GAS ( phase II ) .
Xcetylation, Sulfation) usually yields very polar, Patients who are slow acetylators have t side
inactive metabolites (renally excreted ). effects from certain drugs because of l rate of
metabolism.
228 SECTION I I PHARMACOLOGY PHARMACOLOGY — PHARMACOKINETICS & PHARMACODYNAMICS

Receptor binding

Agonist Agonist plus Agonist Effect of - Agonist Lower

alone competitive T al< ne o antagonist T alone efficacy
antagonist
I o I 50 I Partial agonist
"
alone
o 3
£ Effect of § Agonist plus
competitive noncompetitive
antagonist antagonist i

01 to 10 100 1000 Ot 10 10 00 1000 0.1 1.0 10 100 1000

Agonist dose Agonist dose Agonist dose ,1

AGONIST WITH EFFECT EXAMPLE

© Competitive Sliifts curve right (1 potency), no change Diazepam (agonistl + flumazcnil (competitive
antagonist in efficacy. Can be overcome by t the antagonist) on GABA receptor.
concentration of agonist substrate.

© Noncompetitive Shifts curve down (i efficacy). Cannot be Norepinephrine ( agonist ) + phenoxvbenzamine

antagonist overcome by t agonist substrate concentration. (noncompetitive antagonist) on a-receptors.

® Partial agonist Acts at same site as full agonist, but with lower Morphine ( full agonist) vs buprenorphine
(alone) maximal effect (i efficacy). Potency is an (partial agonist) at opioid p-receptors.
independent variable.

Therapeutic index Measurement of drug safety. TITE: Therapeutic Index = TD-(i / ED50.
Safer drugs have higher IT values. Drugs with
TDJO _ median toxic dose
EDJQ median effective dose lower TI v alues frequently require monitoring
( eg. Warfarin. Theophylline, Digoxin.
Therapeutic window — dosage range that can
safely and effectively treat disease. Lithium; Warning! T hese Drugs arc Lethal!).
.
ID;o ( lethal median dose) often replaces TD;o
in animal studies.
Efficacy Toxicity
100

f , Therapeutic index

i
o ED n
.
ED = Effective dose
TD = Toxic dose

0
 - iu

0
Log (drug concentration) E9

PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS SECTION I I

PHARMACOLOGY — AUTONOMIC DRUGS

Central and peripheral nervous system

A
Parasympathetic

V *-T
Medul a

Pre (long)

Spinal cord
* ©e r f
[“ -
U
T
0
N Prc (short] [ACh Post (long) | ACh M Sweat glands
0
Cardiac and smooth
M
I [ACh ’I muscle, gland cells,
nerve terminals
C
Sympathetic
fACh Renal vasculature
smooth muscle

Adrenal medulla 5
l1:
/
/* //
-[ACh W,
r
S.. Blood
Catecholamine
a, Cardiac
u.
muscle, vessels

transmission

SOMATIC Voluntary motor nerve

[ACh Skeletal muscle
Neuromuscular
junction 0

Adrenal medulla is directly innervated hv preganglionic sympathetic fibers.

Sweat glands are part of the sympathetic pathway but arc innervated bv cholinergic fibers.!

Acetylcholine Nicotinic ACh receptors are ligand-gated Na*/K4 channels. Two subtypes: \N ( found in autonomic
Receptors ganglia, adrenal medulla) and NM (found in neuromuscular junction of skeletal muscle).
Muscarinic ACh receptors are G-protein-coupled receptors that usually act through 2nd
messengers. 5 subty pes: M| f o u n d in heart, smooth muscle, brain, exocrine glands, and on sweat
glands (cholinergic sympathetic).
 PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS

G-protein-linked second messengers

RECEPTOR G- PROTEIN CLASS MAJOR FUNCTIONS
Sympathetic
«1 q t vascular smooth muscle contraction, t pupillary dilator muscle
contraction ( mydriasis), t intestinal and bladder sphincter muscle
contraction
«2 i sympathetic (adrenergic ) outflow, 1 insulin release, i lipolysis, t platelet
* aggregation, l aqueous humor production
A S t heart rate, t contractility ( one heart!t renin release, t lipolvsis
A s Vasodilation, bronchodilation (two lungs)] t lipolysis, t insulin release,
t uterine toire ( tocolysis), ciliary muscle relaxation, t aqueous humor
production
A s t lipolysis, t thermogenesis in skeletal muscle
Parasympathetic
M , q Mediates higher cognitive functions, stimulates enteric nervous system]
M2 i i heart rate and contractility of atria
M3 q t exocrine gland secretions (eg, lacrimal, sweat, salivary, gastric acid ),
t gut peristalsis, t bladder contraction, bronchoconstriction, t pupillary
sphincter muscle contraction ( miosis), ciliary muscle contraction
(accommodation), t insulin releast]

Dopamine
D , S Relaxes renal vascular smooth inuseki activates direct pathway of striatum
Modulates transmitter release, especially in brain, inhibits indirect
° 2
pathway of striatum
Histamine
H , q t nasal and bronchial mucus production, t vascular permeability,
contraction of bronchioles, pruritus, pain
H2 S t gastric acid secretion
Vasopressin
v, q t vascular smooth muscle contraction

v2 s t IRC) permeability and reabsorption in collecting tubules of kidney]

“After qisses ( kisses), you get a qii| 1 kick) out of siq (sick ) sqs (super qinky sex ).”

,..
Hj
M Mj
Uj, Vj,
Receptor Phospholipase C
DAG — Protein
kinase C
HAVe 1 M&M.

Lipids
^ IP , — I i<*V Smooth muscle contraction

Pi. foPi 0,. . Receptor Gs ATP

.
H2 V2
^

G,
Adenylyl cyclase
i f ia>x (heart) Revised
Figure
cAMP Protein kinase A
MJ. < / j. Dj Receptor Myosin light -chain
kinase (smooth
muscle)

MAD 2’s.
 PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS SECTION II 231

Release of norepinephrine from a sympathetic nerve ending is modulated bv NE itself, acting on

Autonomic drugs
presMiaptic ou-autoreceptors negative feedback.
— ^
~
\ mphetamines use the NE transporter ( NET ) to enter the presvnaptic terminal, where they utilize
the vesicular monoamine transporter ( VMAT ) to enter neurosecretory vesicles. This displaces NK
from the vesicles. Once NE reaches a concentration threshold within the presvnaptic terminal .
the action of NKT is reversed, and NE is expelled into the synaptic cleft, contributing to the
characteristics and effects of t NR observed in patients taking amphetamines.
CHOLINERGIC NORADRENERGIC

AXON AXON
Tyrosine
Choline
Tyrosine
Metyrosme
1
i N im
Hemicholinium Choline *
Acetyl- CoA i
Dopamine
LhAT
Reserpine Release -modulating
\o
•

& receptors
Vesamicol
Ca2+ AT II

AO
NE -OO
Ca 2+

Amphetamine
impnc , Reuptake /
ephedrine

—=
Botulinum

Choline +
Cocaine, TCAs,
amphetamine
*
6
Revised
cetate NEQ Figure
& orl Diffusion,
metabolism
00 '
receptor
AChE inhibitors
AChE Adrenoreceptors « or p
H h H
POSTSYNAPTIC MEMBRANE POSTSYNAPTIC MEMBRANE a

Grcie will) routing arrow repreient tramporlrrv Drug n ifaWcs are of historical iignificance.
* * *
232 SECTION II PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS

Cholinomimetic agents
DRUG ACTION APPLICATIONS
Direct agonists
Bethanechol Activates bond and bladder smooth Postoperative ileus, neurogenic ileus, urinary
muscle; resistant to ACliE. "Bethany, call retention
( bethanechol ) me to activate sour bonds and
bladder.”
Carbachol Carbon copy of acetylcholine. Constricts pupil and relieves intraocular
pressure in open-angle glaucoma
Methacholine Stimulates muscarinic receptors in airway when Challenge test for diagnosis of asthma
inhaled.
Pilocarpine Contracts ciliary muscle of eye ( open-angle Potent stimulator of sweat, tears, and saliva
glaucoma ), pupillary sphincter (closed-angle Open-angle and closed-angle glaucoma,
glaucoma); resistant to AChE. “ You cry, drool, xerostomia (Sjogren syndrome)
and sweat on your ‘pilow.’”
Indirect agonists (anticholinesterases)
Galantamine, t ACh. Alzheimer disease ( Alzheimer patients gallantly
donepezil, swim down the riveri
rivastiqminel
Edrophonium t ACh . Historically used to diagnose myasthenia gravis;
anti-AChRAb ( anti-acetvleholine receptor
antibody) test currently useqj
Neostigmine t ACh. Postoperative and neurogenic ileus and
Nco CNS - No CNS penetration (quaternary urinary retention, myasthenia gravis,
amine) . reversal of neuromuscular junction blockade
( postoperative).
Physostigmine .
t ACh Physostigmine “plivxes” atropine Anticholinergic toxicitv; phrccly (freely ) crosses
overdose.
—
blood-brain barrier CNS ( tertiary amine). ^
Pyridostigmine t ACh; t muscle strength. Pyridostigmine gets Myasthenia gravis ( long acting); does not
rid of myasthenia gravis. penetrate CNS (quaternary amine).
Note: With all cholinomimetic agents, watch for exacerbation of COPD, asthma, and peptic ulcers when giving to susceptible
patients.

Cholinesterase Often due to organophosphates, such as DUMBBELSS.

inhibitor poisoning parathion, that irreversibly inhibit AChE.
Causes Diarrhea, Urination, Miosis,
Bronchospasm, Bradycardia, Excitation
of skeletal muscle and CNS, Lacrimation,
Sweating, and Salivation. May lead to
respiratory failure if untreated.
Organophosphates are often components of
insecticides; poisoning usually seen in farmers.
—
Antidote atropine (competitive inhibitor ) +
pralidoxime ( regenerates AChE if given early).
 PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS SECTION II 23

Muscarinic antagonists
DRUGS ORGAN SYSTEMS APPLICATIONS
Atropine, Eye Produce mydriasis and cycioplegia.
homatropine,
tropicamide
Benztropine CNS Parkinson disease ( “ park my Benz").
^
trihexyphenidyl Acute dystonia.
Glycopyrrolate Cl, respiratory Parenteral: preoperative use to reduce airway
secretions.
Oral: drooling, peptic ulcer .
Hyoscyamine, GI Antispasmodics for irritable bowel syndrome.
dicyclomine
Ipratropium, Respiratory COPD, asthma ( “ 1 pray 1 can breathe soonf ).
tiotropium
Oxybutynin, Genitourinary Reduce bladder spasms and urge urinary
solifenacin, incontinence (overactive bladder).
tolterodine
Scopolamine CNS Motion sickness.

Atropine Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications.
ORGAN SYSTEM ACTION NOTES
Eye t pupil dilation , cycioplegia Blocks DUMBBeLSS in cholinesterase
Airway 1 secretions inhibitor poisoning. Docs not block excitation
of skeletal muscle and CNS (mediated by
Stomach J acid secretion
nicotinic receptors ) .
Gut 1 motility
Bladder 1 urgency in cystitis
ADVERSE EFFECTS t body temperature (due to t sweating); Side effects:
rapid pulse; dry mouth ; dry, flushed skin ; Hot as a hare
cycioplegia; constipation; disorientation Drv as a bone
Can cause acute angle-closure glaucoma in Red as a beet
elderly ( due to mydriasis), urinary retention Blind as a bat
in men with prostatic hyperplasia , and Mad as a hatter
hyperthermia in infants Jimson weed ( Datura) -* gardener's pupil
( mydriasis due to plant alkaloids)
 PHARMACOLOGY
4 Rnd * ls
' ‘
^ * 1$

Muscarinic antagonists
DRUGS ORGAN SYSTEMS APPLICATIONS
Atropine, Eye Produce mydriasis and cycloplegia.
homatropine,
tropicamide
Benztropine CNS Parkinson disease (“park my Benz” ).
^
trihexyphenidyl Acute dystonia.
Glycopyrrolate GI, respiratory Parenteral: preoperative use to reduce airway
secretions.
Oral: drooling, peptic ulcer.
Hyoscyamine,
dicyclomine
.
C1 Antispasmodics for irritable bowel syndrome.

Ipratropium, Respiratory GOPD, asthma (“I pray 1 can breathe soon!").

tiotropium
Oxybutynin, Genitourinary Reduce bladder spasms and urge urinary
solifenacin, incontinence (overactive bladder).
tolterodine
Scopolamine CNS Motion sickness.

Atropine Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications.
ORGAN SYSTEM ACTION NOTES
Eye t pupil dilation, cycloplegia Blocks DUMBBeLSS in cholinesterase
Airway i secretions inhibitor poisoning. Docs not block excitation
of skeletal muscle and CNS (mediated by
Stomach i acid secretion
nicotinic receptors ).
Gut 1 motility
Bladder 1 urgency in cystitis
ADVERSE EFFECTS t body temperature (due to t sweating); Side effects:
.
rapid pulse; dry mouth; dry flushed skin; Hot as a hare
cycloplegia; constipation; disorientation Dry as a bone
Can cause acute angle-closure glaucoma in Red as a beet
elderly ( due to mydriasis), urinary retention Blind as a bat
in men with prostatic hyperplasia, and Mad as a hatter
hyperthermia in infants |imson weed ( Datura )
— gardeners pupil
234 SECTION II PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS

Sympathomimetic;
DRUG ACTION APPLICATIONS

Direct sympathomimetics
Albuterol, salmeterol Pz > P, Albuterol for acute asthma or COPD. Salmeterol
for long-term asthma or COPD control.
Dobutamine Pi > P;. « Heart failure ( HK| ( inotropic > chronotropic ),
cardiac stress testing.
Dopamine D| = D, > p > a Unstable bradycardia , HF, shock; inotropic and
chronotropic effects at lower doses due to (5
effects; vasoconstriction at high doses due to a
effects.
Epinephrine P>a Anaphylaxis, asthma, open-angle glaucoma;
a effects predominate at high doses.
-
Significantly stronger effect at P receptor than
norepinephrine.
Fenoldopam D , Postoperative hypertension , hypertensive crisis.
Vasodilator (coronary, peripheral, renal, and
splanchnic). Promotes natriuresis. Can cause
hypotension and tachycardia.
Isoproterenol P, = Pz .
Flectrophvsiologic evaluation of
tachyarrhythmias. Can worsen ischemia.
Midodrine Autonomic insufficiency and postural
“i hypotension. May exacerbate supine
hypertension.
Mirabeqron & Urinarv urge incontinence or overactive bladder.
Norepinephrine oi| > a2 > P| Hypotension, septic shock.

Phenylephrine ai > a: Hypotension ( vasoconstrictor), ocular procedures

( mydriatic ), rhinitis (decongestant ).
Indirect sympathomimetics
Amphetamine Indirect general agonist , reuptake inhibitor, also Narcolepsy, obesity, ADI ID.
releases stored catecholamines
Cocaine Indirect general agonist , reuptake inhibitor Causes vasoconstriction and local anesthesia.
Never give P- blockcrs if cocaine intoxication is
suspected (can lead to unopposed ot| activation
and extreme hypertension ).
Ephedrine Indirect general agonist, releases stored Nasal decongestion, urinary incontinence,
catecholamines hypotension .
 PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS SECTION II 235

Norepinephrine vs
isoproterenol
Nfcjt systolic and diastolic pressures as a result of aj-mediated vasoconstriction f mean arterial
—
pressure reflex bradycardia. I lowever, isoproterenol (no longer commonly used) has little a
—
,
effect but causes |J -mediated vasodilation, resulting in 1 mean arterial pressure and t heart rate
through P| and reflex activity.

Norepinephrine (a > p) Epinephrine la « p) Isoproterenol ip > a)

/
/
/ Widened
pulse
ptnswe
*\ —/ ^
“
\V~ Systole
MAP
-
\ OMStohc Pi > ai
“
S ft
A

^ \
/ ' \ V*“ V
Reflex bxadycardu

x ~

“,
p, > U n o p p o s e d P7

CO <— > CO T CO TT
HR i HR T HR TT
MAP TT MAP T MAP i
PP T PP T PP TT
H

Sympatholytics (a2- agonists )

DRUG APPLICATIONS ADVERSE EFFECTS
Clonidine, guanfacine Hypertensive urgency ( limited situations), CNS depression, bradycardia, hypotension,
ADHD, Tourctte syndrome respirators’ depression, miosis, rebound
hvpertension with abrupt cessation
a- methyldopa Hypertension in pregnancy Direct Coombs ® hemolysis, SLE like syndrome -
236 SECTION I I PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS

a-blockers
DRUG APPLICATIONS ADVERSE EFFECTS
Nonselective
Phenoxybenzaminel Irreversible. Plieochromocytomal ( used
preoperatively) to prevent catecholamine
(hypertensive) crisis Orthostatic hypotension, reflex tachycardia
Phentolamine| Reversible. Give!lo patients on MAO inhibitors
who eat tyramine-containing foods
,
a selective (-osin ending)
Prazosin, terazosin, Urinary symptoms of BPH; PTSD ( prazosin); lst-dose orthostatic hypotension, dizziness,
doxazosin, hypertension (except tamsulosin) headache
tamsulosin
a2 selective
Mirtazapine Depression Sedation, t serum cholesterol, t appetite

Effects of ot-blocker (eg, phentolamine) on BP responses to epinephrine and phenvlephrimj

Epinephrine Phenylephrine
Before u- blockade Alter u-blockade Before a-blockade After a- blockade

a
Net pressor \
0
Net pr«»r \\ 1 ^
a.
eifKt

^ f
Net depressor
effect i
a.
I
A

1
55 Systolic .
>a Unopposed fl2
Suppression of
pressor effect
MAP

ft
Jj
1
_y \_
Pj Reftei tachycardia
f
s
X Reflex bradycardia

Time Time 0

Kpinephrine response exhibits reversal of mean arterial Pheny lephrine response is suppressed but not reversed
pressure from net increase ( the q response) to a net because it is a "pure" q- agonist I lacks fl-agonist
decrease (the 0-, response). properties!
)
 PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS SECTION II 237

p- blockers Accbutolol, atenolol, bctaxolol , bisoprolol , carvedilol, csmolol , labctalol , metoprolol, nadolol .
nebivolol , pindolol , propranolol , timolol .
APPLICATION ACTIONS NOTES/EXAMPLES
Angina pectoris i heart rate and contractility, resulting in 1 O2
consumption
Myocardial infarction! 1 mortality
Supraventricular i AV conduction velocity (class 11 Metoprolol , esmolol
tachycardial antiarrhythmic)
Hypertension 1 cardiac output , 1 renin secretion (due to
Pj-receptor blockade on JGA cells)
Heart failure
Glaucoma! ^ i mortality ( bisoprolol , carvedilol , metoprolol )
l production of aqueous humoii Timolol
Variceal bleeding i hepatic venous pressure gradient and portal Nadolol , propranolol
hypertension
ADVERSE EFFECTS Erectile dysfunction, cardiovascular adverse Use with caution in cocaine users due to risk
effects ( bradycardia , AV' block , HF), CNS of unopposed a-adrenergic receptor agonist
adverse effects (seizures , sedation , sleep activity
alterations ), dyslipidemia ( metoprolol ), and Despite theoretical concern of masking
astluna /COPD exacerbations hypoglycemia in diabetics, benefits likely
outweigh risks; not contraindicated
SELECTIVITY selective antagonists ( P
Pi -partial | > (5, ) — acehutolol Selective antagonists mostly go from A to M ( P(
( agonist), atenolol , bctaxolol , bisoprolol with 1st half of alphabet )
esinolol metoprolol
Nonselective antagonists (P| = P-, ) — nadolol , Nonselective antagonists mostly go from N to 7.
pindolol ( partial agonist ), propranolol timolol
,
-
( P with 2nd half of alphabet )

—
Nonselective a- and (3-antagonists carvedilol . Nonselective a- and P-antagonists have modified
labetalol suffixes ( instead of “ -olol")
Nebivolol combines cardiac-selective
Pi -adrenergic blockade with stimulation
of P -receptors, which activate nitric oxide
^

synthase in the vasculature

 238 SECTION I I PHARMACOLOGY PHARMACOLOGY — AUTONOMIC DRUGS

Ingested seafood toxins

TOXIN SOURCE ACTION SYMPTOMS TREATMENT
Tetrodotoxin Pufferfish. Highly potent toxin; Nausea, diarrhea, tjapportive.
binds fast voltage- paresthesias,
gated Na* channels weakness, dizziness,
in cardiac /nerve loss of reflexes.
tissue, preventing
depolarization.
Ciguatoxin Reef fish such as Opens Na+ Nausea, vomiting, ijrpportive.
barracuda, snapper, channels, causing diarrheal perioral
and moray eel . depolarization. numbness;
reversal of hot and
cold sensations;
bradycardia, heart
block, hypotension!
Histamine Spoiled dark-meat fish Bacterial histidine Mimics anaphylaxis: Antihistamines.
(scombroid such as tuna, mahi- decarboxylase converts acute burning Albuterol and
poisoning) mahi, mackerel, and histidine to histamine. sensation of mouth, epinephrine if needed.
bonito. Frequently flushing of face,
misdiagnosed as fish erythema, urticaria,
allergy . itching. May progress
to bronchospasm,
angioedema .
hypotension.

Beers criteria Widely used criteria developed to reduce inappropriate prescribing and harmful polypharmacy in
the geriatric population. Includes > SO medications that should be avoided in elderly patients due
to 1 efficacy and/or t risk of adverse events. Examples include:
Anticholinergics, antihistamines, antidepressants, benzodiazepines, opioids ( t risk of delirium,
I New I
sedation, falls, constipation, urinary retention|
lEasil a-blockers It risk of hypotension)
• PPIs ft risk of C difficile infection)
NSAlDs ( t risk of Cd bleeding, especially with concomitant anticoagulation )
 PHARMACOLOGY PHARMACOLOGY — TOXICITIES AND SIDE EFFECTS SECTION II 239

1 PHARMACOLOGY - TOXICITIES AND SIDE EFFECTS

Specific toxicity TOXIN TREATMENT

treatments Acetaminophen N-acetvlcystcine ( replenishes glutathione!
ACHE inhibitors, organophosphates Atropine > pralidoxime
Antimuscarinic, anticholinergic agents Physostigmine, control hyperthermia
Arsenic Dimercaprol, succimer
Benzodiazepines Fluinazenil
(J-blockers
Carbon monoxide ^ ropine, glucagon
100% O,, hyperbaric O,
Copper Penicillamine, trientine ( Copper pennv)
Cyanide Nitrite + thiosulfate, hydroxocobalamin
Digitalis (digoxin) Anti- dig Fab fragments
Heparin Protamine sulfate
Iron Deferoxamine, deferasirox, deferiprone
Lead EDTA, dimercaprol, succimer, penicillamine
Mercury Dimercaprol, succimer
Methanol, ethylene glycol (antifreeze) Fomcpizole > ethanol, dialysis
Methemoglobin Methylene blue, vitamin C
Opioids NalOjtCjie
Salicylates ,
NaHCO (alkalinize urine), dialysis
TCAs NaHCO ,
Warfarin Vitamin K (delayed effect), fresh frozen plasma
( immediate)

Drug reactions — cardiovascular

DRUG REACTION CAUSAL AGENTS
Coronary vasospasm .
Amphetamines, cocaine, ergot alkaloids sumatriptanl
Cutaneous flushing Vancomycin, Adenosine, Niacin, Nitrates, Ca=± channel blockers, Kchinocandins ( VANNCKt

Dilated Anthracyclines (eg, doxorubicin, daunorubicin); prevent with dexrazoxane

cardiomyopathy
Torsades de pointes AntiArrhythmics (class L\, III), antiBiotics (eg, macrolides), anti“C”ychotics ( eg, haloperidol ),
antiDepressants (eg, TCAs), antiEmetics (eg, ondansetron) (ABODE).
240 SECTION II PHARMACOLOGY PHARMACOLOGY — TOXICITIES AND SIDE EFFECTS
Drug reactions
DRUG REACTION
— endocrine/ reproductive
CAUSAL AGENTS NOTES
Adrenocortical HPA suppression 2 ° to glucocorticoid
insufficiency withdrawal
Diabetes insipidus Lithium, demedocyclinc
Hot flashes Tamoxifen, clomiphene
Hyperglycemia .
Tacrolimus, Protease inhibitors Niacin, HCTZ, Taking Pills Necessitates Having blood
Corticosteroids Checked
Hypothyroidism Lithium, amiodarone, sulfonamides
SIADH Carbamazcpine, Cyclophosphamide, SSRIs Can’ t Concentrate Serum Sodium

Drug reactions
DRUG REACTION
— gastrointestinal
CAUSAL AGENTS NOTES
Acute cholestatic Erythromycin
hepatitis, jaundice
Diarrhea Acamprosatc, acarbosc, cholinesterase
inhibitors, colchicine, erythromycin,
czctimibc, metformin , misoprostol, orlistat,
pramlintide, quinidine, SSRIs
Focal to massive Ualothane, Amanita phalloides ( death cap Liver “ HAVAc”
hepatic necrosis . .
mushroom ) Valproic acid Acetaminophen
Hepatitis Rifampin, isoniazid , pyrazinamidc, statins,
fibrates
Pancreatitis Didanosine, Corticosteroids, Alcohol , Valproic acid . Drugs Causing A Violent Abdominal Distress
-Vzathioprinc, Diuretics (furosemide, HCTZ )
Pill -induced Bisphosphonates, ferrous sulfate, NSAIDs, Caustic effect minimized with upright posture
esophagitis potassium chloride. tetracvcline4 and adequate water ingestion .
Pseudomembranous Ampicillin. cephalosporins, clindamvcin. Antibiotics predispose to superinfection by
colitis fluoroquinolone
^ resistant C difficile
 PHARMACOLOGY PHARMACOLOGY — TOXICITIES AND SIDE EFFECTS SECTION I I 241

Drug reactions— hematologic

DRUG REACTION CAUSALAGENT 5 NOTES
Agranulocytosis Clozapine, Carbamazcpine, Propylthiouracil, Can Cause Pretty .Major Collapse of
Methimazole, Colchicine, Ganciclovir Granulocytes
Aplastic anemia Carbamazepine, Methimazole, NSAIDs, Can’t Make New Blood Cells Properly
Benzene, Chloramphenicol, Propylthiouracil
Direct Coombs ¬
Methyldopa, penicillin
positive hemolytic
anemia
Druq reaction with Allopurinol, anticonvulsants, antibiotics, Potentially fatal delayed hypersensitivity
eosinophilia and sulfonamides reaction. Latency period { 2-8 weeks)
systemic symptoms followed bv fever, morbilliform!skin rash, and
( DRESS frequent multiorgan involvement. Treatment:
* withdrawal of offending drug, corticosteroids.
Gray baby syndrome Chloramphenicol
Hemolysis in G6PD Isoniazid, Sulfonamides, Dapsone, Primaquine, Hemolysis IS D PAIN
deficiency Aspirin, Ibuprofen, Nitrofurantoin
Megaloblastic anemia Hvdroxvurea, Phcnvtoin, Methotrexate, Sulfa You’re having a mega blast with PMSl

Thrombocytopenia
drug!
Heparin *
Thrombotic OCPs, hormone replacement therapy
complications

Drug reactions— musculoskeletal / skin /connective tissue

DRUG REACTION CAUSAL AGENTS NOTES
Fat redistribution .
Protease inhibitors Glucocorticoids Fat PiG
Gingival hyperplasia Phcnv toin, Ca“+ channel blockers, cyclosporine
Hyperuricemia (gout) Pyrazinamidc, Thiazides, Furosemidc, Niacin, Painful Tophi and Feet Need Care
Cyclosporine
Myopathy Statins, fibrates. niacin, colchicine, dantomvein.
hvdroxvehloroquinc, interferon-a,

Osteoporosis
penicillamine, glucocorticoid!
*
Corticosteroids, progesterone-only birth control,
aromatase inhibitors, anticonvulsants, heparin!
Photosensitivity Sulfonamides, Amiodarone, Tetracyclines, SAT’ For Photo
5-FU
Rash ( Stevens- Anti-epileptic drugs (especially lamotrigine), Steven Johnson has epileptic allergy to sulfa
Johnson syndrome) allopurinol, sulfa drugs, penicillin drugs and penicillin
SLE- like syndrome Sulfa drugs, Hydralazine, Isoniazid, Having lupus is "SHIPP-E”
Procainamide, Phenytoin, Etanercept
Teeth discoloration Tetracyclines
Tendonitis, tendon Fluoroquinolones
rupture, and
cartilage damage
242 SECTION I I PHARMACOLOGY PHARMACOLOGY — TOXICITIES AND SIDE EFFECTS

Drug reactions — neurologic

DRUG REACTION CAUSAL AGENTS NOTES
Cinchonismi Quinidine, quinine! Can present with tinnitus, psy chosis, hearing,
visual and cognitive impairment
Parkinson-like
syndrome
*.
Antipsychotic Reserpine, Metodopramide Cogwheel rigidity of ARM

Seizures Isoniazid (vitamin B6 deficiency), Bupropion, With seizures,IBITE my tongue

Imipenem/cilastatin, Tramadol, Enflurane
Tardive dyskinesia Antipsychotics, metodopramide

Drug reactions— renal/genitourinary

DRUG REACTION CAUSAL AGENTS NOTES
Fanconi syndrome .
Cisplatin, ifosfamide expired tetracyclines .
tenofovid
Hemorrhagic cystitis Cyclophosphamide, ifosfamide Prevent by coadministering with mesna
Interstitial nephritis Penicillins, furosemide. NSA 1IX proton pump
inhibitors

Drug reactions— respiratory

DRUG REACTION CAUSAL AGENTS NOTES
Dry cough ACE inhibitors
Pulmonary fibrosis Methotrexate, Nitrofurantoin, Carmustine, My Nose Cannot Breathe Bad Air
Bleomycin, Busulfan, Amiodarone

Drug reactions— multiorgan

DRUG REACTION CAUSAL AGENTS NOTES
Antimuscarinic Atropine, TCAs, H|-blockers, antipsychotics
Disulfiram-like .
lst-generation Sulfonvlurcas Procarbazine, Sorrv Pals. Can’t Go MingleJ
reaction .
certain Cephalosporins Griseofulvin .
Metronidazole!
Nephrotoxicity/ Aminoglycosides, vancomycin, loop diuretics, Cisplatin toxicity may respond to amifostinc.
ototoxicity cisplatin. amphotericin Bil
 PHARMACOLOGY PHARMACOLOGY — TOXICITIES AND SIDE EFFECTS SECTION II 243

Cytochrome P- 450 Inducers (+) Substrates Inhibitors (-)

interactions ( selected ) Chronic alcohol use Anti-epilcptic! Acute alcohol abuse
St. John's wort Theophylline Macrolides
Phenytoin Warfarin Isoniazid ( 1NH )
Phcnobarbital OCPs Grapefruit
Nevirapine Omeprazole
Rifampin Sulfonamides
Griseofulvin Ouiiiidine
Carbamazepine Cimetidine
Ritonavir
Amiodarone
Ciprofloxacin
Ketoconazole

Chronic alcoholics Steal Always Think When Outdoors Mv AMIGOS give me Quality
Phen-Phcn and Never CRAC hi
Refuse Greasy Garbs

Sulfa drugs Sulfonamide antibiotics, Sulfasalazine, Scary’ Sulfa Pharm FACT’S

Probenecid, Furoscmidc, Acetazolamidc,
Celecoxib, Thiazides, Sulfonylureas.
Patients with sulfa allergies may develop
fever, urinary tract infection, Stevens-
Johnson syndrome, hemolytic anemia,
thrombocytopenia, agranulocytosis, acute
.
interstitial nephritis, and urticaria (hives)
Sy mptoms range from mild to life threatening.
244 SECTION I I PHARMACOLOGY PHARMACOLOGY — MISCELLANEOUS

1 PHARMACOLOGY — MISCELLANEOUS

Drug names
ENDING CATEGORY EXAMPLE
Antimicrobial
- azole Ergosterol synthesis inhibitor Ketoconazole
- bendazole Antiparasitic/antihelminthic Mebendazole
-cillin Peptidoglvcan cross-linking inhibit ! Ampicillin
-cycline Protein synthesis inhibitor Tetracycline
-ivir Neuraminidase inhibitor Oseltamivir
-navir Protease inhibitor Ritonavir
-ovir DNA polymerase inhibitor Acyclovir
-thromycin Macrolide antibiotic Azithromycin
CNS
- ane Inhalational general anesthetic Ilalothanc
-azine Typical antipsychotic Thioridazine
-barbital Barbiturate Phenobarbital
- caine Local anesthetic Lidocaine
- etine SSRI Fluoxetine
-ipramine, -triptyline TCA Imipramine, amitriptyline
-triptan 5-HTIB/ID agonist Sumatriptan
-zepam, -zolam Benzodiazepine Diazepam, alprazolam
Autonomic
- chol Cholinergic agonist Bethanechol, carbachol
-curium, -curonium Nondepolarizing paralytic Atracurium, vecuronium
-olol P-blocker Propranolol
- stigmine AChE inhibitor Neostigmine
-terol P;-agonist Albuterol
-zosin aj-antagonist Prazosin
Cardiovascular
- afil -
PDE 5 inhibitor Sildenafil
- dipine Dihydropvridine Ca2+ channel blocker Amlodipine
-pril ACE inhibitor Captopril
- sartan Angiotensin-II receptor blocker Losartan
- statin HMG-CoA reductase inhibitor Atorvastatin
- xaban Direct factor Xa inhibitor! .
Apixaban, edoxaban rivaroxaban
Other
- dronate Bisphosphonatc Alendronate
- glitazone PPAR-y activator Rosiglitazone
-prazole Proton pump inhibitor Omeprazole
-prost Prostaglandin analog Latanoprost
-antagonist Cimetidinc
-tidine

-tinib
1
^
Tvrosine kinase inhibitoil Imatinib
-tropin Pituitary hormone Somatotropin
-ximab Chimeric monoclonal Ab Basiliximab
-zumab 1Iumanized monoclonal Ab Daclizumab
268 SECTION I I I CARDIOVASCULAR CARDIOVASCULAR — EMBRYOLOGY

Fetal circulation Blood in umbilical vein has a Po-, of = TO nun Hg

To brain (high
and is = 80% saturated with Umbilical
02)
arteries have low O, saturation.
© Ductus T important shunts:
arteriosus
To lungs
(high resistance) O Blood entering fetus through the
To lungs umbilical vein is conducted via the ductus
\ (high resistance)
Superior vena cava . venosus into the IVC, bypassing hepatic
. Pulmonary
© Foramen ovale circulation.
V artery
0 Most of the highly Oxygenated blood
l
'. reaching the heart via the IVC is directed
O Ductus
venosus through the foramen ( Jjvalc and pumped
into the aorta to supplv the head and bodv.
Aorta
© I)eoxygenated blood from the SVC passes
\ Inferior vena cava
— — —
through the RA RV main pulmonary
artery •|l Rictus arteriosus descending
aorta; shunt is due to high fetal pulmonary
Portal vein artery resistance (due partly to low O,
tension).
At birth, infant lakes a breath; i resistance

Umbilical vein —
in pulmonary vasculature t left atrial
pressure vs right atrial pressure; foramen ovale
closes (now called fossa ovalis); t in O, ( from
Internal iliac artery
respiration) and 1 in prostaglandins (from
placental separation) -» closure of ductus
arteriosus.
To placenta
ft
Umbilical
arteries —
indomcthacin helps close PDA ligamentum
arteriosum (remnant of ductus arteriosus).
From placenta
,
Prostaglandins K and 1 ki ll p PDA open.

a I

Fetal-postnatal derivatives
AllaNtois -* urachus MediaN umbilical ligament Urachus is part of allantoic duct between
bladder and umbilicus.
Ductus arteriosus Ligamentum arteriosum
Ductus venosus Ligamentum venosum
Foramen ovale Fossa ovalis
Notochord Nucleus pulposus
UmbiLical arteries McdiaL umbilical ligaments
Umbilical vein Ligamentum teres hepalis ( round ligament of Contained in falciform ligament .
the livcrll
 CARDIOVASCULAR CARDIOVASCULAR — ANATOMY SECTION I I I 269

CARDIOVASCULAR — ANATOMY

Coronary artery anatomy SA undo is usually supplied hv RCA , AV node

is supplied by PDA lie, doiiiinanl circulationL
Right coronary artery ( RCA) Left main coronary artery (LCA)
Infarct may cause nodal dysfunction
left circumflex coronary .
(brady cardia or heart block)
artery (LCX] supplies lateral
and posterior walls of left Right-dominant circulation ( 85%) = PDA arises
ventricle, anterolateral papillary from RCA.
muscle Left-dominant circulation (8%) = PDA arises
Left anterior descending from LCX.
artery ILADI supplies anterior !h Codominant circulation ( 7%) = PDA arises
of interventricular septum,
anterolateral papillary muscle,
from both LCX and RCA.
and antenor surface of left ventricle Coronary artery’ occlusion most commonly
occurs in the LAD.
Right (acute)
left (obtuse) marginal artery Coronary blood flow peaks in early diastole.
Revised marginal artery
supplies right The most posterior part of the heart is the left
Figure
ventncle atrium; enlargement can cause dysphagia (due
to compression of the esophagus) or hoarseness
(due to compression of the left recurrent
Posterior descending/ interventricular artery ( PDA)
supplies AV node posterior Vrof interventricular septum,
laryngeal nerve, a branch of the vagus) .
posterior lh walls of ventndes, and posteromedial papillary muscle
Pericardium consists of 5 layers ( from outer to
inner);
Fibrous pericardium
Parietal layer of serous pericardium
Visceral layer of serous pericardium
Pericardial cavity lies behveen parietal and
visceral layers.
 CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY SECTION III 271

Cardiac output variables

Stroke volume Stroke Volume affected by Contractility, SV CAP.
Aftcrload, and Preload , A failing heart has l SV (systolic and /or diastolic
t SV with: dysfunction )
f Contractility (eg, anxiety, exercise )
t Preload (eg, early pregnancy)
i Aftcrload
Contractility Contractility (and SV') t with: Contractility (and SV' ) i with:

_
( inhibition of phospholambaii
——
Catecholamine stimulation via 0 i receptor
t Cir '
entry into sarcoplasmic reticulum t C’a’*-
induced Ca + release )
• t intracellular Ca + -
• Ppblockade ( 1 cAMP)
HF with systolic dysfunction
• Acidosis
Hvpoxia/hypercapnia ( 1 Po7 / f PcOj)
Non-dihydropyridine Ca 2+ channel blockers
1 extracellular Na + ( 1 activity of Na + /Ca - ~
exchanger)
Digitalis ( blocks Na+/K+ pump

Myocardial oxygen
demand t Contractility
—
-* t intracellular Na* -» i Na + /Ca'+
exchanger activity t intracellular Ca + )
fVlvoCARDial O, demand is t bv:
-

t Afterload ( proportional to arterial pressure )

Wall tension follows Laplace’s law:
Wall tension P urc x radms
2 x wall thickness
t heart Rate
t Diameter of ventricle ( I wall tension )
Preload Preload approximated by ventricular EDV; VEnodilators (eg, nitroglycerin ) t prEload
depends on venous tone and circulating blood
volume.
Afterload Afterload approximated by MAP.
- —
t afterload t pressure t wall tension per
Laplace’s law.
VAsodilators (eg, hydrAlAzine) 1 Aftcrload
( Arterial ).
ACE inhibitors and ARBs i both preload and

Ejection fraction
LV compensates for t aftcrload by thickening
(hypertrophy) itr order to 1 wall tension .
hr
SV
= EDV = -
EDV ESV
EDV
afterload .
Chronic hypertension ( t MAP ) LV
hypertrophy.
EF 1 in systolic HF.
—
EF normal in heart failure with preserved
Left ventricular EF is an index of ventricular ejection fraction 11 IFpEFA
contractility; normal EF is > 55%.
272 SECTION I I I CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY

Starling curve Force of contraction is proportional to end-

E»ercise
diastolie length of cardiac muscle fiber
Ml t DM (preload).
5 t contractility with catecholamines, positive
u
8 inotropcs (eg, digoxin).
I contractility with loss of myocardium ( eg, MI ),
'-' V '
--
. ll
. f. I
E

>
HF + digoxin
P-blockcrs (acutely),non-dihvdropyridine Ca*+
=igure | v
<

I HF
channel blockers, dilated cardiomyopathy.

Ventricular EDV (preload)

Resistance, pressure, AP = Q x R Capillaries have highest total cross-sectional

flow Similar to Ohm’s law: AV = IR area and low est flow velocity.
Volumetric flow rate ( Q ) = flow velocity (v ) x JPressure gradient drives flow from high pressure
cross-scctional area ( A) to low pressure.
Resistance Arterioles account for most of TPR. Veins
_ driving pressure (AP) _ 8r|(viscosity ) x length provide most of blood storage capacity. _
flow ( Q )
Total resistance of vessels in scries:
rtf
* Viscosity depends mostly on hematocrit
Viscosity t in hvpcrprotcinemic states (eg,

-
R| Rj + R, + R . . .
—
Total resistance of vessels in parallel:
multiple myeloma ), polycy themia
V iscosity I in anemia
1 1 I 1
T ~ Rj + R2 + R 1 ,
^
276 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY

Auscultation of the heart

Where to listen: APT M

Aortic area:
Systolic murmur Pulmonic area :
Aortic stenosis Systolic ejection murmur
Flow murmur I Pulmonic stenosis
(eg. physiologic murmur ) Flow murmur
Aortic valve sclerosis

m
Tricuspid area:
Left sternal border P Holosystolic murmur
Diastolic murmur Tricuspid regurgitat on
Aortic regurgitation Ventncular septal defect
Pulmonic regurgitation Diastolic murmur
Systolic murmur Tricuspid stenosis
Hypertrophic T Atnal septal defect (T flow
5
cardiomyopathy across tricuspid valve)
M
Aortic 6 Mitral area (apex ):
Pulmonic Holosystolic murmur
Tricuspid Mitral regurgitation
Mitral Diastolic murmur
Mitral stenosis

ia

BEDSIDE MANEUVER EFFECT

Inspiration ( t venous return to right atrium ) t intensity of right heart sounds
Hand grip ( t afterload ) t intensity of MR, AR, VSD murmurs
1 hvpertroplhc cardiomyopathy murmurs, AS!
MVP: later onset of click /murmur
Valsalva ( phase II ), standing up ( 1 preload ) 1 intensity of most murmurs ( including AS)
t intensity of hypertrophic cardiomyopathy murmur
MVP: earlier onset of click /murmur
Rapid squatting ( t venous return, t preload , t aftcrload ) t intensity of hypertrophic cardiomyopathy murmur
t intensity’ of AS, MR, and VSD murinuri
MVP: later onset of click /murmur
.
Svstolic heart sounds include aortic/pulmonic stenosis, mitral /tricuspid regurgitation, VSD M \ T, hypertrophic
cardiomyopathy
Diastolic heart sounds include aortic/pulmonic regurgitation, mitral /tricuspid stenosis.
 CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY SECTION III 277

Heart murmurs
Systolic
Aortic stenosis Cresccndo-decresccndo systolic ejection murmur (ejection click may he present ).
LV » aortic pressure during systole . Loudest at heart base; radiates to carotids.
SI S2
—
“ Pulsus parvus et tardus” pulses are weak with a delayed peak. Can lead to

LAAAAAAAAAMAMMM I . Syncope , Angina, and Dyspnea on exertion ( SAD ). Most commonly due to age-
related calcification in older patients (> 60 years old ) or in younger patients with
early-onset calcification of bicuspid aortic valve.
Mitral /tricuspid regurgitation I lolosystolic, high-pitched “ blowing murmur.”
St S2 —
Mitral loudest at apex and radiates toward axilla . MR is often due to ischemic heart
disease ( post-MI ), MVP, LV dilatation.
LAAMAAAAAAAAAAAAAJ —
Tricuspid loudest at tricuspid a re4 TR commonly caused by RV dilatation .
Rheumatic fever and infective endocarditis can cause either MR or TR .
Mitral valve prolapse late systolic crescendo murmur with midsystolic click ( MC; due to sudden tensing
of chordae tendineae). Most frequent valvular lesion . Best heard over apex. Loudest
St MC S2
just before S2. Usually benign . Can predispose to infective endocarditis. Can be
I L/rtl caused by myxomatous degeneration ( 1° or 2° to connective tissue disease such as
Marfan or Ehlers-Danlos syndrome), rheumatic fever , chordae rupture.
Ventricular septal defect Holosystolie, harsh-sounding murmur. Loudest at tricuspid area .
SI S2

LVWMAAAAAAAAAAI
Diastolic
Aortic regurgitation High-pitched “ blowing” early diastolic decrescendo murmur. Long diastolic
murmur, hyperdynamic pulse, and head bobbing when severe and chronic. Wide

—
SI S2
pulse pressure. Often due to aortic root dilation, bicuspid aortic valve, endocarditis,
1 Lv / ' /M w y u .. rheumatic fever. Progresses to left I IF.

Mitral stenosis Follows opening snap ( OS; due to abrupt halt in leaflet motion in diastole, after
SI S2 OS
rapid opening due to fusion at leaflet tips) . Delayed rumbling mid-to-latc diastolic
niurimnjff interval between S2 and OS correlates with t severity ). LA » L.V
I LMIW aim *.* pressure during diastole. Often occurs 2° to rheumatic fever. Chronic MS can
result in LA dilatation.
Continuous
Patent ductus arteriosus -
Continuous machine like murmur . Loudest at S2. Often due to congenital rubella
or prematurity. Best heard at left infraclavicular area .
S2

I LAAAAMAAAAAAAAIAAAA
 CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY

Electrocardiogram
——
Conduction pathway — SA node atria P wave — atrial depolarization. Atrial
-* AV node
— bundle of I lis right
left bundle branches -* Purkinje fibers
and repolarization is masked by QRS complex.
PR interval— time from start of atrial
-* ventricles; left bundle branch divides into depolarization to start of ventricular
left anterior and posterior fascicles. depolarization ( normally < 200 msec).
SA node “pacemaker" inherent dominance with QRS complex — ventricular depolarization
slow phase of upstroke. (normally < 120 msec).
AV node — located in posteroinferior part of QT interval— ventricular depolarization,
interatrial septum. Blood supply usually mechanical contraction of the ventricles,
from RCA. 100-msec delay allows time for ventricular repolarization.
ventricular filling. —
T wave ventricular repolarization. T-wave
Pacemaker rates — SA > AV > bundle of His/ inversion may indicate ischemia or recent \H
Purkinje/ventricles. |point — junction betw een end of QRS complex
Speed of conduction — Purkinje > atria and start of ST segment.
> ventricles > AV node. ST segment — isoelectric, ventricles depolarized.
U wave — prominent in hypokalemia,
bradycardia.

5 mm
0 2 seconds
+1.0
Aorta

Superior
vena cava N.
Bachmann PR
segment
- S-T
segment +05
bundle
SA node

P
AV node
Left bundle
/ po re u
0 m\
branch
Bundle of His
--
interval
an
interval
-
O T interval -0.5
Right bundle Left anterior
branch fascicle |_ J
Atm! VcntncuUr VCTtncuU
Purkinje fibers .
depoUnzattor depounzaccm repoianrauon
- Left postenor
fascicle fi
282 SECTION I I I CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY

ECG tracings
RHYTHM DESCRIPTION EXAMPLE
Atrial fibrillation Chaotic and erratic baseline with no discrete P waves in between RR , RR , » RR, x RR ,
irregularly spaced QRS complexes. Irregularly irregular *
heartbeat . Most common risk factors include hypertension and
coronary artery disease (CADl. Can lead to thromboembolic
Irregular baseline (absent P wavesl a
events, particularly stroke.
Treatment includes anticoagulation, rate control, rhythm control,
and/or cardioversion.
Atrial flutter A rapid succession of identical, back-to-back atrial depolarization RR. = RR. = RR,
waves. The identical appearance accounts for the saw tooth
appearance of the flutter waves.
Treat like atrial fibrillation. Definitive treatment is catheter
41 sawtooth pattern
ablation. n

Ventricular A completely erratic rhythm with no identifiable w aves. Fatal

fibrillation arrhythmia without immediate CPR and defibrillation.
AWVA/V No discernible rhythm B

AV block
Firstjdeqree The PR interval is prolonged (> 200 msec). Benign and

Seconcjdegree
asymptomatic. No treatment required.

—^
^PR
= *— PR(J = '
"
PR
^ =
^PR

^
jr' N
B

Mobitz type I Progressive lengthening of PR interval until a beat is ’’dropped’’

( Wenckebach) (a P wave not followed by a QRS complex ). Usually | i

asymptomatic. Variable RR interval with a pattern (regularly

irregular). ' PR

Mobitz type II Dropped beats tlrat are not preceded by a change in the length of
’pg <
^ < / p ware, absent QRS u

Thirdjdegree
(complete )
the PR interval (as in type I).
May progress to srd-degree block. Often treated with pacemaker.
— i—4- PR,

The atria and ventricles beat independently of each other. P waves and QRS complexes not rhythmically
associated. Atrial rate > ventricular rate. Usually treated with pacemaker. Can be caused by Lyme
^
P wave absent QRS
—
a

disease.
RR, RR,

I P wave on ORS compter . Pwave

.
PP = PP, = PP, = PP .
 CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY SECTION I I I 283

Atrial natriuretic Released from atrial myocytes in response to t blood volume and atrial pressure. Acts via cGMP.
peptide Causes vasodilation and i Na* reabsorption at the renal collecting tubule. Dilates afferent renal
arterioles and constricts efferent arterioles, promoting diuresis and contributing to "aldosterone
escape” mechanism.

B- type (brain ) Released from ventricular myocytes in response to t tension. Similar physiologic action to ANP,
natriuretic peptide with longer half-life. B \ P blood test used for diagnosing HF ( very good negative predictive value).
Available in recombinant form (nesiritidc) for treatment of HK

Baroreceptors and chemoreceptors Receptors:

Aortic arch transmits via vagus nerve to solitary nucleus of
AFFERENT EFFERENT
medulla (responds to i and t in BP).
Solitary nucleus
Carotid sinus ( dilated region at carotid bifurcation) transmits via
glossopharyngeal nerve to solitary nucleus of medulla ( responds
Mi au a
'
- chain
y Sympathetic to i and t in BP).
IX: *
Vagus Baroreceptors:
Glossopharyngeal
nerve
nerve
- P n:t
— —
Hypotension— 1 arterial pressure i stretch i afferent
baroreceptor firing t efferent sympathetic firing and
—
COfd Parasympathetic
vagus nerve
A efferent parasympathetic stimulation vasoconstriction,
Carotid sinus
t HR, T contractility, t BP. Important in the response to severe
hemorrhage.
—
baroreceptor Sympathetic
Carotid body
chemoreceptor
- nerves
—
Carotid massage t pressure on carotid sinus t stretch
-* t afferent baroreceptor firing -* t AV node refractory period
- i HR.
Component ot Cushing reflex ( triad of hvpertensioij
Aortic bradycardia, and respirators depression) — t intracranial
chemoreceptor pressure constricts arterioles -* cerebral ischemia -• t pCQ,
Aortic
baroreceptor
SAnode
Blood
vessels

Avnode
— —
and 1 pH central reflex sympathetic t in perfusion pressure
(hypertension )
—
t stretch peripheral reflex baroreceptor-
induccd bradycardia.
Chemoreceptors:
Peripheral — carotid and aortic bodies arc stimulated hv A Pa,
(< 60 mm Hg), t Pco7, and 1 pH of blood.
• Central — are stimulated by changes in pH and Pco, of brain
interstitial fluid, which in turn are influenced by arterial CO-,.
Do not directly respond to Po7.
 CARDIOVASCULAR CARDIOVASCULAR — PHYSIOLOGY SECTION I I I 285

Capillary fluid Starling forces determine fluid movement through capillary membranes:
exchange Pc = capillary pressure — pushes fluid out of capillary
Interstitial fluid
•
Pl = interstitial fluid pressure — pushes fluid into capillary
l
P itc = plasma colloid osmotic (oncotic) pressure — pulls fluid into capillary
It1 = interstitial fluid colloid osmotic pressure — pulls fluid out of capillars
'

P n
Jv = net fluid flow = Kf f(Pc - Pj) - g(ltc - ft,)]
f
Capillary
Kf = permeability of capillary to fluid
C, = reflection coefficient ( measure of permeability of capillary to protein!
Edema — excess fluid outflow into interstitium commonly caused by:
t capillary pressure ( t ; eg, HF)
Pc
* l plasma proteins ( t rtc; eg, nephrotic syndrome, liver failure, protein malnutrition)
t capillary permeability ( t ; eg, toxins, infections, burns)
Kf
t interstitial fluid colloid osmotic pressure ( t TTj; eg, lymphatic blockagel
 CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY SECTION III 287

Congenital heart diseases ( continued )

LEFTTO -RIGHT SHUNTS Late cyanosis ( 2° to Eiscnmcngcr syndrome) — Right-to-L,eft shunts: caRLy cyanosis.
“ blue kids.” Left-to-Right shunts: “I ateR” cyanosis.
Frequency: V'SD > ASD > PDA.
Ventricular septal Most common congenital cardiac defect. ,
O saturation t in RV and pulmonary artery .
defect Asymptomatic at birth, may manifest weeks
later or remain asymptomatic throughout life.
Most self resolve; larger lesions may lead to L.V
overload and HF.
Atrial septal defect Defect in interatrial septum Q; loud SI; wide, .
CL saturation t in RA RV, and pulmonary
fixed split S2. Ostium secundum defects arterv. Mav lead to paradoxical cmbolj
most common and usually occur as isolated

O' - findings; ostium primum defects rarer yet

usually occur with other cardiac anomalies.
Symptoms range from none to HF. Distinct
from patent foramen ovale in that septa are

Patent ductus
rJ missing tissue rather than unfused.

In fetal period, shunt is right to left (normal). “ Endomethacin” (indomcthacin) ends patency
arteriosus In neonatal period, f pulmonary vascular .
of PDA; PCF keeps ductus Going (may be
resistance -* shunt becomes left to right necessary to sustain life in conditions such as

LF
— progressive RVII and/or LVH and HF.
Associated with a continuous, "machine -like"
transposition of the great vessels).
PDA is normal in utcro and normally closes only
PA murmur. Patency is maintained by PGF . after birth.
,
synthesis and low O tension. Uncorrcctcd
PDA Q can eventually result in late cyanosis
LV
in the lower extremities (differential cyanosis).

Eisenmenger Uncorrcctcd Icft-to-right shunt ( VSD, ASD,

syndrome
—
PDA ) t pulmonary blood flow
—
remodeling of vasculature -» pulmonary'
pathologic

arterial hypertension. RVH occurs to

compensate -* shunt becomes right to
left. Causes late cy anosis, clubbing Q, and L
.
polycythemia Age of onset varies. H
VSD

RVII
N
OTHER ANOMALIES
Coarctation of the .
Aortic narrowing near insertion of ductus arteriosus (“ juxtaductal”) Associated with bicuspid aortic-
aorta valve, other heart defects, and Turner syndrome. Hypertension in upper extremities and weak,
delayed pulse in lower extremities (brachial-femoral delay). With age, intercostal arteries enlarge
—
due to collateral circulation; arteries erode ribs notched appearance on CXR. Complications
include HF, t risk of cerebral hemorrhage ( berry aneurysms), aortic rupture, and possible
endocarditis.
288 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY

Congenital cardiac DISORDER DEFECT

defect associations Alcohol exposure in utero ( fetal alcohol VSD, PDA, ASD, tetralogy of Fallot
syndrome)
Congenital rubella PDA, pulmonary artery stenosis, septal defects
Down syndrome AV septal defect (endocardial cushion defect ),
VSD, ASD
Infant of diabetic mother t ransposition of great vessels
Marfan syndrome MVP, thoracic aortic aneurysm and dissection,
aortic regurgitation
Prenatal lithium exposure Ebstein anomaly
Turner syndrome Bicuspid aortic valve, coarctation of aorta
Williams syndrome Supravalvular aortic stenosis
22qll syndromes Truneus arteriosus, tetralogy of Fallot

Hypertension Defined as persistent systolic BP > 140 mm Hg and/or diastolic BP > 90 nun Hg
RISK FACTORS t age, obesity, diabetes, physical inactivity, excess salt intake, excess alcohol intake, family history;
African American > Caucasian > Asian.
FEATURES 90% of hypertension is 1° (essential ) and related to t CTO or t TPR; remaining 10% mostly 2°
to renal/renovascular disease (eg, atherosclerosis, fibromuscular dvsplasiaj [“ string of beads"
appearance Q], usually found in younger women) and 1° hyperaldosteronism .
—
Hypertensive urgency severe (> 180/> 120 mm Hg) hypertension without acute end-organ
l damage.
Hypertensive emergency — severe hypertension with evidence of acute end- organ damage (eg,
encephalopathy, stroke, retinal hemorrhages and exudates, papilledema, MI, HF, aortic dissection,
kidney injury, microangiopathic hemolytic anemia, eclampsia).

PREDISPOSES TO CAD, LVH, HF, AF; aortic dissection, aortic aneurysm; stroke; chronic kidney disease
( hypertensive nephropathy) Q; retinopathy.
9}
tv^
*• '
2
 CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY SECTION III 291

Aortic dissection Longitudinal intimal tear forming a false lumen EJ. Associated with hypertension, bicuspid aortic
valve, inherited connective tissue disorders ( eg, Marfan syndrome). Can present with tearing
chest pain, of sudden onset, radiating to the back +/- markedly unequal BP in arms. CXR shows
mediastinal widening. Can result in organ ischemia, aortic rupture, death. Two types:
Stanford type A (proximal): involves Ascending aorta. May extend to aortic arch or descending
aorta. May result in acute aortic regurgitation or cardiac tamponade. Treatment: surgery.
Stanford type B ( distal ): only involves descending aorta ( Below liganrcntum arteriosum). No
ascending aorta involvement. Treat medically with {{-blockers, then vasodilators.

Ischemic heart disease manifestations

Angina Chest pain due to ischemic myocardium 2° to coronary artery narrowing or spasm; no myocyte
necrosis.
Stable — usually 2° to atherosclerosis; exertional chest pain in classic distribution (usually with
ST depression on KCG), resolving with rest or nitroglycerin.
Variant (Prinzmetal) — occurs at rest 2° to coronary artery spasm; transient ST elevation on
ECC. Known triggers include tobacco, cocaine, and triptans, but trigger is often unknown.
Treat with Ca 2* channel blockers, nitrates, and smoking cessation (if applicable).
:
Unstable — thrombosis with incomplete coronary artery occlusion; +/- ST depression and/or
T-wave inversion on ECG but no cardiac biomarker elevation ( unlike NSTEMI); t in frequency
or intensity of chest pain or any chest pain at rest.

Coronary steal Distal to coronary stenosis, vessels are maximally dilated at baseline. Administration of vasodilators
syndrome (eg, dipyridamole, regadenoson) dilates normal vessels and shunts blood toward well-perfused
—
areas i flow and leads to ischemia in poststenotic regions Principle behind!pharmacologic
stress tests.
Sudden cardiac death Death from cardiac causes within 1 hour of onset of symptoms, most commonly due to a lethal
arrhythmia (eg. VF). Associated with GAD (up to 70% of cases), cardiomyopathy ( hypertrophic,
dilated), and hereditary ion channelopathies ( eg, long QT syndrome, Brugada syndrome). Prevent
with implantable cardioverter-defibrillator (ICD).
Chronic ischemic Progressive onset of HF over many years due to chronic ischemic myocardial damage.
heart disease
Myocardial infarction Most often acute thrombosis due to rupture of coronary artery atherosclerotic plaque, t cardiac
biomarkers (CK-MB, troponins) are diagnostic.
ST- segment elevation Ml ( STEMI) Non- ST- segment elevation Ml (NSTEMI)
Transmural infarcts Subendocardial infarcts
Full thickness of myocardial wall involved Subendocardium (inner At especially
'
ST elevation on EGG, Q waves vulnerable to ischemia
ST depression on ECG

V5

J
 CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY SECTION III

Cardiomyopathies
Dilated Most common cardiomyopathy (90% of cases). Systolic dysfunction ensues.
cardiomyopathy Often idiopathic or familial. Other etiologies Eccentric hypertrophy Q (sarcomeres added in
include chronic Alcohol abuse, wet Beriberi, series).
Coxsackic B viral myocarditis, chronic \BCCCD. _
.
Cocaine use, Chagas disease Doxorubicin Takotsubo cardiomyopathy: "broken heart
toxicity, hemochromatosis, sarcoidosis, syndrome " — ventricular apical ballooning
a
peripartum cardiomyopathy, likely due to increased sympathetic stimulation
bindings: HF, S 3, systolic regurgitant murmur, ( stressful situations).
*>
dilated heart on echocardiogram, balloon
appearance of heart on CXR.
Treatment: Na+ restriction, ACE inhibitors,
p-blockers, diuretics, digoxin, ICD, heart
transplant.
Hypertrophic 60-70% of cases are familial, autosomal Diastolic dysfunction ensues.
cardiomyopathy dominant imost commonly due to mutations Marked ventricular concentric hypertrophy
in genes encoding sarcomeric proteins, such as (sarcomeres added in parallel!H, often septal
myosin binding protein C and 0-mvosin heavy predominance. Myofibrillar disarray and
clnmt Can be associated with Friedreich fibrosis.
ataxia. Causes syncope during exercise and Obstructive hypertrophic cardiomyopathy
may lead to sudden death in young athletes (subset ) — asymmetric septal hypertrophy
due to ventricular arrhythmia. and systolic anterior motion of mitral valve
Findings: S4, systolic murmur. May see mitral
regurgitation due to impaired mitral valve
— —
outflow obstruction dyspnea, possible
syncope.
closure.
Treatment: cessation of high-intensity athletics,
use of 0 -blocker or non-dihydropyridine Ca-+
channel blockers (eg, verapamil). ICD if
patient is high risk.
Restrictive/infiltrative Puppy I.I ASII: I’ostradiation fibrosis, loftier Diastolic dysfunction ensues. Can have loss -
cardiomyopathy syndrome, Endocardial fibroelastosis voltage ECG despite thick myocardium
( thick fihroelaslic tissue in endocardium of (especially amyloid).
.
voung children ! Amyloidosis, Sarcoidosis .
Hemochromatosis ( although dilated
cardiomyopathy is more common )!
 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY

Heart failure Clinical syndrome of cardiac pump dysfunction -* congestion and low perfusion. Symptoms
include dyspnea, orthopnea, fatigue; signs include Ss heart sound, ralej jugular venous distention

HI
(J\'D), pitting edema Q.
Systolic dysfunction — reduced EF, t EDY; J contractility often 2° to isehemia/MI or dilated
cardiomyopathy.
Diastolic dysfunction — preserved EF, normal EDY; 1 compliance often 2° to myocardial
hypertrophy.
Right HF most often results from left HF. Cor pulmonale refers to isolated right HF due to
pulmonary cause.
ACE inhibitors or angiotensin 11 receptor blockers. [Yblockers ( except in acute decompensated HF ),
and spironolactone 1 mortality. Thiazide or loop diuretics are used mainly for symptomatic relief.
Hydralazine with nitrate therapy improves both symptoms and mortality in select patients.
Left heart failure
Orthopnea Shortness of breath when supine: t venous
return from redistribution of blood (immediate
gravity effect ) exacerbates pulmonary vascular
congestion. 1IV contract nty

Paroxysmal Breathless awakening from sleep: t venous

nocturnal dyspnea return from redistribution of blood,
.
Pulmonary
«Jtrra
Pulmonary venous
congestion
1 Carctac

reabsorption of peripheral edema, etc.

Pulmonary edema t pulmonary venous pressure pulmonary
—
venous distention and transudation of fluid.
lRv output
i

..
Reno

It (t( XM
-

Presence of hemosiderin-laden macrophages .

T Renal Na*
(“ HF" cells) in lungs. T System venous
wdHO
ettema tmm teauorpdon
Right heart failure
Hepatomegaly t central venous pressure -* t resistance to T PretoMl * cardoc
output 'compensation;
f IV
.i-'i-i;of .
* Sytnptfnetc
id fly
(nutmeg liver) portal flow. Rarely, leads to "cardiac cirrhosis ” .
Jugular venous t venous pressure.
distention
Peripheral edema t venous pressure
— fluid transudation.

Shock Inadequate organ perfusion and delivery of nutrients necessary for normal tissue and cellular
function. Initially may be reversible but life-threatening if not treated promptly.
PCWP SVR
CAUSED BY SKIN (PRELOAD) CO (AFTERLOAD) TREATMENT
Hypovolemic Hemorrhage, dehydration . Cold. 11 1 t IV fluids
burns clammy
Cardiogenic Acute MI, HF, valvular Inotropes, diuresis
dysfunction, arrhythmia
Obstructive Cardiac tamponade . Cold . t 11 t Relieve obstruction
pulmonary embolism,
clammy
tension pncumothora 4
’
Distributive Sepsis, anaphylaxis Warm l t 11 IV fluids, pressors
CNS injury Dry l 1 11
 CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY SECTION III 297

Bacterial endocarditis Fever (most common symptom), new murmur, Mitral valve is most frequently involved.
Roth spots (round white spots on retina Tricuspid valve endocarditis is associated with
surrounded by hemorrhageJQ), Osier nodes IV drug abuse (don' t “ tri" drugs). Associated
(tender raised lesions on finger or toe pads with S aureus. Pseudomonas, and Candida .
due to immune complex depositing. Janeway Culture © — most likely Coxiella burnetii .
lesions (small, painless, erythematous lesions Bartonella spp., HACEK ( Haemophilus ,
on palm or sole) Q, glomerulonephritis, Aggregatibacter ( formerly Actinobacillus ),
septic arterial or pulmonary emboli, splinter Cardiobacterium , Eikenella, Kingella )
hemorrhages Q on nail bed. Multiple blood V Bacteria FROM JANE V
cultures necessary for diagnosis. Fever
Acute— S aureus ( high virulence). Roth spots
Large vegetations on previously normal Osier nodes
valves Q Rapid onset . Murmur
Subacute — viridans streptococci I low Janeway lesions
virulence ). Smaller vegetations on Anemia
congenitally abnormal or diseased valves. Nail-bed hemorrhage
Sequela of dental procedures. Gradual Emboli
onset.
S bovis ( gallolyticus ) is present in colon cancer,
S epidermidis on prosthetic valves.
Endocarditis may also be nonbacterial
(marantic /thrombotic) 2° to malignancy,
hypercoagulablc state, or lupus.
.
v
/i c 7m
a
298 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY

Rheumatic fever A consequence of pharyngeal infection with JVNT.S (major criteria):

group A P-hemolytic streptococci. Late Joint (migratory polyarthritis)
sequelae include rheumatic heart disease, V (carditis)

if *J .;
' which affects heart valves — mitral > aortic»
tricuspid ( high-pressure valves affected most).
Early lesion is mitral valve regurgitation;
Nodules in skin (subcutaneous)
Erythema marginatum
Sydenham chorea

term late lesion is mitral stenosis. Associated

with Aschoff bodies ( granuloma with giant
cells [blue arrows in 0)), Anitschkow cells
(enlarged macrophages with ovoid, wavy,
rod-like nucleus [red arrow in Q[ ), t anti¬

streptolysin O (ASO) titers.

Immune mediated (type II hypersensitivity);
not a direct effect of bacteria. Antibodies
to M protein cross-react with self antigens
(molecular mimicry).
Treatment /prophylaxis: penicillin.

Acute pericarditis Inflammation of the pericardium [ O, red arrows!. Commonly presents with sharp pain, aggravated
by inspiration, and relieved by sitting up and leaning forward. Often complicated by pericardia]
effusion [white arrow in O]. Presents with friction rub. ECG changes include widespread ST-
segment elevation and/or PR depression.
Causes include idiopathic (most common; presumed viral), confirmed infection (eg,
Coxsackievirus), neoplasia, autoimmune (eg, SLE, rheumatoid arthritis), uremia, cardiovascular
(acute STEMI or Dressier syndrome), radiation therapy.

Cardiac tamponade
— E q u i l i b r a t i o n of diastolic pressures in all 4 chambers.
—
Compression of the heart by fluid (eg, blood, effusions [arrows in 0] in pericardial space) I CO.

.
Findings: Heck tri nl ( Inpotension. distended in i k wins, distant heuit sounds ;, ‘I IK pulsus
p.uudoMJs ECO slums low voltage (JRS and eleetiR .ll ultcm.uis due
heart in large effusion).
Pulsus paradoxus — 1 in amplitude of systolic BP by > 10 mm Hg during inspiration Seen in.
cardiac tamponade, asthma, obstructive sleep apnea, pericarditis, croup.

Syphilitic heart 3° syphilis disrupts the vasa vasorum of the Can result in aneurysm of ascending aorta or
disease aorta with consequent atrophy of vessel wall aortic arch, aortic insufficiency,
and dilatation of aorta and valve ring.
May see calcification of aortic root, ascending
aortic arch, and thoracic aortai Leads to “ tree
bark ” appearance of aorta.
 CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY SECTION III 299

Cardiac tumors .
Most common heart tumor is a metastasis ( eg mclanomaj
Myxomas Most common 1° cardiac tumor in adults Q. 907c occur in the atria (mostly left atrium). Myxomas
are usually described as a "hall valve” obstruction in the left atrium ( associated with multiple
-
syncopal episodes ). Mas hear early diastolic " tumor plop” sound. Histology: Gelatinous material,
myxoma cells immersed in glycosaminoglycans.

Rhabdomyomas Most frequent 1° cardiac tumor in children (associated with tuberous sclerosis ). I listology:
hamartomous growths.

t in ) \ T on inspiration instead of a normal L

—
Kussmaul sign
—
Inspiration negative intTathoraeie pressure not transmitted to heart impaired filling of right
ventricle -* blood backs up into venae cavae -* JVD. May be seen with constrictive pericarditis,
restrictive cardiomyopathies, right atrial or ventricular tumors.
300 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PATHOLOGY

Vasculitides
EPIDEMI010GY/PRESENTATI0N PATHOLOGY/LABS

Large vessel vasculitis

-

Giant cell (temporal) Usually elderly females.
arteritis Unilateral headache ( temporal artery), jaw
claudication.
May lead to irreversible blindness due to
ophthalmic artery occlusion.
Associated with polymyalgia rheumatica.
Takayasu arteritis Usually Asian females < 40 years old.
“ Pulseless disease" ( weak upper extremity
pulses), fever, night sweats, arthritis, myalgias,
skin nodules, ocular disturbances.
Medium- vessel vasculitis
Polyarteritis nodosa Usually middle-aged males]
1 lepatitis It seropositivity in W/ of patients.
Fever, weight loss, malaise, headache.
GI: abdominal pain, melena.
Hypertension, neurologic dysfunction,
cutaneous eruptions, renal damage.
Kawasaki disease Asian children < 4 vears old . CRASH and burn.
(mucocutaneous .
Conjunctival injection Rash ( polymorphous
lymph node
syndrome )
— desquamating), Adenopathy (cervical),
Strawberry tongue (oral mucositis) 0, Hand-
foot changes ( edema, erythema), fever.
Buerger disease Heavy smokers, males < 40 years old.
(thromboangiitis Intermittent claudication may lead to
obliterans) gangrene Q, autoamputation of digits,
superficial nodular phlebitis.
Raynaud phenomenon is often present.
Small-vessel vasculitis
Granulomatosis Upper respiratory tract : perforation of nasal
with polyangiitis septum, chronic sinusitis, otitis media,
( Wegener ) mastoiditis.
Lower respiratory tract: hemoptysis, cough,
dyspnea.
Renal: hematuria, red cell casts.
Microscopic Necrotizing vasculitis commonly involving
polyangiitis lung, kidneys, and skin with pauci-immunc
Most commonly affects branches of carotid
artery .
Focal granulomatous inflammation Q.
t ESR.
Treat with high-dose corticosteroids prior to
temporal artery biopsy to prevent blindness.
Granulomatous thickening and narrowing of
aortic arch Q and proximal great vessels,
t KSR.
Treat with corticosteroids.
Typically involves renal and visceral vessels, not
pulmonary arteries.
JTransmural inflammation of the arterial wall
with fibrinoid necrosis.
Different stages of inflammation may coexist in
different vessels.
Innumerable renal microaneurysms H and spasms
on arteriogram.
Treat with corticosteroids, cyclophosphamide.
May develop coronary- artery- aneurysms 14
thrombosis or rupture can cause death.
Treat with IV immunoglobulin and aspirin.
Segmental thrombosing vasculitis.
Treat with smoking cessation.
Triad:
• Focal necrotizing vasculitis
* Necrotizing granulomas in the lung and
upper airway
Necrotizing glomerulonephritis
PR > -ANCA/c-ANCA Q (anti-proteinase 3).
CXR: large nodular densities.
Treat with cyclophosphamide, corticosteroids.
No granulomas.
MPO-ANCA /p-ANCAd (anti ¬

glomerulonephritis and palpable purpura. myeloperoxidase).

Presentation similar to granulomatosis with Treat with cyclophosphamide, corticosteroids.
polyangiitis but without nasopharyngeal
involvement.
Vasculitides (continued )
EPIDEMIOLOGY/ PRESENTATION PATHOLOGV/ WBS
Small- vessel vasculitis (continued)
Eosinophilic Asthma, sinusitis, skin nodules or purpura, Granulomatous, necrotizing vasculitis with
granulomatosis with peripheral neuropath) (eg, wrist/foot drop). eosinophilia Q.
polyangiitis (Churg- .
Can also involve heart Cl, kidneys ( pauci- MPO-ANCA/p-ANCA, t IgE level.
Strauss) immune glomerulonephritis).
Henoch-Schonlein Most common childhood systemic vasculitis. Vasculitis 2° to IgA immune complex
purpura Often follows URI. deposition.
Classic triad: Associated with IgA nephropathy ( Berger
Skin: palpable purpura on buttocks/legs Q disease).
Arthralgias
• GI: abdominal pain
L ,

3
Y 4
? i

i t

ni „
o) 3?
y C
c
'A
is
02 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PHARMACOLOGY

CARDIOVASCULAR — PHARMACOLOGY

Hypertension treatment
Primary ( essential) Thiazide diuretics, ACE inhibitors, angiotensin
hypertension II receptor blockers ( ARBs ), dihydrops ridine
Ca -+ channel blockers.
Hypertension with Diuretics, ACE inhibitors/ARBs, p-blockers P-blockers must be used cautiously in
heart failure (compensated HE), aldosterone antagonists. decompensated HE and are contraindicated in
cardiogenic shock.
Hypertension with ACE inhibitors/ARBs, Ca -+ channel blockers, ACE inhibitors/,\ RBs are protective against
diabetes mellitus thiazide diuretics, P-blockers. diabetic nephropathy.
Hypertension in Hydralazine, labetalol, methyldopa, nifedipine.
pregnancy

Calcium channel Amlodipine, clevidipine, nicardipine, nifedipine, niniodipine (dihydropyridines, act on vascular
blockers smooth muscle); diltiazem, verapamil (non-dihydropyridines, act on heart).
MECHANISM . —
Block vollage-dependeni 1 -type calcium channels of cardiac and smooth muscle 1 muscle
contractility.
Vascular smooth muscle — amlodipine = nifedipine > diltiazem > verapamil.
Heart — verapamil > diltiazem > amlodipine = nifedipine ( verapamil = ventricle).
CLINICAL USE Dihydropyridines (except niniodipine): hypertension, angina (including Prinzmetal), Raynaud
phenomenon.
Niniodipine: subarachnoid hemorrhage ( presents cerebral vasospasm).
Nicardipine, clevidipinci hypertensive urgenev or emergency
Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter.
ADVERSE EFFECTS Non-dihvdropyridine: cardiac depression, AV block, hyperprolactinemia, constipation.
Dihvdropyridine: peripheral edema, flushing, dizziness, gingival hyperplasia.

Hydralazine
MECHANISM

CLINICAL USE
t cGMP
— smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction.
Severe hypertension (particularly acute), III' ( with organic nitrate). Safe to use during pregnancy.
Frequently coadministered with a P-blocker to prevent reflex tachycardia.
ADVERSE EFFECTS Compensatory tachycardia (contraindicated in angina /CAD), fluid retention, headache, angina.
Lupus-like syndrome.

Hypertensive Drugs include clevidipine, fenoldopam, labetalol, nicardipine, nitroprusside.

emergency
Nitroprusside Short acting; t cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide) .
Fenoldopam Dopamine D| receptor agonist— coronary, peripheral, renal, and splanchnic vasodilation, t BP,
t natriuresis. Also used postoperatively as an antihypertensive. Can cause hypotension and
tachycardia.
« CARDIOVASCULAR CARDIOVASCULAR — PHARMACOLOGY SECTION III 303

Nitrates Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.

MECHANISM —
Vasodilate by t NO in vascular smooth muscle • t in cGMP and smooth muscle relaxation.
Dilate veins» arteries, 4 preload.
CLINICAL USE Angina, acute coronary' syndrome, pulmonary edema.
ADVERSE EFFECTS Reflex tachycardia (treat with (3-blockers), hypotension, flushing, headache, “ Monday disease” in
industrial exposure: development of tolerance for the vasodilating action during the work week
—
and loss of tolerance over the weekend tachycardia, dizziness, headache upon reexposure. _
Contraindicated in right ventricular infarction.

Antianginal therapy Goal is reduction of myocardial O-* consumption (MVOg) by i 1 or more of the determinants of
.
MV02: end-diastolic volume BP, MR, contractility.
COMPONENT NITRATES p- BLOCKERS NITRATES p- BLOCKERS
End- diastolic volume i No effect or t No effect or 4
Blood pressure i 1 i
Contractility No effect t Little/no effect
Heart rate T (reflex response) 1 No effect or 4
Ejection time i t .
L ittle/no effect
MVO2 i l U
Verapamil is similar to (3-blockers in effect.
Pindolol and accbutolol — partial 3-agonists that should be used with caution in angintj

Ranolazine
MECHANISM Inhibits the late phase of sodium current thereby reducing diastolic wall tension and oxygen
consumption. Does not affect heart rate or contractility.
CLINICAL USE Angina refractory to other medical therapies.
ADVERSE EFFECTS Constipation, dizziness, headache, nausea, QT prolongation.

Selective PDE- 3 Milrinone

inhibitor
MECHANISM

— —
Selective PDK -3 inhibitor; 1 cAMP breakdown t Qu±± entry into cardiac mvocvtes and vascular
smooth muscle cells t inotropv, t peripheral arterial/venous vasodilation .
CLINICAL USE Short term use in acute decompensated heart failure.
ADVERSE EFFECTS Arrhy thmias, hypotension .
£4 CARDIOVASCULAR CARDIOVASCULAR — PHARMACOLOGY

Lipid-lowering agents
DRUG LDl HDl TRIGLYCERIDES MECHANISMS OF ACTION ADVERSE EFFECTS/PROBLEMS
HMG -CoA reductase Hi t I Inhibit conversion of HMG- Hepatotoxicity (T LFTs),
inhibitors CoA to mevalonate, a myopathy (esp. when used
(eg, lovastatin, cholesterol precursor; with fibrates or niacin )
pravastatin ) 1 mortality in CAD patients
Bile acid resins U Slightly t Slightly t Prevent intestinal rcabsorption Gl upset, 1 absorption of
Cholestyramine, of bile acids; liver must use other drugs and fat-soluble
colestipol, cholesterol to make more vitamins
colesevelam
Ezetimibe U
— — Prevent cholesterol absorption
at small intestine brush
Rare t LFTs, diarrhea

Fibrates
Gemfibrozil,
bezafibrate,
fenofibrate
1 t 111
border
Upregulate LPL t TG
clearance
Activates PPAR-a to induce
HDL synthesis
— Myopathy (t risk with
statins ), cholesterol
gallstones

Niacin ( vitamin B3) U tt 1 Inhibits lipolysis ( hormone- Red , flushed face, which is
sensitive lipase ) in adipose l by NSAIDs or long-term
tissue; reduces hepatic VLDL use
synthesis Hyperglycemia
Hyperuricemia
PCSK9 inhibitors 111 t 1 Inactivation of LDL reccptor - Myalgias, delirium.
alirocumab, degradation , increasing dementia , other
evolocumab amount of LDL removed neurocognitive effects
from bloodstream

Liver Blood Enterocyte Intestinal lumen

Acetyl CoA
CHOLESTEROL
HMG -CoA ApoE Lymphatics
Ht ABSORPTION
receptc i LHl I

HMG - CoA
CHY
IC. dUC rem E20 - i be
/ Triacylglyceride B *

:
Mevalonate \

1 / /n
‘t L
' FFA

to esterol /'
pool

VLDL
Cholesterol
FFA
-- Cholesterol
FA
>
MEVALONATE
SYNTHESIS
*
Niacin
/ Bile acids

k
Bile acids

BILE ACID
Statins / LPt * c+>-i REABSORPTION
HDL LPL -
Lovastatin receptor FFA
Pravastatin UPREGULATION
Simvastatin HOL ) HDL Bile acid resins
Atorvastatin Lipolysis Fibrates cholestyramine
Rosuvastatin FFA colestipol
gemfibrozil
Adipose tissue bezafibrate colesevelam
LDL fenofibrate
LDL
receptor
*
i V. ADIPOSE LIPOLYSIS

M • i
B 06 SECTION I I I CARDIOVASCULAR CARDIOVASCULAR — PHARMACOLOGY

Antiarrhythmics — Slow or block ( t ) conduction (especially in depolarized cells). I slope of phase 0 depolarization. Are
sodium channel state dependent ( selectively depress tissue that is frequently depolarized [eg, tachycardia] ).
blockers ( class I)
Class IA Quinidine, Procainamide, Disopyram idc. Class IA
“ The Queen Proclaims Diso's pyramid.”
MECHANISM

CLINICAL USE

ADVERSE EFFECTS
t AP duration, t effective refractors period
( ERP ) in ventricular action potential, t QT
interval, some potassium channel blocking
effects
Both atrial and ventricular arrhythmias,
especially re-entrant and ectopic SVT and VT.
Cinchonism ( headache, tinnitus with
Slope of
phase 0

/X n

quinidinc ), reversible SI.E-likc syndrome

(procainamide), heart failure (disopyramide),
thrombocytopenia, torsades dc pointes due to
t QT interval.

r\
Class IB Lidocaine, McxilcTinc. “I'd Buy Liddy's Class IB
Mexican Tacos."
MECHANISM 1 AP duration. Preferentially affect ischemic or Slope of
phase 0
depolarized Purkinje and ventricular tissue.
Phenytoin can also fall into the IB category.
CLINICAL USE Acute ventricular arrhythmias (especially post-
M11, digitalis-induced arrhythmias. IB is Best Vv
post-MI.
ADVERSE EFFECTS CNS stimulation /depression, cardiovascular
depression.

r\
Class 1C I lecainide, Propafenone. “Can 1 have I’ries, Class 1C
Please.”
MECHANISM Significantly prolongs ERP in AV node and
accessors bypass tracts. No effect on ERP in Slope of
phase 0
Purkinje and ventricular tissue
Minimal effect on AP duration.
SV’Is, including atrial fibrillation. Only as a last
a
resort in refractory VT.
ADVERSE EFFECTS Proarrhylhmic, especially post-MI
(contraindicated ). 1C is Contraindicated in
structural and ischemic heart disease.
308 SECTION III CARDIOVASCULAR CARDIOVASCULAR — PHARMACOLOGY

Antiarrhythmics
calcium channel
— Verapamil, diltiazem .

blockers ( class IV )
MECHANISM I conduction velocity, f F.RP, t PR interval.
CLINICAL USE Prevention of nodal arrhythmias (eg, SVT), rate control in atrial fibrillation .
ADVERSE EFFECTS Constipation , flushing, edema, cardiovascular effects ( HF, AV block, sinus node depression ).

_ Class IV
60 i

1:
Slow rise of
action potential Prolonged
repolarization
0 latAV node )
i
i - 30
Y \
Threshold
potential
|-60 -
- 90
0
i
100
i
200
1
500 400
1 1
500 600
r
700
-
Time ( ms) 3

Other antiarrhythmics
Adenosine -
t K+ out of cells -* hvpcrpolarizing the cell and 1 1, decrease AV node conduction . Drug of
choice in diagnosing/terminating certain forms of SVT. Very short acting (~ 15 sec). F,ffects
blunted by theophylline and caffeine ( both arc adenosine receptor antagonists). Adverse effects
include flushing, hypotension, chest pain , sense of impending doom , bronchospasm .
Mg 2 + Effective in torsades de pointes and digoxin toxicity .

Ivabradlne
MECHANISM Selective inhibition of funny sodium channels Ilf I. prolonging slow depolarization phase I phase f ).
1 SA node firing; negative chronotropic effect without inotropv. Reduces cardiac O, requirement .
CLINICAL USE Chronic stable angina who cannot take [5-blockcrs. Chronic heart failure with reduced ejection
fraction.
ADVERSE EFFECTS Luminous phenomcna /visual brightness, hypertension , bradycardia .
HIGH- YIELD SYSTEMS

Endocrine

“ If you skew the endocrine system, you lose the pathways to self . When Embryology 310
endocrine patterns change , it alters the way you think and feel. One shift
in the battem tends to trib another.’’ Anatomy 310
— Hilary Mantel
Physiology 312
“ We have learned that there is an endocrinology of elation and despair, a
chemistry of mystical insight, and , in relation to the autonomic nervous Pathology 321
system, a meteorology and even . . . an astro- physics of changing moods.’’
— Aldous (Leonard ) Huxley Pharmacology 338

“ Chocolate causes certain endocrine glands to secrete hormones that affect

your feelings and behavior by making you happy.”
—Elaine Sherman, Book of Divine Indulgences

309
310 SECTION I I I ENDOCRINE ENDOCRINE — EMBRYOLOGY

ENDOCRINE — EMBRYOLOGY

Thyroid development Thyroid diverticulum arises from floor of Foramen cecum

primitive pharvnx and descends into neck.
Connected to tongue by thyroglossal Persistent
duct, which normally disappears but may thyroglossal
duct
persist as cysts or the pyramidal lobe of
thyroid. Foramen cecum is normal remnant
Thyroid
of thyroglossal duct. Most common gland
ectopic thyroid tissue site is the tongue
( lingual thyroid ). Removal may result in Trachea
hypothyroidism if it is the only thyroid tissue
present.
Thyroglossal duct cyst Q presents as an anterior
midline neck mass that moves with swallowing Thymus
or protrusion of the tongue (vs persistent
cervical sinus leading to branchial cleft cyst in
lateral neck ).
Thyroid tissue and parafollicular cells ( aka,
C cells, produce Calcitoniil) of the thyroid are
derived from endoderni

ENDOCRINE — ANATOMY

Adrenal cortex and Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest ).
medulla
ANATOMY PRIMARY REGULATORY CONTROL SECRETORY PRODUCTS

iff , ’
CORTEX
Zona Glomerulosa

Zona Fasciculate
-

*
'itVvSi
Renin -angiotensin

ACTH. CRH
Mineralocorticoids (aldosterone)

Glucocorticoids (cortisol)
Revised

) Reticularis 3V '
ACTH. CRH
Sex hormones tendrooens)
Figure

imaffin cells Preganglionic sympathetic fibe

ids with Salt (mineralocorticoids Sugar ( glucocorticoi

vou go, the sweeter it gets.” ^
 SECTION III ENDOCRINE ENDOCRINE — PHYSIOLOGY

ENDOCRINE — PHYSIOLOGY

Insulin
I’rcproinsulin ( synthesized in RFR ) cleavage . —
— —
SYNTHESIS C peptide
of “presignal ” proinsulin (stored in secretory
granules ) cleavage of proinsulin exocytosis
of insulin and C-pcptidc equally. Insulin and
C'-peptide are t in insulinoma and sulfonylurea
— Promsulm n- - ii

s
'

use, whereas exogenous insulin lacks C-peptide.

p-chan

SOURCE Released from pancreatic |3 cells.

FUNCTION Binds insulin receptors ( tyrosine kinase Insulin-dependent glucose transporters:
activity © ), inducing glucose uptake (carrier- • GLUTdt adipose tissue, striated muscle
mediated transport) into insulin-dependent ( exercise can also increase GLUT-lt
tissue 0 and gene transcription. expression)
Anabolic effects of insulin: Insulin-independent transporters:
t glucose transport in skeletal muscle and GL.UT1L RBCs, brain, cornea, placenta
adipose tissue GLL 12jlbidirectional): P islet cells, liver,
"

t glycogen synthesis and storage kidney, small intestine

• t triglyceride synthesis • Gl.l"1 brain, placenta
t Na* retention ( kidneys) ^
GLUTEI ( fructose ): spermatocytes, GI tract
t protein synthesis ( muscles) Brain utilizes glucose for metabolism normally
t cellular uptake of K and amino acids
“
and ketone bodies during starvation. RBCs
i glucagon release require much glucose because tiles lack
• t lipolysis in adipose tissue mitochondria for aerobic metabolisirj
Unlike glucose, insulin does not cross placenta. BRICK L, (insulin-independent glucose uptake):
Brain, RBCs, Intestine, Cornea, Kidney,Liver.
REGULATION Glucose is the major regulator of insulin release, t insulin response w ith oral vs IN’ glucose because of
incrctins such as elucagon-like peptide 1 ( GLIM ) and glucose-dependent insulinotropic polypeptide
( GIPi which are released after meals and t P cell sensitivity to glucose.

—
Glucose enters P cells © t ATP generated from glucose metabolism © closes K+ channels (target
of sulfonylureas 0 and depolarizes P cell membrane O. Voltage-gated Ca-+ channels open
— Ca-+ influx Q and stimulation of insulin exocytosis ©
Insulin
e
ATP-sensitive
K* channels close voltage -gited
Ca; chan: i -i
i

v - o ATP O '. v

,
-# -V
prasphonWnii |/ Depolarization
larization
i
o
t ATP/ADP ratio f Intracellular
PtKxpborosilide- 3 • A MV
Ca
- ”
knase pathway :i

an way GLUT -2 /Glycolysis o /

°
GLUI 4
Glucose
;

Glucose
C3 Glucose
, \
bo
of insulin # Irsu n

/ Glycogen
lipid, proie
protein
thesis
e
vesicles Cell growth
containing DNA
GLUT 4 - synthesis Bii i I
vessel
Insulin secretion by pancreatic (J cells
Insulin-dependent glucose uptake
314 SECTION III ENDOCRINE ENDOCRINE — PHYSIOLOGY

Prolactin
SOURCE Secreted mainly by anterior pituitary.
FUNCTION Stimulates milk production in breast; inhibits
ovulation in females and spermatogenesis
in males by inhibiting GnRH synthesis and
release.
REGULATION Prolactin secretion from anterior pituitary
is topically inhibited bv dopamine from
tuberoinfundibular pathway of hypothalamu
Prolactin in turn inhibits its own secretion
by t dopamine synthesis and secretion from
hypothalamus. TRH t prolactin secretion (eg,
in 1° or 2° hypothyroidism).
Structurally homologous to growth hormone.
Excessive amounts of prolactin associated with
1 libido.
Dopamine agonists (eg, bromocriptine) inhibit
prolactin secretion and can be used in
^ treatment of prolactinoma.
Dopamine antagonists (eg, most antipsychoties;
and estrogens (eg, OCPs, pregnancy) stimulat
prolactin secretion.

Sight/cry of baby -©- Higher cortical centers

Hypothalamus

S~®~
Medications
Chest wall injury (via ANSI -© Dopamine TRH T Plasma T3FT4
Nipple stimulation

Posterior
pituitary

Anterior
pituitary

-0— Estrogen - Pregnancy

Prolactin -©- - -
-
SV FSH
Ovulation

-
iGnRH
Renal failure Spermatogenesis
Via reduced S LH
prolactin elimination '
<

Milk production
J
 ENDOCRINE ENDOCRINE — PHYSIOLOGY SECTION III 315

Growth hormone ( somatotropin )

SOURCE Secreted by anterior pituitary.
FUNCTION Stimulates linear growth and muscle mass
through IGF-1 ( somatomedin C) secretion by
liver, t insulin resistance ( diabetogenic).
REGULATION Released in pulses in response to growth Excess secretion ofGH (eg, pituitary adenoma )
hormone-releasing hormone (GHRH ). may cause acromegaly ( adults ) or gigantism
Secretion t during exercise, deep sleep, (children). Treat with somatostatin analogs (eg,
puberty, hypoglycemia. Secretion inhibited by octreotide) or surgery.
glucose and somatostatin release via negative
feedback by somatomedin.

Appetite regulation
Ghrelin Stimulates hunger (orcxigcnic effect ) and GH Ghrelin makes you hunghre.
release (via GH seeretagog receptor ). Produced
by stomach. Sleep deprivation or Prader-Willi

Leptin
—
syndrome t ghrelin production.
Satiety hormone. Produced by adipose tissue. Leptin keeps you thin.
—
Mutation of leptin gene congenital obesity.
—
Sleep deprivation or starvation • i leptin
production.
Endocannabinoids Act at cannabinoid receptors in hypothalamus Exogenous cannabinoids cause " the munchics T
and nucleus accumbens, two key brain areas
for the homeostatic and hedonic control of
—
food intake t appetite.

Antidiuretic hormone
SOURCE Synthesized in hypothalamus ( supraoptic
nuclei i. stored and secreted by posterior
pituitary.
FUNCTION Regulates serum osmolarity ( V 7-receptors) ADI 1 level is i in central diabetes insipidus ( Dl ),
and blood pressure ( V|-reccptorsl. Primary normal or t in nephrogenic DI.
function is serum osmolarity regulation (ADH Nephrogenic Dl can be caused by mutation in
t serum osmolarity, t urine osmolarity) via V, receptor.
-
regulation of aquaporin channel insertion in Desmopressin acetate (ADH analog) is a
principal cells of renal collecting duct. treatment for central DI and nocturnal
enuresis.
REGULATION Osmoreceptors in hvpothalamus ( primarvj;
hvpovolemiaj
 ENDOCRINE ENDOCRINE — PHYSIOLOGY SECTION III 313

Glucagon
SOURCE Made by a cells of pancreas.
REGULATION Secreted in response to hypoglycemia. Inhibited by insulin, hyperglycemia, and somatostatin.

Hypothalamic- pituitary hormones

HORMONE FUNCTION CUNICAL NOTES
CRH t AC'I'H, MSH, P-cndorphin 1 in chronic exogenous steroid use
Dopamine 1 prolactin, TSH Dopamine antagonists (eg, antipsychotics) can
cause galactorrhea due to hyperprolactinemia
GHRH t GH Analog (tesamorelin) used to treat
HIV-associated lipodystrophy
GnRH .
t FSH LH Suppressed by hyperprolactinemia
Tonic GnRH suppresses 1li’G axis
Pulsatile GnRH leads to puberty, fertility
Prolactin l GnRH
—
Pituitary prolactinoma amenorrhea,
osteoporosis, hy pogonadism, galactorrhea
Somatostatin t GH, TSH Analogs used to treat acromegaly
TRH t TSH, prolactin t TRH ( eg, in 172: hvDothvroidisml mav
increase prolactin secretion -» galactorrhea
 ENDOCRINE ENDOCRINE — PHYSIOLOGY SECTION III 315

Growth hormone ( somatotropin )

SOURCE Secreted by anterior pituitary.
FUNCTION Stimulates linear growth and muscle mass
through IGF-I (somatomedin C) secretion by
liver, f insulin resistance ( diabetogenic ).
REGULATION Released in pulses in response to growth Excess secretion of GH (eg, pituitary adenoma 1
hormone-releasing hormone ( GHRH). may cause acromegaly ( adults) or gigantism
Secretion t during exercise, deep sleep, (children). Treat with somatostatin analogs ( eg,
puberty, hypoglycemia. Secretion inhibited bv octreotide) or surgery.
glucose and somatostatin release via negative
feedback by somatomedin.

Appetite regulation
Ghrelin Stimulates hunger (orcxigcnic effect) and GH Ghrelin makes you hunghre.
release (via GH secretagog receptor ). Produced
by stomach. Sleep deprivation or Prader-Willi

Leptin
—
syndrome t ghrelin production.
Satiety hormone. Produced by adipose tissue. Leptin keeps you thin.
—
Mutation of leptin gene congenital obesity.
Sleep deprivation or starvation -* t leptin
production.
Endocannabinoids Act at cannabinoid receptors in hypothalamus Exogenous cannabinoids cause “ the munchics.’l
and nucleus aceumbens, two key brain areas
for the homeostatic and hedonic control of
food intake -» t appetite.

Antidiuretic hormone
SOURCE Synthesized in hypothalamus ( supraoptic
nuclei), stored and secreted by posterior
pituitary.
FUNCTION Regulates serum osmolarity ( VVreceptors) ADI 1 level is 1 in central diabetes insipidus ( Dl ),
and blood pressure ( V|-receptors). Primary normal or t in nephrogenic DI.
function is serum osmolarity regulation ( ADII Nephrogenic DI can be caused by mutation in
1 serum osmolarity, t urine osmolarity) via ,
V -receptor.
regulation ofaquaporin channel insertion in Desmopressin acetate (ADH analog) is a
principal cells of renal collecting duct. treatment for central DI and nocturnal
enuresis .
REGULATION Osmoreceptors in hvpothalamus iprimarvi;
hvpovolemiai
Adrenal steroids and congenital adrenal hyperplasias
ACTH Ke'oeofwole { blocks several steps in steroidogenesisI

? i 1
Cholesterol desmoUtse
Cholesterol
Anastrorole. exemeslsne

l n i/ li 1
Pregnenolone 17 - hydroxypregnenolone Dehydroepiandrosterone (DHEA) /

SJJ- hydroxysteroid
dehydrogenase

Progesterone
17u-hydroxylase
17-hydroxyprogesterone
I Androstenedione
Aromatasc
Estrone

o 21-hydroxylase

11-deoxycorticosterone ll-deoxycortiso(
I Testosterone
Aromatase
Estradiol

0
I Corticosterone
I
Cortisol
5«-reductase
Dihydrotestosterone

X
IDHT1

T
Aldosterone synthase

Aldosterone
11—
Cortisone
© — Glycyrrhetic acid

Finasteride
Angiotensin II
ZONAGLOMERUIOSA ZONA FASCICULATA ZONA RETICULARIS
Mineralocorticoids Glucocorticoids Androgens .
Estrogens DHT

Adrenal cortex

SEX
ENZYME DEFICIENCY MINERALOCORTICOIDS CORTISOL HORMONES BP [K+] LABS PRESENTATION

Q 17u-hydroxylase 8 t 1 i t t i androstenedione XV: ambiguous

genitalia,
undescended testes
XX: lacks 2° sexual
development
© 21-hydroxylase 8 i i t i t t renin activity Most common
-
t 17 hvdroxy - Presents in infancy Is;
progeslerone wasting) or childhoc
i precocious puberty
XX: virilization
i aldosterone J t t 1 1 renin activity XX: virilization
0 lip-hydroxylase8
-
t 11 deoxycorti ¬

costerone
(results in
t BP)

‘All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to t ACTH
hvpcrpigmentationi
stimulation ( in response to i cortisol i, and skin
 ENDOCRINE ENDOCRINE — PHYSIOLOGY SECTION III 317

Cortisol
SOURCE Adrenal zona fasciculata. Bound to corticosteroid-binding globulin.
FUNCTION t Blood pressure: Cortisol is a BIG FIB.
Upregulates ot|-receptors on arterioles Exogenous corticosteroids can cause
— t sensitivity to norepinephrine and
epinephrine |permissive action!
)
reactivation of T B and candidiasis ( blocks IL-2
production).
At high concentrations, can bind to
mineralocorticoid (aldosterone) receptors
t Insulin resistance (diabetogenic )
t Gluconeogenesis, lipolysis, and proteolysis
I Fibroblast activity ( causes striae)
i Inflammatory and Immune responses:
Inhibits production of leukotrienes and
prostaglandins
Inhibits WBC adhesion -• neutrophilia
Blocks histamine release from mast cells
.
F osinopenia, lvinphopeiiial
• Blocks IL-2 production
1 Bone formation (i osteoblast activity)
REGULATION CRH ( hypothalamus ) stimulates ACTH release Chronic stress induces prolonged secretion.
—
(pituitary) cortisol production in adrenal
zona fasciculata. Excess cortisol 1 CRH,
ACTH, and cortisol secretion.

Calcium homeostasis Plasma Ca-+ exists in three forms:

lonized/free (~ 45%, active formj
t in piI
—t affinity of albumin (t negative
—
charge ) to bind Ca’+ hypocalcemia ( cramps,
Bound to albumin (- 40%) pain, paresthesias, carpopedal spasm ) . Ionized /
Bound to anions (- 15%) free Cali is 1° regulator of PTH; changes in
pH alter PTII secretion, whereas changes in
albumin do not

Vitamin D|
SOURCE
-
D from exposure of skin to sun, ingestion of
fish and plants. D7 from ingestion of plants,
—
Deficiency rickets in kids, osteomalacia in
adults. Caused by malabsorption, i sunlight,
fungi, yeasts. Both converted to 25-011 in liver poor diet, chronic kidney failure.
and to l,25-( OH ) vitamin D ( active form) in
i ,
24,25-(OH), D is an inactive form of vitamin D
kidnevj PPH leads to t Ca -+ rcabsorption and
t absorption of dietary Ca~* and P04
,_. i PO_ j’ reabsorption in the kidney, whereas
FUNCTION
Enhances bone mineralization. l,25-(OHl;D leads ,,
_ to t absorption of both
Ca’+ and PO+ in the gut.
REGULATION t PTH, 1 Ca’*,i P04
production.
'>-
-
t l,25-(OH),

l,25-(OH) j feedback inhibits its own

production.
 ENDOCRINE ENDOCRINE — PHYSIOLOGY

Calcitonin
SOURCE Parafollicular cells ( C cells) of thyroid, Calcitonin opposes actions of PTU. Not
FUNCTION i bone resorption of Ca-*. important in normal Ca-+ homeostasis.
Calcitonin tones down Ca-' Calcitonin times
REGULATION t serum Ca-+ -* calcitonin secretion.
down Ca^± levels and keeps it in boncj

Thyroid hormones Iodine-containing hormones that control the body’s metabolic rate.
( T3 /T4 )
SOURCE
tissues.
-
Follicles of thyroid. Most T formed in target -
T functions
Brain maturation
— lB’s:

FUNCTION Bone growth (synergism with GH) Bone growth

CNS maturation
t P| receptors in heart = t CO, HR, SV,
contractility
t basal metabolic rate via t Na+/K+-ATPase
activity -» t O-, consumption RR, body .
temperature
t glycogenols sis, gluconeogenesis, lipolysis
REGULATION TRH ( hypothalamus) stimulatesTSH
( pituitary), which stimulates follicular cells.
May also be stimulated by thyroid-stimulating
immunoglobulin ( TSI ) in Graves disease.
Negative feedback by free T?, Tj to anterior
pituitary i sensitivity to TRIP
Wolff-Chaikoff effect — excess iodine
temporarily inhibits thyroid peroxidase
-* t iodine organification I T5/T4
production.
— Propylthiouracil inhibits both thyroid peroxidase
(l-adrcncrgic effects
Basal metabolic rate t
Thyroxine-binding globulin (TBG) hinds most
T;/Tj in blood; only free hormone is active,
i TBG in hepatic failure, steroids; t TBG in
pregnancy or OCP use (estrogen t TBG ).
Tj is major thyroid product; converted to T in -
peripheral tissue by >'-deiodinasc.
-
T binds nuclear receptor w ith greater affinity
than T4 .
Thyroid peroxidase is the enzyme responsible
for oxidation and organification of iodide as
well as coupling of monoiodots rosine (MIT)
and di-iodotvrosinc ( Dl l ). 1111' + 1111’ = Tg.
DIT + MIT = TV
and 5'-dciodinasc. Methimazolc inhibits
thyroid peroxidase only. Glucocorticoids
inhibit peripheral conversion of 1 to IT '

Hypothalamus - -©- Peripheral tissue Blood Thyroid follicular epithelial cell Follicular lumen

1
TRH
TG TG

Thyroglobuiin

I
Anterior pituitary \ Q - h - Oxidation
l V.-
TSH
"
Somatostatin
S Downstream thyroid
Na* on,
Thyroid
function Deiodinase peroxidase Organification
,
of I
Thyroid
l
Thyroid follicular ceils
MIT. DiT
peroxidase

iv
TJ,
TSI T , -orr - DIT

J
;+
T,*
5 -dciodinasc
T , 1
TyTj
—
( to circulation) Coupling reaction
Tr
TG
"
DIT
MIT , .“
tndocytosis
Tr
TG
DIT
MIT
MIT
Thyroid peroxidase
i
Effector organs
320 SECTION I I I ENDOCRINE ENDOCRINE — PHYSIOLOGY

Signaling pathways of endocrine hormones

cAMP
-
. .
FSH,UI ACTH, TSH, GRII, I CG, ADI 1
( Vj receptor), MSH, PTH, calcitonin, GHRH,
FLAT ChAMP

glucagon, histamine ( H-,-receptorl

cGMP BNP, ANP, EDRF (NO) BAD GraMPa
Tliink vasodilators

•P3 GnRH, Oxytocin, ADH ( Vprcccptor), TRH,

.
Histamine ( Hpreceptor) Angiotensin II,
GOAT HAG

Gastrin
Intracellular receptor Progesterone, F,strogen, Testosterone, Cortisol, PET CAT on TV
Vldosterone, IVIp V'itamin D
Receptor tyrosine .
Insulin, ICF-1, FGF, PDGF, EGF MAP kinase pathway
kinase Think Growth factors
Nonreceptor tyrosine Prolactin, Immunomodulators (eg, cytokines JAK/STAT pathway
kinase .
IL-2, IL-6, IKN) GH, G-GSF, Erythropoietin, Think acidophils and cytokine:
Thrombopoietin PIGGLET

Signaling pathway of Steroid hormones are lipophilic and therefore

Cytoplasm Nucleus
steroid hormones must circulate bound to specific binding
globulins, which t their solubility.
Binding to enhancer -
In men, f sex hormone-binding globulin l e element In DNA ^Pre-mRNA
I
( SIIBG) lowers free testosterone
* (WW

H
-» gynecomastia. Transformation of mRNA
In women, 1 SI 1BG raises free testosterone receptor to expose DNA -
binding domain mRNA
-» hirsutism.
OCPs, pregnancy
— t SI IBG.
Bmding to receptor
located in nucleus or
in cytoplasm

i 1
I
I
BWBE
I

H) Hormone
 ENDOCRINE ENDOCRINE — PATHOLOGY SECTION III 321

ENDOCRINE — PATHOLOGY

Cushing syndrome
ETIOLOGY t cortisol due to a variety of causes:
Exogenous corticosteroids — result in i ACTH, bilateral adrenal atrophy. Most common cause.
Primary adrenal adenoma, hyperplasia, or carcinoma — result in t ACTH, atrophy of
uninvolved adrenal gland. Can also present with pseudohyperaldosteronism.
ACTH-sccrcting pituitary adenoma (Cushing disease); paraneoplastic ACTH secretion (eg,
small cell lung cancer, bronchial carcinoids) — result in t ACTH, bilateral adrenal hyperplasia.
Cushing disease is responsible for the majority of endogenous cases of Cushing syndrome.
FINDINGS Hypertension, weight gain, moon facies Q, abdominal striae Q and truncal obesity, buffalo hump,
skin changes icg. thinning, striadl. osteoporosis, hyperglycemia (insulin resistance), amenorrhea,
immunosuppression.
DIAGNOSIS Screening tests include: t free cortisol on 24-hr urinalysis, t midnight salivary cortisol, and no
suppression with overnight low - dose dexamethasone test. Measure serum ACTH. If I, suspect
adrenal tumor or exogenous glucocorticoids. If t, distinguish between Cushing disease and
ectopic ACTH secretion with a high-dose|dexamethasone suppression test and CRH stimulation
test. Ectopic secretion w ill not decrease with dexamethasone because the source is resistant to
negative feedback: ectopic secretion will not increase with CRH because pituitary ACTH is
suppressed.

Measure ACTH

v
Suppressed Elevated

1
ACTH - independent ACTH-dependent
Cushing syndrome Cushing syndrome

r
r T
High-dose dexamethasone suppression test CRH stimulation test
or adrenal tumor (consider
MRI to confirm)

Adequate
L
No suppression =
1
.
No f ACTH cortisol =
suppression = ectopic ACTH t ACTH. cortisol = ectopic
Cushing disease secretion Cushing disease ACTH secretion
22 ENDOCRINE ENDOCRINE — PATHOLOGY

Adrenal insufficiency Inability of adrenal glands to generate enough
glucocorticoids +/— mineralocorticoids for the
body's needs. Symptoms include weakness,
fatigue, orthostatic hypotension, muscle
aches, weight loss, GI disturbances, sugar and/
or salt cravings. Treatment: glucocorticoid/
mineralocorticoid replacement.
Primary adrenal Deficiency of aldosterone and cortisol
insufficiency production due to loss of gland function
A
-» hypotension ( hvponatremie volume
i contraction), hyperkalemia, metabolic acidosis, Waterhouse-Friderichsen syndrome — acute
skin and mucosal hyperpigmentation Q ( due
to t MSII, a byproduct of ACTH production
from proopiomelanocortin [POMC ]).
Acute — sudden onset (eg, due to massive
V7 s- l hemorrhage). May present with shock in
/3 acute adrenal crisis.
Chronic — aka Addison disease. Due to
adrenal atrophy or destruction by disease
(autoimmune destruction most common in
the Western world; TB most common in the
developing world).
Secondary adrenal Seen with 1 pituitary ACTH production.
insufficiency No skin/mucosal hyperpigmentation, no
hyperkalemia laldosterone synthesis preserved
due to intact RAA axi 4).
Tertiary adrenal Seen in patients with chronic exogenous
insufficiency steroid use, precipitated by abrupt withdrawal.
Aldosterone synthesis unaffected.
Diagnosis involves measurement of scrum
electrolytes, morning/random serum cortisol
and ACTH ( low cortisol, high ACTI1 in 1°
adrenal insufficiency; low cortisol, low ACTH
in 27?° adrenal insufficiency due to pituitary/
hypothalamic disease ), and response to ACTH
stimulation test .
Alternatively, can use metyrapone stimulation
test: metyrapone blocks last step of cortisol
synthesis ( ll-deoxycortisol -* cortisol). Normal
response is 1 cortisol and compensatory
t ACTH and 11-deoxycortisol. In 1° adrenal
insufficiency, ACTH is t but ll-deoxycortisol
remains 1 after test. In 273° adrenal
insufficiency, both ACTH and ll-deoxycortisol
remain l after test.
Primary Pigments the skin/mucosa.
Associated with autoimmune polyglandular
syndromes.
lc adrenal insufficiency due to adrenal
hemorrhage associated with septicemia
(usually Neisseria meningitidis ), DIC,
endotoxic shock.
Secondary Spares the skin/mucosa.
Tertiary from Treatment.

Hyperaldosteronism Increased secretion of aldosterone from adrenal gland. Clinical features include hypertension, 1 or
normal K+, metabolic alkalosis. No edema due to aldosterone escape mechanism.
Primary Seen with adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia! t aldosterone,
hyperaldosteronism 1 renin.
Secondary Seen in patients w ith renovascular hypertension, juxtaglomerular cell tumor (due to independent
hyperaldosteronism activation of rcnin-angiotensin-aldostcrone system), t aldosterone, t renin. Kdeina mav be seen 2
to causes such as heart failure or cirrhosis.
324 SECTION III ENDOCRINE ENDOCRINE — PATHOLOGY

Pheochromocytoma
ETIOLOGY Most common tumor of the adrenal medulla in Rule of 10's:
adults Q. Derived from chromaffin cells (arise 10% malignant
from neural crest). 10% bilateral
Up to 25% of cases associated with germline .
10% extra-adrenal ( eg bladder wall, organ of
mutations ( eg, NF I , VHL , RET [MEN 2A . Zuckcrkandl1
my 10% calcify
7 10% kids

SYMPTOMS Most tumors secrete epinephrine, Episodic hyperadrenergic symptoms ( 5 P’s):

norepinephrine, and dopamine, which can Pressure ( t BP)
cause episodic hypertension. Pain ( headache)
—
Symptoms occur in "spells” relapse and remit. Perspiration
Palpitations ( tachycardia)
Pallor
FINDINGS t catecholamines and metanephrines in urine
and plasma.
TREATMENT Irreversible a-antagonists (eg, Phenoxybenzamine (16 letters) is given for
phenoxybenzamine) followed by (1-blockers phcochromocs Ionia (also 16 letters).
prior to tumor resection, a-blockade must be
achieved before giving [5-blockcrs to avoid a
hypertensive crisis.
 ENDOCRINE ENDOCRINE — PATHOLOGY SECTION III 325

Hypothyroidism vs hyperthyroidism
Hypothyroidism Hyperthyroidism
SKiNS / SYMPTOMS Cold intolerance ( t heat production) Heat intolerance ( t heal production!
Weight gain, t appetite Weight loss, t appetite
.
Hvpoactivitv lethargy, fatigue, weakness, Hyperactivity, anxiety, insomnia, hand tremor
depressed rnooq
Constipation Iivperdefecationl
t reflexes (delayed/slow relaxing) t reflexes ( brisk )
Hypothyroid myopathy ( proximal muscle Thyrotoxic myopathy ( proximal muscle
weakness, t CK ) weakness, normal CK )
Myxedema ( facial/periorbital ) Pretibial myxedema ( Graves disease), periorbital
edema
Dry, cool skin; coarse, brittle hair Warm, moist skin; fine hair
Bradycardia, dyspnea on exertion Chest pain, palpitations, arrhythmias,
t number and sensitivity of |3-adrenergic
arrhvthmias (eg. atrial fibrillation!, receptors
(permissive effect )
LAB FINDINGS t TSH (if 1°) A TSH (if 1°)
t free T, and T+ t free or total T, and T
^
Hypercholesterolemia (due to 1 LDL receptor Hypocholesterolcmia (due to t LDL receptor
expression) expression)

Causes of goiter
Smooth/diffuse Nodular
Graves disease multinodular goiter
'loxic
Hashimoto tliyroiditis Thyroid adenoma
Iodine deficiency Thyroid cancer
TSH-sccreting pituitary adenoma Thyroid cyst
326 SECTION III ENDOCRINE ENDOCRINE — PATHOLOGY

Hypothyroidism
Hashimoto thyroiditis Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder with
antithyroid peroxidase (antiinicrosomal) and antithyroglobulin antibodies. Associated with HLA-
DR3 and -DR t risk of non-Hodgkin lymphoma (typically of B-cell origin).
^
May be hvperthyroid early in course due to thyrotoxicosis during follicular rupture.
Histologic findings: Hurthle cells, lymphoid aggregates with germinal centers Q.
Findings: moderately enlarged, nontender thyroid.
Congenital Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis
hypothyroidism (most common cause in US), iodine deficiency, dyshormonogenetic goiter.
(cretinism)
Poor brain development: the 6 P’s Q Q.
.
Findings: Pot-bellied, Pale, Puffy-faced child with Protruding umbilicus Protuberant tongue, and

Subacute Self-limited disease often following a flu-like illness (eg, viral infection).
granulomatous May be hyperthyroid early in course, followed by hypothyroidism.
thyroiditis (de Histology: granulomatous inflammation.
Quervain) Findings: t ESR, jaw pain, very tender thyroid, (de Quervain is associated with pain.)
Riedel thyroiditis Thyroid replaced by fibrous tissue with inflammatory infiltrate 0. Fibrosis may extend to local
structures (eg, trachea, esophagus), mimicking anaplastic carcinoma. A are hypothyroid.
Considered a manifestation of IgG -related systemic disease (eg, autoimmune pancreatitis,
^ aortitis).
retroperitoneal fibrosis, noninfectious
Findings: fixed, hard rock-like), painless goiter.
(
Other causes Iodine deficiency Q, goitrogens (eg, amiodarone, lithium), Wolff-Chaikoff effect (thyroid gland
downregulation in response to t iodide).

mm
m mm r»- »5
K
m &
-
• m
Before treatment
••
BC
•
After treatment
-
M f t. j : Mm i\
r

mmMX .

- r-V
• : ."
 ENDOCRINE ENDOCRINE — PATHOLOGY SECTION III 329

Diagnosis of
parathyroid disease

2° hyperparathyroidism
( vitamin D deficiency,
-
l hy perparathyroidism
Ihypi rplasia, adenoma,
chronic re lal failure) carcinoma ) :

jL. ,
, |

Normal

1° hypoparathyroidism PT H- independent
(surgica resection, ypercalcemi
autoi nmune) .
(excesi Ca2+ intake :ancer )

4 6 8 10 12 14 16 18 20
Ca2+ (mg /dL) 0

Hypoparathyroidism Due to accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge
syndrome. Findings: tetany, hypocalcemia, hyperphosphatemia.
—
Chvostek sign — tapping of facial nerve (tap the Cheek) contraction of facial muscles.
Trousseau sign — occlusion of brachial artery with BP cuff (cuff the Triceps) carpal spasm.
—
Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy) — unresponsiveness of
—
kidney to PTH hypocalcemia despite t PTH levels. Characterized by shortened 4th/ 5th digits,
short stature. Autosomal dominant. Due to defective Gs protein a-subunit causing end-organ
resistance to PTH. Defect must be inherited from mother due to imprinting.
Pseudopseudohypoparathyroidism — physical exam features of Albright hereditary
osteodystrophy but without end-organ PTH resistance (PTH level normal j Occurs when
defective G& protein a-subunit is inherited from father.
 330 SECTION III ENDOCRINE ENDOCRINE — PATHOLOGY
Hyperparathyroidism
Primary Usually due to parathyroid adenoma or —
Osteitis fibrosa cystica cystic bone spaces
hyperparathyroidism hyperplasia . Hypercalcemia , hypercalciuria filled with brown fibrous tissue Q (“ brown
(renal stones), hypophosphatemia , t PTH, tumor" consisting of osteoclasts and deposited
t ALP, t cAMP in urine . Most often hemosiderin from hemorrhages; causes bone
asymptomatic. May present with weakness and pain ).

mI
constipation ( “ groans"), abdominal /flank pain “ Stones, bones, groans, and psychiatric
( kidney stones, acute pancreatitis), depression overtones."
(“ psychiatric overtones” ).

Secondary
hyperparathyroidism
-
2° hyperplasia due to i Ca + absorption
and /or t PO 5-, most often in chronic
renal disease^ (causes hvpovitaminosis
D and hyperphosphatemia -» I Calzj).
•

Hypocalcemia , hyperphosphatemia in
—
— —
Renal osteodystrophy renal disease 2° and
3° hyperparathyroidism bone lesions.

chronic renal failure (vs hypophosphatemia

with most other causes), t ALP, t PTH .
Tertiary Refractory (autonomous) hyperparathyroidism
hyperparathyroidism resulting from chronic renal disease tt PTH ,
,

t Ca 2+.

Familial hypocalciuric Defective G-coupled Ca =± sensing receptors in multiple tissues (eg, parathyroids, kidneys). Higher
He -
located
Fact
hypercalcemia
—
hypercalcemia and hvpocalciuria with normal to t PTH levels.
=
than normal Ca levels required to suppress PTIT . Excessive renal Ca ± reuptake -*• mild

Pituitary adenoma Benign tumor, most commonly prolactinoma (arises from lactotrophs). Adenoma Q may be
functional ( hormone producing) or nonfunctional (silent). Nonfunctional tumors present with
mass effect ( bitemporal hemianopia , hypopituitarism , headache). Functional tumor presentation
is based on the hormone produced .
Prolactinoma symptoms: females present with galactorrhea , amenorrhea , and 1 bone density due
to suppression of estrogen . Males present with low libido and infertility. Treatment includes
dopamine agonists (eg, bromocriptine, cabergoline), transsphenoidal resectioij

Nelson syndrome Enlargement of existing ACTH-secreting pituitary adenoma after bilateral adrenalectomy for
refractory Cushing disease (due to removal of cortisol feedback mechanism ). Presents with
hyperpigmentation, headaches and bitemporal hemianopia . Treatment: pituitary irradiation or
surgical resection .
332 SECTION III ENDOCRINE ENDOCRINE — PATHOLOGY
Diabetes insipidus Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH
(central ) or failure of response to circulating ADH (nephrogenic).
Central Dl Nephrogenic Dl
ETIOLOGY Pituitary tumor, autoimmune, trauma , surgery, Hereditary (ADH receptor mutation ), 2 °
ischemic encephalopathy, idiopathic to hypercalcemia , hypokalemia , lithium ,
demeclocycline (ADH antagonist)
FINDINGS iADH Normal or t ADH levels
Urine specific gravity < 1.006 Urine specific gravity < 1.006
Serum osmolality > 290 mOsm/kg Serum osmolality > 290 mOsm /kg
Hyperosmotic volume contraction Hyperosmotic volume contraction
WATER DEPRIVATION TEST3 > 50% t in urine osmolality only after Minimal change in urine osmolality, even after
administration of ADH analog administration of ADH analog
TREATMENT Desmopressin acetate HCTZ, indomethacin , amiloride
Hydration Hydration , avoidance of offending agent
aNo water intake for 2-3 hr followed by hourly measurements of urine volume and osmolarity and plasma Na + concentration
and osmolarity. ADH analog (desmopressin acetate) is administered if serum osmolality > 295-300 mOsm /kg, plasma
Na+ > 145, or urine osmolality does not rise despite a rising plasma osmolality.

Syndrome of Characterized by: Causes include:

inappropriate Excessive free water retention * Ectopic ADH (eg, small cell lung cancer)

antidiuretic Euvolemic hyponatremia with continued 5

CNS disorders/head trauma
fiormone secretion urinary Na + excretion Pulmonary disease
J
Urine osmolality > serum osmolality Drugs (eg, cyclophosphamide)

—
Body responds to water retention with Treatment: fluid restriction, salt tablets, IV
1 aldosterone and t ANP and BNP hypertonic saline, diuretics, conivaptan,
_
—
t urinary Na+ secretion -*• normalization
of extracellular fluid volume euvolemic
hyponatremia. Very low serum Na+ levels
can lead to cerebral edema , seizures. Correct
slowly to prevent osmotic demyelination
tolvaptan, demeclocycline.
Increased urine osmolarity during water
deprivation test indicates psychogenic
polydipsia .

syndrome (formerly known as central pontine

myelinolysis).
336 SECTION III ENDOCRINE ENDOCRINE — PATHOLOGY
Hyperosmolar
hyperqlycemid
nonketotic syndrome
-
—
State of profound hyperglycemia induced dehydration and t serum osmolalihl classically seen

—
in elderly type 2 diabetics with limited ability to drink . Hyperglycemia excessive osmotic
diuresis dehydration -* eventual onset of HHNS. Symptoms: thirst , polyuria , lethargy, focal
neurological deficits ( eg, seizures), can progress to coma and death if left untreated . Labs:
hyperglycemia (often > 600 mg /dL ), T serum osmolalihi (> 320 mOsm/kg), no acidosis ( pH >
7.3, ketone production inhibited by presence of insulin ). Treatment: aggressive IV fluids, insulin
therapy.

Glucagonoma Tumor of pancreatic a cells -*• overproduction of glucagon . Presents with dermatitis ( necrolvtic
migratory erythema), diabetes ( hyperglycemia), DVT, declining weight, depression. Treatment:
octreotide, surgery.

Insulinoma Tumor of pancreatic P cells

— —
overproduction of insulin hypoglycemia. May see Whipple triad:
low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope, diplopia ), and resolution of
symptoms after normalization of glucose levels. Symptomatic patients have i blood glucose and
t C -peptide levels (vs exogenous insulin use). ~ 10% of cases associated with MEN 1 syndrome .
Treatment: surgical resection.

Somatostatinoma Tumor of pancreatic 6 cells

— —
overproduction of somatostatin 1 secretion of secretin ,
cholecvstokinin , glucagon , insulin, gastrin , gastric inhibitory peptide ( GIPl May present with
diabetes/glucose intolerance, steatorrhea , gallstones, achlorhvdrial Treatment: surgical resection;
somatostatin analogs (eg, octreotide) for symptom control .

Carcinoid syndrome Rare syndrome caused by carcinoid tumors Rule of l /3s:

mm ( neuroendocrine cells Q; n le prominent

°
rosettes [arrow] ), especially metastatic small
bowel tumors, which secrete high levels
of serotonin ( 5-HT). Not seen if tumor is
limited to GI tract ( 5-HT undergoes first-pass
1/ 3 metastasize
1/ 3 present with 2 nd malignancy
1 / 3 are multiple
Most common malignancy in the small
intestine.
metabolism in liver). Results in recurrent
diarrhea , cutaneous flushing, asthmatic
wheezing, right-sided valvular heart disease
( tricuspid regurgitation , pulmonic stenosis) .
t 5-hydroxyindoleacetic acid ( 5-HIAA) in
urine, niacin deficiency ( pellagra ).
Treatment: surgical resection, somatostatin
analog (eg, octreotide).

Zollinger- Ellison Gastrin-secreting tumor ( gastrinoma ) of pancreas or duodenum . Acid hypersecretion causes
syndrome recurrent ulcers in duodenum and jejunum . Presents with abdominal pain ( peptic ulcer disease,
distal ulcers), diarrhea (malabsorption ). Positive secretin stimulation test: gastrin levels remain
elevated after administration of secretin , which normally inhibits gastrin release. May be
associated with MEN 1 .
338 SECTION III ENDOCRINE ENDOCRINE — PHARMACOLOGY

ENDOCRINE — PHARMACOLOGY

Diabetes mellitus Treatment strategies:

drugs Type 1 DM — low-carbohydrate diet, insulin replacement
Type 2 DM — dietary modification and exercise for weight loss; oral agents, non-insulin injectables,
insulin replacement
Gestational DM (GDM) — dietary modifications, exercise, insulin replacement if lifestyle
modification fails
DRUG CLASSES CLINICAL USE ACTION RISKS/CONCERNS
Insulin preparations
Insulin, rapid acting Type 1 DM, type 2 DM, Binds insulin receptor (tyrosine Hypoglycemia, lipodystrophy,
Lispro, GDM (postprandial glucose kinase activity) rapidly, no rare hypersensitivity reactions.
Aspart, control). LAG.
Glulisine Liver: t glucose stored as
glycogen.
Muscle: t glycogen, protein
synthesis; t Ki uptake.
Fat: t TG storage.
Insulin, short acting Type 1 DM, type 2 DM,
Regular GDM, DKA (IV),
hyperkalemia (+ glucose),
stress hyperglycemia.
Insulin, intermediate Type 1 DM, type 2 DM,
acting GDM.
NPH

Insulin, long acting Type 1 DM, type 2 DM, GDM

Detemir, ( basal glucose control).
glargine
Oral hypoglycemic drugs
Biguanides Oral. First-line therapy in type Inhibits hepatic GI upset; most serious adverse
Metformin 2 DM, causes modest weight gluconeogenesis and effect is lactic acidosis (thus
loss. the action of glucagon. contraindicated in renal
Can be used in patients 1 gluconeogenesis, insufficiency).
without islet function. t glycolysis, t peripheral
glucose uptake ( t insulin
sensitivity).
Sulfonylureas Stimulate release of Close IC channel in 3-cell Risk of hypoglycemia t in renal
First generation:
chlorpropamide,
endogenous insulin in
type 2 DM. Require some
—
membrane cell depolarizes
-* insulin release via t Ca —
•
failure, weight gain.
First generation: disulfiram-like
tolbutamide islet function, so useless in influx. effects.
Second generation: typeJi JDM. Second generation:
glimepiride, hypoglycemia.
glipizide,
glyburide
Glitazones/ Used as monotherapy in t insulin sensitivity in Weight gain, edema.
thiazolidinediones typeJ2JDM or combined with peripheral tissue. Binds to Weight gain, edema, HH t risk
Pioglitazone, above agents. Safe to use in PPAR-Y nuclear transcription of fractures.
rosiglitazone renal impairment. regulator.-
 ENDOCRINE ENDOCRINE — PHARMACOLOGY SECTION III 339

Diabetes mellitus drugs (continued )

DRUG CLASSES CLINICAL USE ACTION RISKS /CONCERNS

Oral hypoglycemic drugs (continued)

Meglitinides Used as monotherapy in Stimulate postprandial Hypoglycemia ( t risk with
Nateglinide, type 2 DM or combined with insulin release by binding renal failure), weight gain.
repaglinide metformin. to Kt channels on (3 -cell
membranes (site differs from
sulfonvlureas).
GLP- 1 analogs Type 2 DM. t glucose- dependent insulin Nausea, vomiting, pancreatitis;
Exenatide, release, 1 glucagon release. modest weight loss.
liraglutide (sc injection) 1 gastric emptying, t satiety.
DPP- 4 inhibitors Type 2 DM. Inhibits DPP-4 enzyme that Mild urinary or respiratory
Linagliptin, deactivates GLP-1, thereby infections; weight neutral.
saxagliptin, t glucose-dependent insulin
sitagliptin release, 1 glucagon release,
1 gastric emptying, t satiety.
Amylin analogs Type 1 DM, type 2 DM. 1 gastric emptying, 1 glucagon. Hypoglycemia (in setting of
Pramlintide mistimed prandial insulin),
(sc injection) nausea.
Sodium- glucose Type 2 DM. Block reabsorption of glucose Glucosuria, UTIs, vaginal yeast
co -transporter 2 in PCT. infections, hyperkalemia,
( SGLT 3D inhibitors dehydration (orthostatic
Canagliflozin, hypotension ), weight los 4
dapagliflozin,
empagliflozin
a- glucosidase Type 2 DM. Inhibit intestinal brush-border GI disturbances.
inhibitors a-glucosidases.
Acarbose, Delayed carbohydrate
miglitol hydrolysis and glucose
absorption -* 1 postprandial
hyperglycemia.
aGenes activated by PPAR-y regulate fatty acid storage and glucose metabolism. Activation of PPAR-y t insulin sensitivity and
levels of adiponectin.

Thionamides Propylthiouracil (PTU), methimazole.

MECHANISM Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling
—
of iodine inhibition of thyroid hormone synthesis. Propylthiouracil also blocks 5'-deiodinase
-* i peripheral conversion of to T$.
CLINICAL USE Hyperthyroidism. PTU blocks Peripheral conversion PTU used in first trimester of pregnancy ( due
to methimazole teratogenicity); methimazole used in second and third trimesters of pregnancy
( due to risk of PTU-induced hepatotoxicityt
ADVERSE EFFECTS Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity.
Methimazole is a possible teratogen (can cause aplasia cutis).
340 SECTION III ENDOCRINE ENDOCRINE — PHARMACOLOGY

Levothyroxine (T4), triiodothyronine (T3 )

MECHANISM Thyroid hormone replacement.
CLINICAL USE Hypothyroidism, myxedema. Used off-label as weight loss supplements.
ADVERSE EFFECTS Tachycardia, heat intolerance, tremors, arrhythmias.

Hypothalamic / pituitary drugs

DRUG CLINICAL USE
ADH antagonists SIADH, block action of ADH at V 7-receptor.
(conivaptan,
tolvaptan)
Desmopressin acetate Central (not nephrogenic) DI, von Willebrand diseaseT sleep enuresi4
GH GH deficiency, Turner syndrome.
Oxytocin Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage.
Somatostatin Acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices.
(octreotide)

Demeclocycline
MECHANISM ADH antagonist (member of tetracycline family).
CLINICAL USE SIADH.
ADVERSE EFFECTS Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.

Fludrocortisone
MECHANISM Synthetic analog of aldosterone with little glucocorticoid effects.
CLINICAL USE Mineralocorticoid replacement in 1° adrenal insufficiency.
ADVERSE EFFECTS Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation.

Cinacalcet
MECHANISM

CLINICAL USE
Sensitizes Ca-+-sensing receptor (CaSR) in parathyroid gland to circulating Ca 2+
1° or 2° hyperparathyroidism.
— 1 PTH.

ADVERSE EFFECTS Hypocalcemia.

HIGH- YI E LD SYSTEMS

Gastrointestinal

“A good set of bowels is worth more to a man than any quantity of brains Embryology 342
— josh Billings
Anatomy 343
“ Man should strive to have his intestines relaxed all the days of his life
— Moses Maimonides Physiology 354
“ Is life worth living? It all depends on the liver ” Pathology 357
— William James Pharmacology 379

341
342 SECTION III GASTROINTESTINAL GASTROINTESTINAL — EMBRYOLOGY

GASTROINTESTINAL — EMBRYOLOGY

Foregut — esophagus to upper duodenum

Normal
gastrointestinal ^
Midgut — lower duodenum!to proximal 1h of transverse colon.
embryology Hindgut— distal /? of transverse colon to anal canal above pectinate line.
'
Midgut development:
" 6th week — physiologic midgut herniates through umbilical ring
1
10 th week — returns to abdominal cavity + rotates around superior mesenteric artery (SMA),
total 270° counterclockw ise

Ventral wall defects Developmental defects due to failure of:
Rostral fold closure — sternal defects
Lateral fold closure — omphalocele,
gastroschisis
Caudal fold closure — bladder exstrophy
Gastroschisis — extrusion of abdominal
contents through abdominal folds (typically
right of umbilicus); not covered by peritoneum
or amnioij
Omphalocele —|ierniation of abdominal
contents into umbilical cord, sealed by
peritoneum Q. _
Congenital umbilical hernia — form of
incomplete closure of umbilical ring. Many-
close spontaneously.

Tracheoesophageal Esophageal atresia (EA) with distal tracheoesophageal fistula (TEF) is the most common (85%).
anomalies Polyhydramnios in utero. Neonates drool, choke, and vomit with first feeding. TEF allows air to
enter stomach (visible on CXR). Cyanosis is 2° to laryngospasm (to avoid reflux-related aspiration).
Clinical test: failure to pass nasogastric tube into stomach.
In Il-type, the fistula resembles the letter H. In pure EA the CXR shows gasless abdomen .
Esophagus
Tracheoesophageal
Trachea fistula
1
S
V Esophageal
atresia
&
1Normal anatomy Pure EA Pure TEF EA with distal TEF
( atresia or stenosis) (H- type) (most common) E)

Intestinal atresia Presents w ith bilious vomiting and abdominal distension within first 1-2 days of life.
—
Duodenal atresia — failure to recanalize dilation of stomach and proximal duodenum (“ double
bubble” on x-ray O). Associated with Down syndrome.
—
Jejunal and ileal atresia — disruption of mesenteric vessels ischemic necrosis segmental
resorption (bowel discontinuity or “ apple peel” ). lejunal atresia commonly associated with “ triple
—
bubble" sign on x-rav.
 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 343

Hypertrophic pyloric Most common cause of gastric outlet obstruction in infants ( 1:600). Palpable “olive” mass in
stenosis epigastric region, visible peristaltic waves!and nonbilious projectile vomiting at ~ 2-6 weeks old.
More common in firstborn males; associated with exposure to macrolides. Results in hypokalemic
hypochloremic metabolic alkalosis ( 2° to vomiting of gastric acid and subsequent volume
contraction). Treatment is surgical incision ( pyloromyotomy).

Pancreas and spleen Pancreas — derived from foregut. Ventral pancreatic buds contribute to uncinate process and main
embryology pancreatic duct. The dorsal pancreatic bud alone becomes the body, tail, isthmus, and accessory
pancreatic duct. Both the ventral and dorsal buds contribute to pancreatic head.
Annular pancreas — ventral pancreatic bud abnormally encircles 2nd part of duodenum; forms a
ring of pancreatic tissue that may cause duodenal narrowing Q and Vomiting.
Pancreas divisum — ventral and dorsal parts fail to fuse at 8 weeks. Common anomaly; mostly
asymptomatic, but may cause chronic abdominal pain and/or pancreatitis.
Spleen — arises in mesentery of stomach (hence is mesodermal) but has foregut supply (celiac trunk
— splenic artery).
Gallbladder

Accessory
pancreatic duct Pancreat c
duct
Minoi
oapilla
Dorsal
Major papilla pancreatic
bud
Ventral
pancreatic bud Main
pancreatic
Uncinate duct
process

GASTROINTESTINAL — ANATOMY

Retroperitoneal Retroperitoneal structures include GI structures SAD PUCKER:

structures that lack a mesentery and non-GI structures. Suprarenal (adrenal) glands [not shown]
Injuries to retroperitoneal structures can cause Aorta and IVC
blood or gas accumulation in retroperitoneal Duodenum (2nd through 4th parts)
space. Pancreas (except tail)
Ureters [not shown]
Right Duodenum Left Colon (descending and ascending)
Kidneys
Peritoneum Esophagus (thoracic portion) [not shown]
Pancreas

*
Rectum ( partially) [not shown]

^ MML . “
'
Ascending
colon
Av\ Descending

renal
space
Kidney

Transversalis fascia Aorta

 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 345

Digestive tract Layers of gut wall (inside to outside — MSMS):

anatomy Mucosa — epithelium, lamina propria, muscularis mucosa
• Submucosa — includes Submucosal nerve plexus (Meissner), Secretes fluid
Muscularis externa — includes Myenteric nerve plexus ( Auerbach), Motility
Serosa ( when intraperitoneal), adventitia (when retroperitoneal)
Ulcers can extend into submucosa, inner or outer muscular layer. Erosions are in the mucosa only.
Frequencies of basal electric rhythm ( slow waves):
ri
Stomach — 3 waves /min
* Duodenum — 12 waves/min
11eum — 8-9 waves/min

Tunica muscularis
externa Mucosa
- pithelium
Tunica submucosa » Lamina propria
Muscularis mucosa
Mesentery
Intestinal villi
Submucosa

m
Vein

—
Submucosal gland
Artery -
submucosal Lymph vessel
^
9
Epithelium Lumen
>v Yv
S Submucosal nerve
' > plexus (Meissner)
-
Muscularis mucosa - y
Muscularis
Myenteric nerve plexus Inner circular layer
(Auerbach) Myenteric nerve plexus
(Auerbach)
- Tunica serosa Outer longitudinal layer
Enlarged view Iperitoneuml Serosa
cross-section

Digestive tract histology

Esophagus Nonkeratinized stratified squamous epithelium.
Stomach Gastric glands.
Duodenum Villi and microvilli t absorptive surface.
Brunner glands (HC02--secreting cells of submucosa) and crvpts of Lieberkuhn (contain stem cells
that replace enterocytes/goblet cells and Paneth cells that secrete defensins, lysozyme, and TNFl
Jejunum Plicae circulares and crypts of Lieberkuhn.
Ileum Peyerpatches (lymphoid aggregates in lamina propria, submucosa), plicae circulares (proximal
ileum), and crypts of Lieberkuhn.
Largest number of goblet cells in the small intestine.
Colon Crypts of Lieberkuhn but no villi; abundant goblet cells.
 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 347

Celiac trunk Branches of celiac trunk: common hepatic,

Esophageal branch of Left gastric artery splenic, and left gastric. These constitute the
Short gastric arteries main blood supply of the stomach.
left gastric artery .
Celiac artery Strong anastomoses exist between:
Left and right gastroepiploics
Proper hepatic
artery
Left and right gastrics
Right gastric artery -
Posterior duodenal ulcers penetrate
Common gastroduodenal artery causing hemorrhage .
hepatic artery
Gastroduodenal
Spleen
artery
Left gastroepiploic
* artery
Splenic artery

Right gastroepiploic artery

-Posterior superior
pancreaticoduodenal artery
Anterior superior
pancreaticoduodenal
arteries
 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 349

Pectinate ( dentate ) Formed where endoderm ( hindgut) meets ectoderm .

line
Internal
lemormoKK
Above pectinate line —internal hemorrhoids, Internal hemorrhoids receive visceral
adenocarcinoma . innervation and are therefore not painful .
Lymphatic drainage to internal iliac lymph

— ——
Arterial supply from superior rectal artery
( branch of IMA) . nodes.
Venous drainage: superior rectal vein inferior

J
r
S II
mesenteric vein splenic vein portal
5 5 system!
==
.
as —
Below pectinate line external hemorrhoids, External hemorrhoids receive somatic
'amj$ anal fissures, squamous cell carcinoma . innervation (inferior rectal branch of pudendal
Arterial supply from inferior rectal artery ( branch nerve) and are therefore painful if thrombosed .
if
External
lemorrhoid
Pect irate
line
of internal pudendal artery).

— —
Venous drainage: inferior rectal vein internal
Lymphatic drainage to superficial inguinal nodes.

—
Anal fissure tear in the anal mucosa below the
pudendal vein internal iliac vein -* common Pectinate line. Pain while Pooping; blood on
-
iliac vein *• IVC.
toilet Paper. Located Posteriorly because this
area is Poorly Perfused . Associated with low-
fiber diets and constipation .
 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 351

Biliary structures Gallstones ( filling defects, red arrows in Q) that reach the confluence of the common bile and
pancreatic ducts at the ampulla of Vater can block both the common bile and pancreatic ducts
(double duct sign), causing both cholangitis and pancreatitis, respectively.
Tumors that arise in head of pancreas (usually ductal adenocarcinoma) can cause obstruction of
common bile duct
— enlarged gallbladder with painless jaundice (Courvoisier sign!

A Cystic duct
Liver

Gallbladder — ^
1 Common hepatic duct

Common bile duct

0
Accessory Ned Ron
pancreatic duct
Pancreas
Head
Sphincter of Oddi
Ampulla of Vater -
Main pancreatic duct
Duodenum 0

Femoral region
ORGANIZATION Lateral to medial: Nerve-Artery-Vein- You go from lateral to medial to find your
Lymphatics. N AVeL.
'

Femoral triangle Contains femoral nerve, artery, vein. Venous near the penis.
Femoral sheath Fascial tube 3-4 cm below inguinal ligament.
Contains femoral vein, artery, and canal (deep
inguinal lymph nodes) but not femoral nerve.
Femoral Nerve

Inguinal Femoral Artery

ligament
Femoral Vein

Sartorius .ymphatics
muscle
Femoral ring-site of
femoral hernia

Revised
Figure
Femoral
sheath

Adductor longus
muscle
 GASTROINTESTINAL GASTROINTESTINAL — ANATOMY SECTION III 353

Hernias A protrusion of peritoneum through an opening, usually at a site of weakness. Contents may be at
risk for incarceration (not reducible back into abdomen/pelvis) and strangulation (ischemia and
necrosis). Complicated hernias can present with tenderness, erythema, fever.
Diaphragmatic hernia Abdominal structures enter the thorax; Sliding hiatal hernia is most common.
may occur due to congenital defect of Gastroesophageal junction is displaced
pleuroperitoneal membrane Q, or as a result upward; “ hourglass stomach.”
of trauma. Commonly occurs on left side due Paraesophageal hernia — gastroesophageal
to relative protection of right hemidiaphragm junction is usually normal. Fundus protrudes
by liver. into the thorax.
Most commonly a hiatal hernia, in which
stomach herniates upward through the
esophageal hiatus of the diaphragm.
Indirect inguinal Goes through the internal (deep) inguinal ring, An indirect inguinal hernia follows the path of
hernia external (superficial) inguinal ring, and into descent of the testes. Covered by all 3 layers of
the scrotum. Enters internal inguinal ring spermatic fascia.
lateral to inferior epigastric vessels. Occurs in
X infants owing to failure of processus vaginalis
to close (can form hydrocele). Much more
common in males Q.

Direct inguinal hernia Protrudes through the inguinal ( Hesselbach)
triangle. Bulges directly through abdominal
wall medial to inferior epigastric vessels. Goes
through the external (superficial) inguinal ring Lateral to inferior epigastric vessels = Indirect
only. Covered by external spermatic fascia.
Usually in older men.
Femoral hernia Protrudes below inguinal ligament through
femoral canal below and lateral to pubic
tubercle. More common in females, but
overall inguinal hernias are the most common.
MDs don’t Lie:
Medial to inferior epigastric vessels = Direct
hernia.
hernia.
More likely to present with incarceration or
strangulation than inguinal hernias.

Inguinal Rectus abdominis muscle

.m £
(Poupart)
Inferior
ligament.
epigastric vessels Inguinal ( Hesselbach) triangle:
Indirect Direct inguinal hernia * Inferior epigastric vessels
inguinal hernia Lateral border of rectus abdominis
Inguinal ( Hesselbach) triangle
Inguinal ligament
X
Femoral artery. Femoral hernia
Femoral vein
356 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PHYSIOLOGY

Pancreatic secretions
ENZYME
Isotonic fluid; low flow
ROLE
— high Cl , high flow
— NOTES
,
high HCO -.

a- amylase Starch digestion Secreted in active form

Lipases Fat digestion
Proteases Protein digestion Includes trypsin, chymotrvpsin, elastase,
carboxypeptidases
Secreted as proenzymes also known as
zymogens
Trypsinogen Converted to active enzyme trypsin Converted to trypsin by enterokinase/
-* activation of other proenzymes and cleaving enteropeptidase, a brush-border enzyme on
of additional trypsinogen molecules into active duodenal and jejunal mucosa
trypsin ( positive feedback loop)

Carbohydrate Only monosaccharides ( glucose, galactose, fructose) are absorbed by enterocytes. Glucose and
absorption galactose are taken up by SGLT1 (Na+ dependent). Fructose is taken up by facilitated diffusion by
GLUT-5. All are transported to blood by GLUT-2.
D-xylose absorption test: distinguishes GI mucosal damage from other causes of malabsorption.

Vitamin/mineral absorption
Iron Absorbed as Fe-+ in duodenum. Iron Fist, Bro
Folate Absorbed in small bowel. Clinically relevant in patients with small bowel
disease or after resection.
,
b2 Absorbed in terminal ileum along with bile
salts, requires intrinsic factor.

Peyer patches Unencapsulated lymphoid tissue Q found in Think of IgA, the Intra-gut Antibody. And
lamina propria and submucosa of ileum. always say “ secretory IgA.”

m
Wm Contain specialized M cells that sample and
present antigens to immune cells.
B cells stimulated in germinal centers of Peyer
patches differentiate into IgA-secreting plasma
cells, which ultimately reside in lamina

A&lMf i propria. IgA receives protective secretory

component and is then transported across the
epithelium to the gut to deal with intraluminal
antigen.

Bile Composed of bile salts (bile acids conjugated to glycine or taurine, making them water soluble),
phospholipids, cholesterol, bilirubin, water, and ions. Cholesterol 7a-hydroxylase catalyzes
rate-limiting step of bile acid synthesis.
Functions:
Digestion and absorption of lipids and fat-soluble vitamins
Cholesterol excretion ( bodvs primary means of eliminating cholesterol)
* Antimicrobial activity (via membrane disruption)
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 357

Bilirubin Heme is metabolized by heme oxygenase to biliverdin, which is subsequently reduced to bilirubin.
Unconjugated bilirubin is removed from blood by liver, conjugated with glucuronate, and excreted
in bile.
Direct bilirubin — conjugated with glucuronic acid; water soluble.
Indirect bilirubin — unconjugated; water insoluble.

Excreted in urine as
—
urobilin ( » yellow color) . Kidney

90 m
mterohepatic

20%
Macrophages Bloodstream Liver Gut

Albumin
Unconjugated Unconjugated bilirubin- Conjugated
RBCs Heme Urobilinogen
bilirubin albumin complex bilirubin
JDP -
glucuronosyl-
' i' bat ana 80 %
transferase

Indirect bilirubin Direct bilirubin

( water insoluble) [ water soluble )
Excreted in feces as
—
stercobilin ( » brown
color of stool)

GASTROINTESTINAL — PATHOLOGY

Salivary gland tumors Most commonly benign and in parotid gland. Tumors in smaller glands more likely malignant.
Typically present as painless mass/swelling. Facial pain or paralysis suggests malignant

wmm
involvement of CN VII.
Pleomorphic adenoma ( benign mixed tumor) — most common salivary gland tumor Q.

mm g
Composed of chondromyxoid stroma and epithelium and recurs if incompletely excised or
- ruptured intraoperativelv.
Mucoepidermoid carcinoma — most common malignant tumor, has mucinous and squamous
components.
—
Warthin tumor (papillary cystadenoma lymphomatosum) benign cystic tumor with germinal
centers . Typically found in white smokers . Bilateral in 10%; malignant in 107c .
360 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY
Gastritis
Acute gastritis Erosions can be caused by:
—
protection

-*• mucosal ischemia

—
NSAIDs i PGE -, i gastric mucosa

—
Burns (Curling ulcer ) hypovolemia
Especially common among alcoholics and
patients taking daily NSAIDs (eg, patients with
rheumatoid arthritis).

Burned by the Curling iron .

— -
stimulation t ACh t H + production
—
Brain injury (Cushing ulcer) t vagal
Always Cushion the brain .

Chronic gastritis

H pylori
cancers).
—
Mucosal inflammation, often leading to atrophy
( hypochlorhydria hvpergastrinemia ) and
intestinal G -cell metaplasia ( t risk of gastric

Most common t risk of peptic ulcer disease,

, Affects antrum first and spreads to body of
MALT lymphoma. stomach .
Autoimmune Autoantibodies to parietal cells and intrinsic Affects body/fundus of stomach.
factor, t risk of pernicious anemia .

Menetrier disease
—
Gastric hyperplasia of mucosa hypertrophied rugae ( looking like brain gyri Cl), excess
mucus production with resultant protein loss and parietal cell atrophy with I acid production .
Precancerous.

A
Gastric cancer Most commonly gastric adenocarcinoma ; —
Virchow node involvement of left
lymphoma , GI stromal tumor, carcinoid ( rare). supraclavicular node by metastasis from
L <$ Early aggressive local spread with node/liver stomach .
—
V
metastases. Often presents late, with weight Krukenberg tumor bilateral metastases to
wr
i t f. f loss, early satiety, and in some cases acanthosis ovaries. Abundant mucin-secreting, signet ring
nigricans or Leser-Trelat sign . cells.
1
— —
Intestinal associated with H pylori, dietary Sister Mary Joseph nodule subcutaneous
* nitrosamines (smoked foods ), tobacco periumbilical metastasis.
smoking, achlorhydria , chronic gastritis.
Commonly on lesser curvature; looks like
ulcer with raised margins.
—
Diffuse not associated with H pylori ; signet
ring cells ( mucin-filled cells with peripheral
nuclei) Q; stomach wall grossly thickened
and leathery ( linitis plastica ).

Inflammatory bowel diseases
LOCATION
GROSS MORPHOLOGY
MICROSCOPIC MORPHOLOGY
COMPLICATIONS
INTESTINAL MANIFESTATION
EXTRAINTESTINAL MANIFESTATIONS
TREATMENT
GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 363
Crohn disease Ulcerative colitis
Any portion of the GI tract, usually the terminal Colitis = colon inflammation. Continuous
ileum and colon. Skip lesions, rectal sparing. colonic lesions, always with rectal involvement.
Transmural inflammation -*• fistulas. Mucosal and submucosal inflammation only.
—
Cobblestone mucosa, creeping fat, bowel wall Friable mucosal pseudopolyps (compare
thickening ( “ string sign” on barium swallow normal Q with diseased Q) w ith freely
x-ray Q), linear ulcers, fissures. hanging mesentery. Loss of haustra “ lead
pipe” appearance on imaging.
Noncaseating granulomas and lymphoid Crypt abscesses and ulcers, bleeding, no
aggregates. granulomas.
Malabsorption /malnutrition, colorectal cancer Malabsorption /malnutrition , colorectal cancer
( t risk with pancolitis). ( t risk with pancolitis).
Fistulas (eg, enterovesical fistulae, which can Fulminant colitis, toxic megacolon , perforation .
cause recurrent UTI and pneumaturia ),
phlegmon /abscess, strictures (causing
obstruction ), perianal disease.
Diarrhea that may or may not be bloody. Bloody diarrhea.
Rash ( pyoderma gangrenosum , erythema nodosum ), eye inflammation (episcleritis, uveitis), oral
ulcerations (aphthous stomatitis), arthritis ( peripheral, spondylitis).
Kidney stones (usually calcium oxalate), 1° sclerosing cholangitis. Associated with
gallstones. Mav be <£> for anti-Saccharomyces p-ANCA.
cervisiae antibodies (ASCA ) .
Corticosteroids, azathioprine, antibiotics (eg, 5-aminosalicylic preparations (eg, mesalamine),
ciprofloxacin , metronidazole), infliximab, 6-mercaptopurine, infliximab, colectomy.
adalimumab.
For Crohn , think of a fat granny and an old Ulcerative colitis causes ULCCCERS:
crone skipping down a cobblestone road away Ulcers
from the wreck ( rectal sparing ). Large intestine
Continuous, Colorectal carcinoma, Crypt
abscesses
Extends proximally
Red diarrhea
Sclerosing cholangitis
<
1 2,-
a
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 365

Zenker diverticulum Pharyngoesophageal false diverticulum Q. Elder MIKE has bad breath .
Esophageal dysmotility causes herniation of Elderly
mucosal tissue at Killian triangle between the Males
thyropharvngeal and cricopharyngeal parts of Inferior pharyngeal constrictor
the inferior pharyngeal constrictor. Presenting Killian triangle
symptoms: dysphagia , obstruction , gurgling, Esophageal dysmotility
aspiration, foul breath, neck mass. Most Halitosis
common in elderly males.

Meckel diverticulum True diverticulum. Persistence of the vitelline The rule oil 2 s:
duct . May contain ectopic acid-secreting 2 times as likely in males.
gastric mucosa and/or pancreatic tissue. Most 2 inches long.
Umbilicus
common congenital anomaly of GI tract . Can 2 feet from the ileocecal valve.
t? cause hematochezia/melena ( less commonly! 2% of population .
/ RLQ pain, intussusception , volvulus, or
obstruction near terminal ileum . Contrast with
Commonly presents in first 2 years of life.
May have 2 types of epithelia ( gastric/
omphalomesenteric cyst = cystic dilation of pancreatic).
vitelline duct .
Meckel diverticulum Diagnosis: pertechnetate study for uptake by
ectopic gastric mucosa.

Hirschsprung disease Congenital megacolon characterized by lack p.isk t with Down syndrome.
of ganglion cells/enteric nervous plexuses Diagnosed hv rectal suction biopsy, which shows
( Auerbach and Meissner plexuses) in distal absence of ganglionic cell4
segment of colon. Due to failure of neural crest Treatment: resection .
cell migration . Associated with mutations in
RET.
Presents with bilious emesis, abdominal
distention , and failure to pass meconium
within 48 hours -*• chronic constipation .
Normal portion of the colon proximal to the
aganglionic segment is dilated, resulting in a
“ transition zone.”

Malrotation

L v ei
—
Anomaly of midgut rotation during fetal development improper positioning of bowel , formation
of fibrous bands ( Ladd bands). Can lead to volvulus, duodenal obstruction.

Ladd
rands
Large
Small
intestine

0
 366 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY
Volvulus Twisting of portion of bowel around its

_
mesentery; can lead to obstruction and
infarction Q 0. Can occur throughout the
GI tract. Midgut volvulus more common in
infants and children . Sigmoid volvulus more
common in elderly.

I New 1
llmagel

Intussusception Telescoping Q of proximal bowel segment into

—
distal segment, commonly at ileocecal junction .

fl
Compromised blood supply intermittent
abdominal pain often with “ currant jelly” stools. ::
Unusual in adults (associated with intraluminal
mass or tumor that acts as lead point that
is pulled into the lumen). Majority of cases
i
occur in children ( usually idiopathic; may be
associated with recent viral infection , such as
> cfflMfiSl

adenovirus -* Pever patch hypertrophy -* lead

^
point also associated with rotavirus vaccin ;
most common pathologic lead point is Meckel
/
«
diverticulum ). Abdominal emergency in early
childhood, with bulls-eye appearance on
ultrasound.
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 367

Other intestinal disorders

Acute mesenteric Critical blockage of intestinal blood flow (often embolic occlusion of SMA) -* small bowel necrosis
ischemia -* abdominal pain out of proportion to physical findings. May see red ‘currant jelly” stools.
Chronic mesenteric “Intestinal angina”: atherosclerosis of celiac artery, SMA, or IMA -* intestinal hypoperfusion
ischemia
Colonic ischemia
— —
postprandial epigastric pain food aversion and weight loss.
Reduction in intestinal blood flow causes ischemia. Crampv abdominal pain followed by
hematochezia. Commonly occurs at watershed areas (splenic flexure, distal colon). Typically
affects elderly.
Angiodysplasia Tortuous dilation of vessels -*• hematochezia. Most often found in the right- sided colori More
common in older patients. Confirmed by angiography.
Adhesion Fibrous band of scar tissue; commonly forms after surgery; most common cause of small bowel
obstruction. Can have well-demarcated necrotic zones.
Ileus Intestinal hypomotilitv without obstruction -* constipation and 1 flatus; distended/tympanic
abdomen with 1 bowel sounds. Associated with abdominal surgeries, opiates, hypokalemia, sepsis.
Treatment: bowel rest, electrolyte correction, cholinergic drugs (stimulate intestinal motility).
Meconium ileus In cystic fibrosis, meconium plug obstructs intestine, preventing stool passage at birth.
Necrotizing Seen in premature, formula-fed infants with immature immune system. Necrosis of intestinal
enterocolitis mucosa ( primarily colonic) with possible perforation, which can lead to pneumatosis intestinalis,
free air in abdomen, portal venous gas.
368 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Colonic polyps Growths of tissue within the colon Q. May be neoplastic or non-neoplastic. Grossly characterized
as flat, sessile, or pedunculated (on a stalk) on the basis of protrusion into colonic lumen.
Generally classified by histologic type.
HISTOLOGIC TYPE CHARACTERISTICS
Generally non-neoplastic
Hamartomatous Solitary lesions do not have significant risk of transformation. Growths of normal colonic tissue
with distorted architecture. Associated with Peutz- Jeghers syndrome and juvenile polyposis.
Small, usually < 5 mm. Look similar to normal mucosa. Clinically insignificant
Mucosa)
Inflammatory
^
Result of mucosal erosion in inflammatory bowel disease. When in clusters may be associated with
pseudopolypst dysplasia]
Submucosal May include lesions such as lipomas, leiomyomas, fibromas, and others.
Hyperplastic Generally smaller and predominantly located in the rectosigmoid region. May occasionally evolve
into serrated polyps and more advanced lesions.
Malignant potential
Adenomatous Neoplastic, via chromosomal instability pathway with mutations in APC and KRAS . Tubular |
histology has less malignant potential than villous H; tubulovillous has intermediate malignant
potential. Usually asymptomatic; may present with occult bleeding.
Serratedl Premalignant, via CpG hypermethylation phenoty pe pathway with microsatellite instability and
mutations in BRAF. “ Saw-tooth ” pattern of crypts on biopsy. Up to 20% of cases of sporadic CRC J

nm.
"
A
Polyp *
-

Essa
a

Polyposis syndromes
Familial adenomatous Autosomal dominant mutation of APC tumor suppressor gene on chromosome 5q. 2-hit hypothesis.
polyposis Thousands of polyps arise starting after puberty; pancolonic; always involves rectum. Prophylactic
colectomy or else 100% progress to CRC.
Gardner syndrome FAP + osseous and soft tissue tumors, congenital hypertrophy of retinal pigment epithelium,
impacted/supernumerary teeth.
Turcot syndrome FAP + malignant CNS tumor (eg, medulloblastoma, gliomaj Turcot = Turban .
Peutz-Jeghers Autosomal dominant syndrome featuring numerous hamartomas throughout GI tract, along with
syndrome hyperpigmented mouth, lips, hands, genitalia. Associated with t risk of breast and GI cancers (eg,
colorectal, stomach, small bowel, pancreatic).
Juvenile polyposis Autosomal dominant syndrome in children (typically < 5 years old) featuring numerous
syndrome hamartomatous polyps in the colon, stomach, small bowel. Associated with t risk of CRC.
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 369

Lynch syndrome Previously known as hereditary nonpolyposis colorectal cancer (HNPCC). Autosomal dominant
mutation of DNA mismatch repair genes with subsequent microsatellite instability. ~ 80%
progress to CRC. Proximal colon is always involved. Associated with endometrial, ovarian, and
skin cancers.

Colorectal cancer
EPIDEMIOLOGY Most patients are > 50 years old. ~ 25% have a
family history.
RISK FACTORS Adenomatous and serrated polyps, familial
cancer syndromes, 1BD, tobacco use, diet of
processed meat with low fiber.
PRESENTATION Rectosigmoid > ascending > descending. Right side bleeds; left side obstructs.
Ascending — exophytic mass, iron deficiency
anemia, weight loss.
Descending— infiltrating mass, partial
obstruction, colicky pain, hematochezia.
Rarely, presents with S( bovis ( gallolvticus )
bacteremia.
DIAGNOSIS Iron deficiency anemia in males (especially > 50
years old) and postmenopausal females raises
suspicion.
Screen patients > 50 years old with
colonoscopy Q, flexible sigmoidoscopy, fecal
occult blood test, or fecal DNA test.
“Apple core” lesion seen on barium enema
x-ray Q.
CEA tumor marker: good for monitoring
recurrence, should not be used for screening.

Molecular Chromosomal instability pathway: mutations in APC cause FAP and most sporadic CRC (via
pathogenesis of adenoma-carcinoma sequence; (firing) order of events is AK-53).
colorectal cancer Microsatellite instability pathway: mutations or methylation of mismatch repair genes (eg, MLH 1 )
cause Lynch syndrome and some sporadic CRC (via serrated polyp pathway). Overexpression of
CQX-2 has been linked to colorectal cancer, NSAIDs may be chemopreventive.
Chromosomal instability pathway
Loss of tumor suppressor
Loss of APC gene KRAS mutation gene( s) (p53, DCC)
Normal colon Colon at risk Adenoma Carcinoma

-J. intercellular adhesion

t proliferation
Unregulated
intracellular
signaling
fffi '
T tumorigenesis
9
••
!
41
&
0
370 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Cirrhosis and portal hypertension

Cirrhosis — diffuse bridging fibrosis (via stellate cells) and regenerative nodules (red arrows in EJ;
whitqarrow shows splenomegaly) disrupt normal architecture of liver; t risk for hepatocellular
carcinoma (HCC ). Etiologies include alcohol (60-70% of cases in the US), nonalcoholic
steatohepatitis, chronic viral hepatitis, autoimmune hepatitis, biliary disease, genetic/metabolic
disorders.
Portal hypertension — t pressure in portal venous system. Etiologies include cirrhosis (most
common cause in Western countries), vascular obstruction (eg, portal vein thrombosis, Budd-
Chiari syndrome), schistosomiasis.

Es .
(- hematemesis)
Gastric varices Hematologic
(-* melena)
Thrombocytopenia
Anemia
Coagulation disorders

Metabolic
Hyperbilirubinemia
Hyponatremia
Gynecomastia
Amenorrhea
Cardiovascular
Cardiomyopathy
- Peripheral edema

Primary / spontaneous Idiopathic infection of ascites fluid. Often asymptomatic, but can cause fevers, chills, abdominal
bacterial peritonitis pain, ileus, or worsening encephalopathy. Most common pathogens are gram negatives, especially
E coli .
Diagnosis: Paracentesis with absolute neutrophil count ( ANC ) > 250 cells/mm —
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 371

Serum markers of liver pathology

ENZYMES RELEASED IN LIVER DAMAGE

Aspartate t in most liver disease: ALT > AST

aminotransferase t in alcoholic liver disease: AST > ALT
and alanine AST > ALT in nonalcoholic liver disease suggests progression to advanced fibrosis or cirrhosis
aminotransferase
Alkaline phosphatase t in cholestasis (eg, biliary obstruction), infiltrative disorders, bone disease
y- glutamyl t in various liver and biliary diseases ( just as ALP can), but not in bone disease; associated with
transpeptidase alcohol use
FUNCTIONAL LIVER MARKERS
Bilirubin t in various liver diseases (eg, biliary obstruction, alcoholic or viral hepatitis, cirrhosis), hemolysis
Albumin 1 in advanced liver disease, marker of livers synthetic function
Prothrombin t in advanced liver disease (i production of clotting factors, thereby measuring the livers synthetic
function)
Platelets 1 in advanced liver disease (1 thrombopoietin, liver sequestration) and portal hypertension
(splenomegaly/splenic sequestration)

Reye syndrome Rare, often fatal childhood hepatic encephalopathy. Findings: mitochondrial abnormalities, fatty-
liver (microvesicular fatty change), hypoglycemia, vomiting, hepatomegaly, coma. Associated with
viral infection (especially VZV and influenza B) that has been treated with aspirin. Mechanism:
aspirin metabolites 1 P-oxidation by reversible inhibition of mitochondrial enzymes. Avoid aspirin
in children, except in those with Kawasaki disease.
372 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Alcoholic liver disease

Hepatic steatosis Macrovesicular fatty change that may be
reversible with alcohol cessation.
Alcoholic hepatitis Requires sustained, long-term consumption. Make a toAST with alcohol:
Swollen and necrotic hepatocytes with AST > ALT (ratio usually > 2:1).
neutrophilic infiltration. Mallory bodies Q
(intracytoplasmic eosinophilic inclusions of
damaged keratin filaments).
Alcoholic cirrhosis Final and irreversible form. Micronodular,
irregularly shrunken liver with “ hobnail”
appearance. Sclerosis (arrows in Q) around
central vein (zone III). Manifestations
of chronic liver disease (eg, jaundice,
hypoalbuminemia).

gg-
t * \ *
-I aim
.w

si
m m1
gP &ai|
SB

*
K :
¥ . m -
.
m
M
i
’ i
X ..

t i m .

Nonalcoholic fatty Metabolic syndrome (insulin resistance); ALT > AST (Lipids)
liver disease
—
obesity fatty infiltration of hepatocytes
-* cellular “ ballooning” and eventual necrosis.
• .V.
••
May cause cirrhosis and HCC. Independent of
alcohol use.

7 7 -:

Hepatic
encephalopathy
Cirrhosis
— — —
portosystemic shunts I Nfty metabolism neuropsychiatric dysfunction,
Reversible neuropsychiatric dysfunction ranging from disorientation /asterixis (mild ) to difficult
arousal or coma (severe!Triggers:
t Nfty production and absorption (due to dietary protein, GI bleed, constipation, infection).
-
i NH removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS).
Treatment: lactulose ( t NPty+ generation) and rifaximin or neomycin (1 NH producing gut
bacteria). ^
372 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Alcoholic liver disease

Hepatic steatosis Macrovesicular fatty change that may be
reversible with alcohol cessation.
Alcoholic hepatitis Requires sustained, long-term consumption. Make a toAST with alcohol:
Swollen and necrotic hepatocytes with AST > ALT (ratio usually > 2:1).
neutrophilic infiltration. Mallory bodies Q
(intracytoplasmic eosinophilic inclusions of
damaged keratin filaments).
Alcoholic cirrhosis Final and irreversible form. Micronodular,
irregularly shrunken liver with “ hobnail”
appearance. Sclerosis (arrows in Q) around
central vein (zone III). Manifestations
of chronic liver disease (eg, jaundice,
hypoalbuminemia).

gg-
t * \ *
-I aim
.w

si
m m1
gP &ai|
SB

*
K :
¥ . m -
.
m
M
i
’ i
X ..

t i m .

Nonalcoholic fatty Metabolic syndrome (insulin resistance); ALT > AST (Lipids)
liver disease
—
obesity fatty infiltration of hepatocytes
-* cellular “ ballooning” and eventual necrosis.
• .V.
••
May cause cirrhosis and HCC. Independent of
alcohol use.

7 7 -:

Hepatic
encephalopathy
Cirrhosis
— — —
portosystemic shunts I Nfty metabolism neuropsychiatric dysfunction,
Reversible neuropsychiatric dysfunction ranging from disorientation /asterixis (mild ) to difficult
arousal or coma (severe!Triggers:
t Nfty production and absorption (due to dietary protein, GI bleed, constipation, infection).
-
i NH removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS).
Treatment: lactulose ( t NPty+ generation) and rifaximin or neomycin (1 NH producing gut
bacteria). ^
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 373

Hepatocellular Most common 1° malignant tumor of liver B

carcinoma / hepatoma in adults Q. Associated with HBV (+/ —
cirrhosis) and all other causes of cirrhosis

Ev * :I'#'
(including HCV, alcoholic and nonalcoholic
fatty liver disease, autoimmune disease,
hemochromatosis, (Xj-antitrypsin deficiency)
and specific carcinogens (eg, aflatoxin
v
from Aspergillus ). May lead to Budd-Chiari
syndrome. *
Findings: jaundice, tender hepatomegaly,
ascites, polycythemia, anorexia . Spreads
hematogenously.
Diagnosis: t a-fetoprotein ; ultrasound or
contrast CT/MRI Q, biopsy.

Other liver tumors

Cavernous Common , benign liver tumor Q; typically occurs at age 30-50 years. Biopsy contraindicated
hemangioma because of risk of hemorrhage.

4
7. -y:
A
V
m mi

Hepatic adenoma Rare, benign liver tumor, often related to oral contraceptive or anabolic steroid use; may regress
spontaneously or rupture (abdominal pain and shock).
Angiosarcoma Malignant tumor of endothelial origin; associated with exposure to arsenic, vinyl chloride.
Metastases GI malignancies, breast and lung cancer. Most common overall ; metastases rarely solitanj

Budd -Chiari syndrome Thrombosis or compression of hepatic veins with centrilobular congestion and necrosis
-*• congestive liver disease ( hepatomegaly, ascites, varices, abdominal pain , liver failure). Absence
of JVD. Associated with hypercoagulable states, polycythemia vera , postpartum state, HCC. May
cause nutmeg liver ( mottled appearance).

-antitrypsin
^deficiency
—
Misfolded gene product protein aggregates in
hepatocellular ER cirrhosis with in alveoli
— •

—
In lungs, 1 (X|-antitrypsin -* uninhibited elastase
I elastic tissue panacinar

!m v
PAS © globules in liver. Codominant trait . emphysema .
374 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Jaundice Abnormal yellowing of the skin and/ HOT Liver — Common causes of increased
or sclera Q due to bilirubin deposition. levels of bilirubin.
Hyperbilirubinemia 2° to t production or Hemolysis
1 disposition ( impaired hepatic uptake, Obstruction
conjugation, excretion). Tumor
Liver disease

Unconjugated Hemolytic, physiologic (newborns), Crigler-Najjar, Gilbert syndrome.

(indirect )
hyperbilirubinemia
Conjugated (direct) Biliary tract obstruction: gallstones, cholangiocarcinoma, pancreatic or liver cancer, liver fluke.
hyperbilirubinemia Biliary tract disease:
1° sclerosing cholangitis
1° biliary cholangitij
.
Excretion defect: Dubin-Johnson syndrome Rotor syndrome .
Mixed (direct Hepatitis, cirrhosis.
and indirect)
hyperbilirubinemia

Physiologic
neonatal jaundice
At birth, immature UDP-glucuronosyltransferase -* unconjugated hyperbilirubinemia
— jaundice/
kernicterus ( deposition of unconjugated, lipid-soluble bilirubin in the brairj particularly basal
ganglia).
Occurs after first 24 hours of life and usually resolves without treatment in 1-2 weeks.
Treatment: phototherapy (non-UV) isomerizes unconjugated bilirubin to water-soluble form.
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 375

Hereditary All autosomal recessive.

hyperbilirubinemias

O Gilbert syndrome Mildly 1 UDP-glucuronosyltransferase Relatively common, benign condition!

conjugation and impaired bilirubin uptake.
Asymptomatic or mild jaundice usually with
stress, illness, or fasting t unconjugated
bilirubin without overt hemolysis. Bilirubin
t jLv ith fasting and stress.

© Crigler- Najjar Absent UDP-glucuronosyltransferase. Presents Type II is less severe and responds to
syndrome, type I early in life; patients die within a few years. phenobarbital, which t liver enzyme synthesis.
Findings: jaundice, kernicterus (bilirubin
deposition in brain), t unconjugated bilirubin.
Treatment: plasmapheresis and phototherapy.

© Dubin-Johnson Conjugated hyperbilirubinemia due to defective Q Rotor syndrome is similar, but milder in
syndrome liver excretion. Grossly black liver. Benign. presentation without black liver. Due to
impaired hepatic uptake and excretion.

HEPATIC SINUSOID
Circulating bilirubin Hemoglobin
( albumin bound, unconjugated, water insoluble)
Kupffer cell
(macrophage)

A
Endothelial celt

Space of Disse
Hepatocyte BILIRUBIN
V
. UPTAKE
Unconjugated bilirubin

f
I2 o CONJUGATION
0
Conjugated bilirubin
.
(bilirubin diglucuronide water soluble)

© INTRACELLULAR
Q TRANSPORT

Bile -\ Sfas/ s
Obstructive jaundice
canaliculus Bite low ( downstream)
lumen
Hepatocyte
0
376 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Wilson disease Autosomal recessive!mutations in hepatocyte copper-transporting ATPase ( ATP7 B gene;

( hepatolenticular
degeneration )
—
chromosome 13) 1 copper excretion into bile and incorporation into apoceruloplasmin
(I serum ceruloplasmin). Copper accumulates, especially in liver, brain, cornea, kidneys; t urine
copped

©
Presents before age 40 with liver disease (eg, hepatitis, acute liver failure, cirrhosis), neurologic
disease (eg, dysarthria, dystonia, tremor, parkinsonism), psychiatric disease, Kayser-Fleischer rings
(deposits in Descemet membrane of cornea) Q, hemolytic anemia, renal disease (eg, Fanconi
syndrome).
Treatment: chelation with penicillamine or trientine, oral zinc.

Hemochromatosis Recessive mutations in HFE gene (C282Y > H63P, chromosome 6, associated with HLA-A j)
-*• abnormal iron sensing and t intestinal absorption ( t ferritin, t iron, 1 TIBC -*• t transferrin
saturation). Iron overload can also be 2° to chronic transfusion therapy (eg, (3-thalassemia major).
Iron accumulates, especially in liver, pancreas, skin, heart, pituitary, joints. Hemosiderin (iron)
can be identified on liver MRI or biopsy with Prussian blue stain Q.
Presents after age 40 when total bod}' iron > 20 g; iron loss through menstruation slows progression
in women. Classic triad of cirrhosis, diabetes mellitus, skin pigmentation (“ bronze diabetes” ). Also
causes restrictive cardiomyopathy ( classic ) or dilated cardiomyopathy ( reversibid), hypogonadism,
arthropathy (calcium pyrophosphate deposition; especially metacarpophalangeal joints). HCC is
common cause of death.
Treatment: repeated phlebotomy, chelation with deferasirox, deferoxamine, oral deferiprone.

Biliary tract disease May present with pruritus, jaundice, dark urine, light-colored stool, hepatosplenomegaly. Typically
with cholestatic pattern of LFTs ( t conjugated bilirubin, t cholesterol, t ALP).
PATHOLOGY EPIDEMIOLOGY ADDITIONAL FEATURES
Primary sclerosing Unknown cause of concentric Classically in middle-aged men Associated with ulcerative
cholangitis “ onion skin” bile duct with IBD. colitis. p-ANCA ©. t IgM.
fibrosis - alternating Can lead to 2° biliary
strictures and dilation with cholangitii t risk of
“ beading” of intra- and cholangiocarcinoma and
extrahepatic bile ducts on gallbladder cancer.
ERCP, magnetic resonance
cholangiopancreatography
(MRCP).
Primary biliary Autoimmune reaction Classically in middle-aged Anti-mitochondrial antibody ©,
cholanqitisi -*• lymphocytic infiltrate women. t IgM. Associated with other
+ granulomas -*• destruction autoimmune conditions
of intralobular bile ducts. (eg, Sjogren syndrome,
Hashimoto thyroiditis,
CREST, rheumatoid arthritis,
celiac disease).
Secondary biliary Extrahepatic biliary obstruction Patients with known May be complicated by
cholanaitisi -*• t pressure in intrahepatic obstructive lesions ( gallstones, ascending cholangitis.
ducts -*• injury/ fibrosis and biliary strictures, pancreatic
bile stasis. carcinoma).
 GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY SECTION III 377

Gallstones t cholesterol and/or bilirubin, 1 bile salts, and Risk factors (4 F s):
( cholelithiasis) gallbladder stasis all cause stone% 1. Female
2 types of stones: 2. Fat
Cholesterol stones (radiolucent with 10-20% 3. Fertile ( pregnant)
opaque due to calcifications) — 80% of stones. 4. Forty
Associated with obesity, Crohn disease, Diagnose with ultrasound . Treat with elective
advanced age, estrogen therapy, multiparity, cholecystectomy if symptomatic!
rapid weight loss, Native American origin. pan cause fistula between gallbladder and

—— —
2
” Pigment stonesJQ (black = radiopaque, Ca + Gjtract air in biliary tree (pneumobilia)
bilirubinate, hemolysis; brown = radiolucent, passage of gallstones into intestinal tract
infection). Associated!with Crohn disease, obstruction of ileocecal valve (gallstone
chronic hemolysis, alcoholic cirrhosis, ileus). _
advanced age, biliary infections, total
_
parenteral nutrition ( TPN).
Most common complication is cholecystitis;
also, acute pancreatitis, ascending cholangitis]

RELATED PATHOLOGIES CHARACTERISTICS

Biliary colic Uncomplicated disease associated with nausea /vomiting and dull right upper quadrant ( RUQ) pain.
Neurohormonal activation (eg, by CCK after a fatty meal ) triggers contraction of gallbladder,
forcing stone into cystic duct. Labs are normal, ultrasound shows cholelithiasis.
Choledocholithiasis Presence of gallstone(s) in common bile duct, often leading to elevated ALP, GGT, direct bilirubin,
and/or AST/ALT.
Cholecystitis Acute or chronic inflammation of gallbladder usually from cholelithiasis (stone at neck of
gallbladder [red arrow in HI with gallbladder wall thickening [ yellow arrows!). Gallstones most

—
commonly blocking the cystic duct • 2° infection; less commonly from acalculous due to
ischemia and stasis, or infection (eg, CMV ). Murphv sign: inspiratory arrest on RUQ palpation
due to pain. ALP if bile duct becomes involved (eg, ascending cholangitis).
Diagnose with ultrasound or cholescintigraphv ( HIDA scan ).
v
9 '
Porcelain gallbladder Calcified gallbladder due to chronic cholecystitis; usually found incidentally on imaging [»].
Treatment: prophylactic cholecystectomy due to high rates of gallbladder cancer (mostly

tJ
adenocarcinoma).

Ascending cholangitis Infection of biliary tree usually due to obstruction that leads to stasis/bacterial overgrowth.
Charcot triad of cholangitis:
Jaundice
Fever
RUQ pain
Reynolds pentad adds:
Altered mental status
a
Shock
378 SECTION III GASTROINTESTINAL GASTROINTESTINAL — PATHOLOGY

Acute pancreatitis Autodigestion of pancreas by pancreatic enzymes (Q shows pancreas [ yellow arrows] surrounded by
n edema [red arrows]).
Causes: Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune disease,
Scorpion sting, Hypercalcemia /Hypertriglyceridemia (> 1000 mg/dL), ERCP, Drugs (eg, sulfa
drugs, NRTIs, protease inhibitors).I GET SMASHED.
Diagnosis by 2 of > criteria: acute epigastric pain often radiating to the back, t serum amylase or
v
'Art lipase (more specific) to 3x upper limit of normal, or characteristic imaging findings.
Complications: pseudocyst Q (lined by granulation tissue, not epithelium), necrosis, hemorrhage,
infection, organ failure (ARDS, shock, renal failure), hypocalcemia (precipitation of Ca 2+ soaps).

Chronic pancreatitis Chronic inflammation, atrophy, calcification of the pancreas Q. Major causes are alcohol abuse
and idiopathic. Complications include pancreatic insufficiency ( also a problem in cystic fibrosis)
and pseudocystfr
Pancreatic insufficiency may manifest with steatorrheaL fat-soluble vitamin deficiency, diabetes
mellitus.
Amylase and lipase may or may not be elevated (almost always elevated in acute pancreatitis).
rr,

Pancreatic Very aggressive tumor arising from pancreatic ducts (disorganized glandular structure with cellular
adenocarcinoma infiltration Q); often metastatic at presentation, with average survival ~ 1 year after diagnosis.
Tumors more common in pancreatic head Q (-* obstructive jaundice). Associated with CA 19-9

>•
V V;/
.' r r V'
..‘.fW.
‘
*
tumor marker (also CEA, less specific).
Risk factors:
a Tobacco use
'
Chronic pancreatitis (especially > 20 years)
Diabetes
Age > 50 years
Jewish and African-American males
Often presents with:
Abdominal pain radiating to back
7 8
Weight loss (due to malabsorption and anorexia)
Migratory thrombophlebitis — redness and tenderness on palpation of extremities (Trousseau
syndrome)
m * Obstructive jaundice with palpable, nontender gallbladder (Courvoisier sign)
Treatment: Whipple procedure, chemotherapy, radiation therapy.
 GASTROINTESTINAL GASTROINTESTINAL — PHARMACOLOGY SECTION III 379

GASTROINTESTINAL — PHARMACOLOGY
Acid suppression therapy

jRP

Vagus nerve
G cells rQy+ ECL cells

A h H stam ne Somatostatin Prostaglandins

Atropine -0 — | l1 —0 “ H 2 blockers
?
M
V
, receptor
LCK
ptor
H , receptor
f

_ s, .
_AT
Q

'
HCOj (
alkaline tide"- T blood pH
" TT NpY HCO, t H*
"
Ct cAMP : -- & -
after gastric acid secretion
(eg , after meals, vomiting ) m Gastric
parietal
|Carbonic anhydrase I cell
Cq+ H,
ATPase

— ——
Proton pump inhibitors © |
e Lumen
Misoprostol
Antacids ©J j [ ]*
•

^
|* Sucralfate,
bismuth

H2 blockers Cimetidine, ranitidine, famotidine, nizatidine. Take H ? blockers before you dine. Think “ table

MECHANISM

CLINICAL USE

ADVERSE EFFECTS
Peptic ulcer, gastritis, mild esophageal reflux. —
Reversible block of histamine H 7-receptors i H+ secretion by parietal cells.
for 2” to remember H7.

Cimetidine is a potent inhibitor of cytochrome P-450 ( multiple drug interactions); it also has
antiandrogenic effects ( prolactin release, gynecomastia , impotence, 1 libido in males); can
cross blood-brain barrier (confusion , dizziness, headaches) and placenta . Both cimetidine and
ranitidine 1 renal excretion of creatinine . Other H7 blockers are relatively free of these effects.

Proton pump inhibitors Omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole .

MECHANISM Irreversibly inhibit H+/K+ ATPase in stomach parietal cells.
CLINICAL USE Peptic ulcer, gastritis, esophageal reflux, Zollinger-Ellison syndrome, component of triple therapy
for H pylori, stress ulcer prophylaxis
ADVERSE EFFECTS t risk of C difficile infection, pneumonia i serum Mg“ + with long-term use.
,
 GASTROINTESTINAL GASTROINTESTINAL — PHARMACOLOGY SECTION III 381

Loperamide
MECHANISM Agonist at p- opioid receptors; slows gut motility. Poor CNS penetration ( low addictive potential).
CLINICAL USE Diarrhea.
ADVERSE EFFECTS Constipation, nausea.

Ondansetron
MECHANISM 5-HT antagonist; 1 vagal stimulation. Powerful central-acting antiemetic.
^
CLINICAL USE Control vomiting postoperatively and in patients
undergoing cancer chemotherapy.
ADVERSE EFFECTS Headache, constipation, QT interval prolongation, serotonin syndrome
^
Metoclopramide
MECHANISM D,- receptor antagonist, t resting tone, contractility. LES tone, motility, promotes gastric emptying
Does not influence colon transport time.
CLINICAL USE Diabetic and postsurgerv gastroparesis, antiemetic, persistent GERDi
ADVERSE EFFECTS t parkinsonian effects, tardive dyskinesia. Restlessness, drowsiness, fatigue, depression, diarrhea.
Drug interaction with digoxin and diabetic agents. Contraindicated in patients with small bowel
obstruction or Parkinson disease (due to D? -receptor blockade).

Orlistat
MECHANISM

CLINICAL USE
Inhibits gastric and pancreatic lipase
Weight loss.
— 1 breakdown and absorption of dietary fats.

ADVERSE EFFECTS Steatorrhea, 1 absorption of fat-soluble vitamins.

Laxatives Indicated for constipation or patients on opiates requiring a bowel regimen.

TYPE MECHANISM ADVERSE EFFECTS

Bulk-forminq Draws water into gut lumen, bulk forming Bloating

(eq, psyllium,
methylcellulose)
Stimulant (eq, senna)
Emollients (eq,
Enteric nerve stimulation
Osmotic draw into lumen
— colonic contraction Diarrhea, melanosis coli
Diarrhea
docusate)

Aprepitant

I Fact MECHAN ) SM Substance P antagonist. Blocks NKi receptors in brain.

CLINICAL USE Antiemetic for chemotherapy-induced nausea and vomiting.

i
HIGH- YIELD SYSTEMS

Hematology
and Oncology

“ Of all that is written , I love only what a person has written with his own Anatomy 384
blood .”
— Friedrich Nietzsche Physiology 387

“ I used to get stressed out , but my cancer has put everything into Pathology 392
perspective."
— Delta Goodrem Pharmacology 411

“ The best blood will at some time get into a fool or a mosquito.”
— Austin O’Malley

“ Carcinoma works cunningly from the inside out. Detection and

treatment often work more slowly and gropingly , from the outside in.”
— Christopher Hitchens

Study tip: When reviewing oncologic drugs, focus on mechanisms and

side effects rather than details of clinical uses, which may be lower yield.

383
384 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — ANATOMY

HEMATOLOGY AND ONCOLOGY — ANATOMY

Erythrocyte Carries 0? to tissues and C02 to lungs.
Anucleate and lacks organelles; biconcave Q,
with large surface area-to-volume ratio for
rapid gas exchange. Life span of 120 days.
Source of energy is glucose (90% used
in glycolysis, 10% used in HMP shunt).
Membrane contains Cl-/HC(X - antiporter,
which allows RBCs to export HC05 and "
transport CO? from the periphery to the lungs
for elimination.
Eryth = red; cyte = cell.
Erythrocytosis = polycythemia = t hematocrit.
Anisocytosis = varying sizes.
Poikilocytosis = varying shapes.
Reticulocyte = immature RBC; reflects
erythroid proliferation.
Bluish color on Wright-Giemsa stain of
reticulocytes represents residual ribosomal
RNA.

Thrombocyte Involved in 1° hemostasis. Small cytoplasmic Thrombocytopenia or i platelet function results

( platelet ) fragment Q derived from megakaryocytes. in petechiae.
Life span of 8-10 days. When activated by vWF receptor: Gplb.
endothelial injury, aggregates with other Fibrinogen receptor: GpIIb/IIIa.
platelets and interacts with fibrinogen to
form platelet plug. Contains dense granules
(ADP, Ca~+) and a granules (vWF, fibrinogen,
fibronectin). Approximately XA of platelet pool
is stored in the spleen .

Leukocyte Divided into granulocytes (neutrophil, Leuk = white; cyte = cell,

eosinophil, basophil, mast celt) and
mononuclear cells (monocytes, lymphocytes).
WBC differential count froirjl highest to lowest
(normal ranges per USMLE):
Neutrophils (~ 60% j Neutrophils Like Making Everything Better.
Lymphocytes (~ 30% j
Monocytes (~ 6%fe
Eosinophils (~
Basophils (~ YXj)

Neutrophil Acute inflammatory response cell. Increased in Hypersegmented neutrophils (nucleus has 6+
bacterial infections. Phagocytic. Multilobed lobes) are seen in vitamin BJ2/ folate deficiency,
L5
nucleus Q. Specific granules contain leukocyte t band cells (immature neutrophils) reflect states
alkaline phosphatase (LAP), collagenase, of t myeloid proliferation ( bacterial infections,
lysozyme, and lactoferrin. Azurophilic CML)
granules (lysosomes) contain proteinases, Important neutrophil chemotactic agents: C 5 a,
acid phosphatase, myeloperoxidase, and IL- 8, LTB , kallikrein, platelet-activating
P-glucuronidase. factor. ^
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — ANATOMY SECTION III 385

Monocyte Differentiates into macrophage in tissues. Mono = one (nucleus); cyte = cell .
Large, kidney-shaped nucleus Q. Extensive Monocyte: in the blood .

WJocFb “ frosted glass” cytoplasm.

Macrophage Phagocytoses bacteria , cellular debris, and Macro = large; phage = eater.
senescent RBCs. Long life in tissues. Macrophage: in the tissue. Name differs in

Hi
Macrophages differentiate from circulating each tissue tvpe ( eg, Kupffer cell in the liver,
blood monocytes Q. Activated by y-interferon. histiocytes in connective tissue).
ISwappedl
Can function as antigen-presenting cell via Important component of granuloma formation
| Image |
MHC II. ( eg, TB, sarcoidosis).
Lipid A from bacterial LPS binds CD14 on
macrophages to initiate septic shock .

Eosinophil Defends against helminthic infections (major Eosin = pink dye; philic = loving.
basic protein ). Bilobate nucleus. Packed Causes of eosinophilia = NAACP:
Q
r
• with large eosinophilic granules of uniform Neoplasia
A ^ size Q. Highly phagocytic for antigen- Asthma
antibody complexes. Allergic processes
V# %/ Produces histaminase, major basic protein
( MBP, a helminthotoxin ), eosinophil
Chronic adrenal insufficiency
Parasites ( invasive)
A
* w
peroxidase, eosinophil cationic protein , and
eosinophil -derived neurotoxiri

Basophil Mediates allergic reaction . Densely basophilic

granules Q contain heparin (anticoagulant )
—
Basophilic staining readily with basic stains.
Basophilia is uncommon, but can be a sign of
and histamine (vasodilator). Leukotrienes myeloproliferative disease, particularly CML .
synthesized and released on demand .

Mast cell Mediates allergic reaction in local tissues. Involved in type I hypersensitivity reactions.
Mast cells contain basophilic granules Q and Cromolyn sodium prevents mast cell
originate from the same precursor as basophils degranulation (used for asthma prophylaxis),

> but are not the same cell type. Can bind the

—
Fc portion of IgE to membrane . IgE cross¬
links upon antigen binding degranulation
-*• release of histamine , heparin , trvptase, and
eosinophil chemotactic factors.
A
386 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — ANATOMY

Dendritic cell Highly phagocytic APC Q. Functions as link between innate and adaptive immune systems.
Expresses MHC class II and Fc receptors on surface. Called Langerhans cell in the skin.

4 &

Lymphocyte Refers to B cells, T cells, and NK cells. B cells and T cells mediate adaptive immunity. NK cells are

90 'p«
part of the innate immune response. Round, densely staining nucleus with small amount of pale
cytoplasm Q.
Om

OaA £
Bcell Part of humoral immune response. Originates B = Bone marrow,
CD20 CD21 from stem cells in bone marrow and matures in
CD19 marrow. Migrates to peripheral lymphoid tissue

...
'- ' LI
(follicles of lymph nodes, white pulp of spleen,
unencapsulated lymphoid tissue). When antigen
is encountered, B cells differentiate into plasma
cells (which produce antibodies) and memory
cells. Can function as an APC via MHC II.

T cell Mediates cellular immune response. Originates T is for Thymus.

from stem cells in the bone marrow, but CD4+ helper T cells are the primary target of
“ \ matures in the thymus. T cells differentiate HIV.

4 4
into cytotoxic T cells (express CD8, recognize MHC x CD = 8 (eg, MHC 2 x CD4 = 8, and
MHC I), helper T cells (express CD4, MHC 1 x CD8 = 8).
recognize MHC II), and regulatory T cells.
CD28 (costimulatory signal) necessary for
T-cell activation. The majority of circulating
lymphocytes are T cells (80%).
388 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY

Blood groups

ABO classification Rh classification

A B AB 0 Rh© Rh©
RBC type

lift & (©) m

Group antigens on
RBC surface A B A&B Rh (D)
NONE NONE
0
Antibodies in plasma Anti- B Anti- A Anti- A Anti-B Anti- D

JOCC AX*
YV
IgM
-fv
IgM
NOBE

IgM
yXc NONE
Y IgG

Clinical relevance Receive B or AB Receive A or AB Universal recipient Receive any non-0 Universal recipient Treat mother with
- hemolytic - hemolytic of RBCs; universal - hemolytic of RBCs anti-D Ig (RhoGAM)
reaction reaction donor of plasma reaction during and after each
Universal donor pregnancy to prevent
of RBCs; universal anti-D IgG formation
recipient of plasma

Rh hemolytic disease IgM does not cross placenta; IgG does cross placenta.
of the newborn Rh © mothers exposed to fetal Rh© blood (often during delivery) may make anti-D IgG. In
subsequent pregnancies, anti-D IgG crosses the placenta -*• hemolytic disease of the newborn
(erythroblastosis fetalis) in the next fetus that is Rh©. Administration of anti-D IgG ( RhoGAM)
to Rh© pregnant women during third trimester and early postpartum period!prevents maternal
anti-D IgG production.
Rh © mothers have anti-D IgG only if previously exposed to Rh © blood.

ABO hemolytic disease Most common form. Usually occurs in a type O mother with a type A, B, or AB fetus. Can occur in
of the newborn a first pregnancy as maternal anti-A and/or anti-B IgG antibodies are formed early in life. Does not
worsen with future pregnancies. Presents as mild jaundice in the neonate within 24 hours of birth;
treatment is phototherapy or exchange transfusion.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY SECTION III 389

Hemoglobin electrophoresis
On a gel, hemoglobin migrates from the
Origin
negatively charged cathode to the positively
AA -^ Normal adult
; charged anode. HbA migrates the farthest,
1 T AF — ^Normal newborn followed by HbF, HbS, and IIbfl This is
i ; because the missense mutations in HbS and
I AS — » Sickle cell trait
X HbC replace glutamic acid © with valine
SS -» Sickle cell disease (neutral) and lysine ©, respectively, impacting
i i
the net protein charge.
X AC — >Hb C trait

—
CC »Hb C disease

; xx SC — >Hb SC disease
c s F A
© ©
Cathode A: normal hemoglobin (5 chain (HbA, adult) Anode
F: normal hemoglobin y chain (HbF, fetal) A Fat Santa Claus
S: sickle cell hemoglobin p chain (HbS)
C hemoglobin C p chain (HbC) B

Coagulation and kinin pathways

Collagen, • HMWK
basement membrane, y'
activated platelets
Kallikrein -- T Vasodilation

Contact
Bradykinin •$; - t Permeability
activation
(intrinsic) XII — li XIla
Kinin cascade Pain
pathway XI - *- Xla

IX
i

jVHIa
VIII
Ticcu» firtnr
Tissue factor
(extrinsic)
V|, Tissue factor
Vila
with vWF) ANTICOAGULANTS: lla ( thrombin)
- heparin (greatest efficacy)
- LMWH (dalteparin, enoxaparin)
pathway
- direct thrombin inhibitors (argatroban,
bivalirudin, dabigatran)
ANTICOAGULANTS: factor Xa
- LMWH (greatest efficacy)
- heparin Prothrombin Thrombin
Plasminogen
- direct Xa inhibitors (apixaban, rivaroxaban) .
,THROMBOLYTICS:
- fondaparinux
m is tPA
X alteplase, reteplase,
streptokinase, tenecteplase
Fibrinogen Fibrin monomers
X Aminocaproic acid
Hemophilia A: deficiency of factor VIII (XR) Plasmin
Hemophilia B: deficiency of factor IX ( XR) Combined Fibrinolytic system
Hemophilia C: deficiency of factor XI (AR )

Note: Kallikrein activates bradykinin; ACE inactivates bradykinin

* = require Ca2*, phospholipid
pathway
> Xllla

Fibrin degradation
= inhibited by vitamin K antagonist warfarin products
= cofactor Fibrin mesh stabilizes
activates but not part of coagulation cascade platelet plug 0
390 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY
Coagulation cascade components
Procoagulation Warfarin inhibits the enzyme vitamin K
epoxide reductase.
Epoxide (acts as inactive precursors of II, VII, IX, X, C, S
reductase cofactor )
Neonates lack enteric bacteria , which produce
Oxidized reduced
vitamin K vitamin K
y-glutamyl transferase vitamin K .
mature (active) II, VII, IX, X, C, S Vitamin K deficiency: 1 synthesis of factors II,
VII , IX, X, protein C, protein S.
vWF carries/ protects VIII ( volksWagen
Factories make grS ( great ) car ? j
Anticoagulation Antithrombin inhibits activated forms of factors
Thrombin-thrombomodulin complex Protein II , VII , IX, X, XI , XII.
{endothelial cells) S Heparin enhances the activity of antithrombin .
Protein C activated protein C cleaves and inactivates Va, Villa
Principal targets of antithrombin : thrombin and
factor Xa.
tPA
Plasminogen plasmin Fibrinolysis: Factor V Leiden mutation produces a factor V
1. cleavage of fibrin mesh resistant to inhibition by activated protein C.
2. destruction of coagulation factors
tPA is used clinically as a thrombolytic.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY SECTION I I I 391

Platelet plug formation ( primary hemostasis)

o 0 © (J) ©
INJURY
Endothelial damage
-* transient
vasoconstriction via
neural stimulation reflex
.! EXPOSURE
vWF binds to exposed
collagen
vWF is from Weibel-Palade
bodies of endothelial
St

and endothelm (released
from damaged cell)
-
A
ADHESION
Platelets bind vWF via Gplb
receptor at the site of injury
—
only (specific ) » platelets
undergo conformational
ACTIVATION
ADP binding to receptor
induces Gpllb/ llla
expression at platelet
surface
AGGREGATION
Fibnnogen binds Gpllb /llla receptors and links platelets
Balance between
Pro-aggregation factors: Anti- aggregation factors:
TXA2 (released PGI2 and NO (released
cells and a-granules of change
platelets
Platelets release ADP and
Ca 2+ (necessary
ary for
J by platelets) by endothelial cells)
i blood flow T blood flow
T platelet aggregation i platelet aggregation
coagulation cascade), TXA2

*
ADP helps platelets
atelets adhere
urn
to endothelium
.
*
Temporary plug stops bleeding; unstable, easily dislodged

2* hemostasis
Coagulation cascade

Thrombogenesis Formation of insoluble fibrin mesh.

Aspirin irreversibly inhibits cyclooxygenase,
thereby inhibiting TXA 2 synthesis
Clopidogrel, prasugrel, and ticlopidine inhibit
ADP-induced expression of GpIIb/IIIa.
Abciximab, eptifibatide, and tirofiban inhibit
GpIIb/IIIa directly.
Clopidogrel, prasugrel,
ticlopidine Platelet Ristocetin activates vWF to bind Gplb. Failure
(vWR
of aggregation!with ristocetin assay occurs in
Aspirin platelets von Willebrand disease and Bernard-Soulier
Q (fibrinogen)
syndrome.
Fibrinogen
COX
Arachidonic TXA
ADP receptor
Kir: Platelet phospholipid
V

Deficiency: Glanzmann thrombasthenia

Gpllb / llla

)- Activated
Deficiency: Bernard - Abciximab, Protein C protein C
Gpllb/ llla
Soulier syndrome n s e i ‘on ~ Vascular endothelial cells
Thrombomodulin /
/
0 Willebrand
^ Inside |
|(vWF + factor VIII)
Subendothel al lisease endothelial thromboplastin
:ollagen cells tPA, PGI,

O
392 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY

HEMATOLOGY AND ONCOLOGY — PATHOLOGY

Pathologic RBC forms

TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Acantho = spiny.

Vj
Acanthocyte Liver disease,
("spur cell")JO abetalipoproteinemia (states of
cholesterol dysregulation).

Basophilic stippling Q

yo Lead poisoning, sideroblastic

anemias, mvelodysplastic
syndromes.
Seen primarily in peripheral smear,
as opposed to ringed sideroblasts
seen in bone marrow.

Mi Aggregation of residual ribosomes.

Dacrocyte
("teardrop cell") jg

Degmacyte
w1 Bone marrow infiltration (eg,
myelofibrosis).

G6PD deficiency.
RBC “sheds a tear ” because it’s
mechanically squeezed out of its
home in the bone marrow.

("bite cell")J0

0
End-stage renal disease, liver
Echinocyte
("burrceinjg W* SS* disease, pyruvate kinase
Different from acanthocyte; its
projections are more uniform and

»*§00 «
deficiency. smaller.

Elliptocyte J Hereditary elliptocytosis, usually

asymptomatic; caused by
mutation in genes encoding RBC
membrane proteins (eg, spectrin).

Macro- ovalocyteJO Megaloblastic anemia (also

c hvpersegmented PMNs), marrow
failure.

? So!
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 393

Pathologic RBC forms ( continued )

TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Ringed siderobiast (JJ QV "
W Sideroblastic anemia. Excess iron Seen in bone marrow, as opposed
in mitochondria . to basophilic stippling in
'

iW peripheral smear.

DIC , TTP/ HUS, Examples include helmet cell.

DO
Schistocyte jj
HELLP syndrome, mechanical
hemolysis (eg, heart valve
prosthesis).

Sickling occurs with dehydration ,

Si
Sickle cellJJJ
deoxvgenation , and at high
altitude.

Spherocyte SJJ Hereditary spherocytosis, drug- and

infection-induced hemolytic
anemia .

f% 0

Target celljQ HbC disease, Asplenia , Liver “ HALT,” said the hunter to his
disease, Thalassemia. target.

Other RBC abnormalities

TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Heinz bodies Q Seen in G 6PD deficiency. Oxidation of Hb -SH groups
—
to -S S- -* Hb precipitation
( Heinz bodies), with subsequent
phagocytic damage to RBC
membrane -*• bite cells.
0
Howell -Jolly bodiesJQJ Seen in patients with functional Basophilic nuclear remnants found
Swapped
v . hvposplenia or asplenia. in RBCs.
Howell-Jolly bodies are normally
_
Image
removed from RBCs by splenic
(V macrophages.
t w . qi
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 393

Pathologic RBC forms ( continued )

TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Ringed siderobiast (JJ QV "
W Sideroblastic anemia. Excess iron Seen in bone marrow, as opposed
in mitochondria . to basophilic stippling in
'

iW peripheral smear.

DIC , TTP/ HUS, Examples include helmet cell.

DO
Schistocyte jj
HELLP syndrome, mechanical
hemolysis (eg, heart valve
prosthesis).

Sickling occurs with dehydration ,

Si
Sickle cellJJJ
deoxvgenation , and at high
altitude.

Spherocyte SJJ Hereditary spherocytosis, drug- and

infection-induced hemolytic
anemia .

f% 0

Target celljQ HbC disease, Asplenia , Liver “ HALT,” said the hunter to his
disease, Thalassemia. target.

Other RBC abnormalities

TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES
Heinz bodies Q Seen in G 6PD deficiency. Oxidation of Hb -SH groups
—
to -S S- -* Hb precipitation
( Heinz bodies), with subsequent
phagocytic damage to RBC
membrane -*• bite cells.
0
Howell -Jolly bodiesJQJ Seen in patients with functional Basophilic nuclear remnants found
Swapped
v . hvposplenia or asplenia. in RBCs.
Howell-Jolly bodies are normally
_
Image
removed from RBCs by splenic
(V macrophages.
t w . qi
394 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY

Anemias

ANEMIAS

1
MCV < 80 fL MCV 80-100 fL MCV > 100 fL
(Microcytic) (Normocytic ) (Macrocytic )

NONHEMOLYTIC HEMOLYTIC NON -

(Reticulocyte count (Reticulocyte count t )
MEGALOBLASTIC
MEGALOBLASTIC
normal or i)

INTRINSIC EXTRINSIC

[ Sideroblastic anemia3 J ( I r o n deficiency (early) J RBC membrane defect: [ Autoimmune J( F o l a t e deficiency J ( L i v e r disease J
' ' ' '
C
(
X
j
ACD (late)

Lead poisoning
D C
] (
I
ACD (early)

Aplastic anemia
J
)
hereditary spherocytosis

RBC enzyme deficiency:

.
G6PD pyruvate kinase
I
( Microangiopathic ) (
( Macroangiopathic ) f
^ ""
^
I
B deficiency

Orotic aciduria
) (
] (
I
Alcoholism

Diamond-Blackfan anemia
)
]
I T
( Thalassemias ) ( Chronic kidney disease ) f HbC disease
Keetons )
( Iron deficiency (late) ) Paroxysmal nocturnal
hemoglobinuria
( SALTI)

Sickle cell anemia

On a peripheral blood smear, a lymphocyte nucleus is approximately the same size as a normocytic RBC. If RBC is larger than lymphocyte nucleus, consider macrocytosis; if RBC is smaller,
consider microcytosis.
aCopper deficiency can cause a microcytic sideroblastic anemia .

Microcytic ( MCV < 80 fL ), hypochromic anemia

Iron deficiency I iron due to chronic bleeding (eg, GI loss, menorrhagia), malnutrition, absorption disorders, GI
surgery (eg, gastrectomy! or t demand (eg, pregnancy) • t final step in heme synthesis.
—
Labs: i iron, t TIBC, i ferritin, l transferrin saturation . Microcytosis and hypochromasia (central
pallor) El-
Symptoms: fatigue, conjunctival pallor Q, pica (consumption of nonfood substances), spoon nails
(koilonychia).
May manifest as glossitis, cheilosis] Plummer-Vinson syndrome (triad of iron deficiency anemia,
esophageal webs, and dysphagia).
a- thalassemia Defect: a-globin gene deletions —
i a-globin synthesis, cis deletion ( both deletions occur on
same chromosome) prevalent in Asian populations; trans deletion (deletions occur on separate
chromosomes) prevalent in African populations.
4 allele deletion: r o a-globin. Excess y-globin forms ( Hb Barts). Incompatible with life (causes
hydrops fetalis). ^
3 allele deletion: inheritance of chromosome with cis deletion + a chromosome with 1 allele
—
deleted HbH disease. Very little a-globin. Excess p-globin forms ( HbH)
2 allele deletion: less clinically severe anemia.
.
1 allele deletion: no anemia (clinically silent).
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 395

Microcytic ( MCV < 80 fL ), hypochromic anemia ( continued )

P-thalassemia
Mediterranean populations. —
Point mutations in splice sites and promoter sequences i p-globin synthesis. Prevalent in

P-thalassemia minor ( heterozygote): p chain is underproduced. Usually asymptomatic. Diagnosis

confirmed by t HbA2 (> 3.5%) on electrophoresis.

—
P-thalassemia major ( homozygote): P chain is absent severe microcytic, hypochromic

— —
anemia with target cells and increased anisopoikilocytosis Q requiring blood transfusion
( 2° hemochromatosis). Marrow expansion (“ crew cut ” on skull x-ray) skeletal deformities.
“ Chipmunk ” facies . Extramedullary hematopoiesis hepatosplenomegaly. t risk of parvovirus
B19-induced aplastic crisis t HbF (a2y2). bF is protective in the infant and disease becomes
,

^
symptomatic only after 6 months, when fetal hemoglobin declines.
HbS/ p-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of
P-globin production.
Lead poisoning

1
—
Lead inhibits ferrochelatase and ALA dehydratase -* i heme synthesis and t RBC protoporphyrin .
>

Also inhibits rRNA degradation RBCs retain aggregates of rRNA ( basophilic stippling ).
Symptoms of LEAD poisoning:
Lead Lines on gingivae ( Burton lines) and on metaphyses of long bones Q] on x-ray.
Encephalopathy and Erythrocyte basophilic stippling.
* Abdominal colic and sideroblastic Anemia .

* Drops
—
wrist and foot drop. Dimercaprol and EDTA are 1st line of treatment .
Succimer used for chelation for kids ( It “ sucks” to be a kid who eats lead ).
Exposure risk t in old houses with chipped paint .
Sideroblastic anemia [Causes: genetic (eg, X-linked defect in A-ALA synthase gene), acquired!( myelodvsplastic
syndromes), and reversible (alcohol is most common ; also lead , vitamin B6 deficiency, copper
deficiency, isoniazid ).
Lab findings: t iron , normal / i TIBC , t ferritin . Ringed sideroblasts ( with iron-laden, Prussian

.
blue-stained mitochondria ) seen in bone marrow Q. Peripheral blood smear: basophilic stippling
of RBCs.
Treatment: pyridoxine ( B6, cofactor for 5-ALA synthase).

y.:®
m
0O% « O n
> Oft tt
2P 0rS5 q
396 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY
Macrocytic ( MCV > 100 fL ) anemia

Megaloblastic anemia
4Q
DESCRIPTION

—
Impaired DNA synthesis maturation of
nucleus of precursor cells in bone marrow
delayed relative to maturation of cytoplasm .
FINDINGS
RBC macrocvtosis, hypersegmented
neutrophils Q, glossitis.

o^
«0 J
Folate deficiency Causes: malnutrition (eg, alcoholics),
malabsorption , drugs (eg, methotrexate,
trimethoprim , phenytoin ), t requirement (eg,
hemolytic anemia , pregnancy).
Vitamin B12 Causes: insufficient intake (eg, veganism ),
(cobalamin ) malabsorption (eg, Crohn disease), pernicious
deficiency anemia , Diphyllobothrium latum (fish
tapeworm), gastrectomy.
Orotic aciduria Inability to convert orotic acid to UMP
(de novo pyrimidine synthesis pathway)
because of defect in UMP synthase.
Autosomal recessive. Presents in children as
failure to thrive, developmental delay, and
megaloblastic anemia refractor}' to folate
and Bp. No hyperammonemia (vs ornithine
—
transcarbamylase deficiency t orotic acid
with hyperammonemia ).
Nonmegaloblastic Macrocytic anemia in which DNA synthesis is
anemia unimpaired.
Causes: alcoholism , liver disease .
Diamond - Blackfan Rapid-onset anemia within 1st year of life due to
anemia intrinsic defect in ervthroid progenitor cells.
t homocysteine, normal methylmalonic acid.
No neurologic symptoms (vs Bp deficiency).
t homocysteine, t methylmalonic acid.
Neurologic symptoms: dementia , subacutcl
combined degeneration (due to involvement of
Bp in fatty acid pathways and myelin synthesis):
spinocerebellar tract, lateral corticospinal tract,
dorsal column dysfunction .
Historically diagnosed with the Schilling test,
a 4-stage test that determines if the cause is
dietary insufficiency vs malabsorption .
Anemia secondary to insufficient intake may take
several years to develop due to livers ability to
store Bp (as opposed to folate deficiency).
Orotic acid in urine.
Treatment: uridine monophosphate to bypass
mutated enzyme.
RBC macrocvtosis without hypersegmented
neutrophils.
t 7c HbF ( but i total Hb).
Short stature, craniofacial abnormalities, and
upper extremity malformations ( triphalangeal
thumbs) in up to 50% of cases.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 397

Normocytic, Normocytic, normochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic
normochromic anemia anemias are further classified according to the cause of the hemolysis (intrinsic vs extrinsic to the
RBC ) and by the location of the hemolysis (intravascular vs extravascular).
Intravascular Findings: 1 haptoglobin, t LDH, schistocytes and t reticulocytes on blood smear. Characteristic
hemolysis hemoglobinuria, hemosiderinuria, and urobilinogen in urine. May also see t unconjugated
bilirubin. Notable causes are mechanical hemolysis (eg, prosthetic valve), paroxysmal nocturnal
hemoglobinuria, microangiopathic hemolytic anemias.
Extravascular Findings: macrophages in spleen clear RBCs. Spherocytes in peripheral smear, t LDH, no
hemolysis hemoglobinuria/hemosiderinuria, t unconjugated bilirubin, which can cause jaundice. Can
present with urobilinogen in urine.

Nonhemolytic, normocytic anemia

DESCRIPTION FINDINGS
Anemia of chronic
disease
—
Inflammation t hepcidin (released by liver,
binds ferroportin on intestinal mucosal
1 iron, 1 TIBC, t ferritin.
Normocytic, but can become microcytic.
cells and macrophages, thus inhibiting Treatment: EPO (chronic kidney disease only).
iron transport) -*• I release of iron from
macrophages and i iron absorption from gut.
Associated with conditions such as rheumatoid
arthritis, SLE, neoplastic disorders, and
chronic kidney disease.
Aplastic anemia Caused by failure or destruction of myeloid 1 reticulocyte count, t EPO.
stem cells due to: Pancytopenia characterized by severe anemia,
X
> leukopenia, and thrombocytopenia. Normal

m
a Radiation and
t. drugs (benzene,
chloramphenicol, alkylating agents, cell morphology, but hvpocellular bone
antimetabolites) marrow with fatty infiltration Q (dry bone
Viral agents (parvovirus B19, EBV, HIV, marrow tap).

? 5
hepatitis viruses)
Fanconi anemia (DNA repair defect
causing bone marrow failure; macrocytosis
may be seen on CBC ); also short staturej
t incidence of tumors/leukemia, cafe-au-lait
spots, thumb/radial defects
° Idiopathic (immune mediated, 1° stem cell
defect); may follow acute hepatitis
Symptoms: fatigue, malaise, pallor, purpura,
mucosal bleeding, petechiae, infection.
Treatment: withdrawal of offending
agent, immunosuppressive regimens (eg,
antithvmocyte globulin, cyclosporine), bone
marrow allograft, RBC/platelet transfusion,
bone marrow stimulation (eg, GM-CSF).
398 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY

LONG PAGE - Edit to lose lines?

Intrinsic hemolytic anemia

DESCRIPTION
Hereditary Extravascular hemolysis due to defect in
spherocytosis proteins interacting with RBC membrane
skeleton and plasma membrane (eg, ankyrin,
band 3, protein 4.2, spectrin). Mostly
autosomal dominant inheritance .
Results in small, round RBCs with less surface
area and no central pallor (t MCHC)
-*• premature removal by spleen.
G6PD deficiency Most common enzymatic disorder of RBCs.
Causes extravascular and intravascular
hemolysis.
X-linked recessive.
—
Defect in G6PD 1 glutathione t RBC
—
susceptibility to oxidant stress. Hemolytic
anemia following oxidant stress (eg, sulfa
drugs, antimalarials, infections, fava beans).
Pyruvate kinase Autosomal recessive. Defect in pyruvate kinase
deficiency
— — —
1 ATP rigid RBCs extravascular
hemolysis.
HbC disease Glutamic acid-to-lysine mutation in P-globin.
Causes extravascular hemolysis.
Paroxysmal nocturnal t complement-mediated intravascular RBC
hemoglobinuria lysis (impaired synthesis of CPI anchor for
decay-accelerating factor that protects RBC
membrane from complement). Acquired
mutation in a hematopoietic stem cell,
t incidence of acute leukemias. Patients
may complain of red or pink urine ( from the
hemoglobinuriaj
Sickle cell anemia HbS point mutation causes a single amino
acid replacement in P chain (substitution
FINDINGS
Splenomegaly, aplastic crisis ( parvovirus B19
infection).
Labs: osmotic fragility test ©. Normal to
l MCV with abundance of cells.
Treatment: splenectomy.
Back pain, hemoglobinuria a few days after
oxidant stress.
Labs: blood smear shows RBCs with Heinz
bodies and bite cells.
“ Stress makes me eat bites of fava beans with
Heinz ketchup.”
Hemolytic anemia in a newborn.
Patients with HbSC ( 1 of each mutant gene)
have milder disease than HbSS patients.
Labs ( homozygotes): blood smear shows
hemoglobin crystals inside RBCs and target
cells.
Triad: Coombs © hemolytic anemia,
pancytopenia, and venous thrombosis.
Labs: CD 55 /59 © RBCs on flow cytometry.
Treatment: eculizumab (terminal complement
inhibitor).
Complications in sickle cell disease:
Aplastic crisis (due to parvovirus B19).

v of glutamic acid with valine). Causes

extravascular and intravascular hemolysis.
Pathogenesis: low 02, high altitude, or acidosis
Autosplenectomv (Howell-Jolly bodies)
-* t risk of infection by encapsulated
organisms ( eg, S pneumoniae ).

* precipitates sickling (deoxvgenated HbS

polymerizes) -*• anemia and vaso-occlusive
Splenic infarct /sequestration crisis.
Salmonella osteomyelitis.
0

disease. Painful crises (vaso-occlusive): dactylitis Q

^
a Newborns are initially asymptomatic because of
t HbF and I HbS.
Heterozygotes (sickle cell trait) also have
resistance to malaria.
8% of African Americans carry an HbS allele.
Sickle cells are crescent-shaped RBCs EJ.
“ Crew cut ” on skull x-ray due to marrow
expansion from t erythropoiesis (also seen in
thalassemias).
(painful swelling of hands/feet), priapism,
acute chest syndrome, avascular necrosis,
stroke.
Renal papillary necrosis (1 Po2 in papilla) and
microhematuria (medullary infarcts).
Diagnosis: hemoglobin electrophoresis.
Treatment: hydroxyurea ( t HbF), hydration.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 399

Extrinsic hemolytic anemia

DESCRIPTION FINDINGS
Autoimmune —
Warm ( IgG) chronic anemia seen in SLE Autoimmune hemolytic anemias are usually
hemolytic anemia and CLL and with certain drugs (eg, Coombs ®.

n a-methyldopa) (“ warm weather is Great ” ).

Cold ( IgM and complement ) acute —
anemia triggered by cold; seen in CLL,
Mycoplasma infections, and
—
Direct Coombs test anti- Ig antibody ( Coombs
reagent ) added to patients RBC ? j RBCs
agglutinate if RBCs are coated with Ig.
—
Indirect Coombs test normal RBCs added to
infectious Mononucleosis (“ cold weather is patients serum . If serum has anti-RBC surface
MMMiserable” ). RBC agglutinates Q may Ig, RBCs agglutinate when Coombs reagent
cause painful, blue fingers and toes with cold added .
exposure.
Many warm and cold AIHAs are idiopathic in
etiology.
Patient component Reagent( s) © Result 0 Result
( agglutination ) (no agglutination )

#
y j*

! X/
-C - A
I RBCs +/- anti-RBC Ab Anti- human globulin 0Result
Y
© Result
(Coombs reagent ) Anti-RBC Ab present Anti-RBC Ab absent

K
A x
u -< Donor blood
X
I A A .Sx Y

Patient serum +/- Anti-human globulin © Result © Result

anti-donor RBC Ab (Coombs reagent) Anti-donor RBC Ab present Anti-donor RBC Ab absent

Microangiopathic Pathogenesis: RBCs are damaged when passing Schistocytes (eg, “ helmet cells” ) are seen on
anemia through obstructed or narrowed vessel lumina. peripheral blood smear due to mechanical
Seen in PIC, TTP/ HUS, SLE, HELLP destruction ( schisto = to split) of RBCs.
syndrome, and malignant hypertensioij

Macroangiopathic Prosthetic heart valves and aortic stenosis may Schistocytes on peripheral blood smear.
anemia also cause hemolytic anemia 2° to mechanical
destruction of RBCs.
Infections t destruction of RBCs (eg, malaria , Babesia ).
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 401

Heme synthesis . The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the
porphyrias, and lead accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis,
poisoning leading to a similar condition.
CONDITION AFFECTED ENZYME ACCUMULATED SUBSTRATE PRESENTING SYMPTOMS
Lead poisoning Ferrochelatase and Protoporphyrin, 5-ALA Microcytic anemia ( basophilic stippling in
ALA dehydratase (blood) peripheral smear , ringed sideroblasts in

^
bone marro\ , GI and kidney disease.
Children — exposure to lead paint mental
—
deterioration.
Adults — environmental exposure (eg, batteries,
ammunition) -* headache, memory loss,
demyelination.
Acute intermittent Porphobilinogen Porphobilinogen, Symptoms ( 5 P’s):
porphyria deaminase 5-ALA, • Painful abdomen
coporphobilinogen 0
Port wine-colored urine
(urine) Polyneuropathy
Psychological disturbances
u
Precipitated by drugs (eg, cytochrome P-450
inducers), alcohol, starvation
Treatment: glucose and heme, which inhibit
ALA synthase. Exacerbated with alcohol
consumption.
Porphyria cutanea Uroporphyrinogen Uroporphyrin (tea- Blistering cutaneous photosensitivitv and
tarda decarboxylase colored urine)
^
hvperpigmentatioi Q. Most common
porphyria.
Most common porphyria. Exacerbated with
alcohol consumption.
V
Location Intermediates Enzymes Diseases

Glucose, heme
Glycine + succinyl-CoA
6- aminolevulinic acid synthase:
J
^
Mitochondria B» I' u rate-limiting step
Sideroblastic anemia (X linked)
5-aminolevulinic acid

1
Porphobilinogen
5-aminolevulinic acid dehydratase
( Lead poisoning

^
1 Porphobilinogen deaminase
( Acute intermittent porphyria
Cytoplasm Hydroxymethylbilane

Uroporphyrinogen III
^
1
Coproporphyrinogen III
Uroporphyrinogen decarboxylase
f Porphyria cutanea tarda
J

Mitochondria
f«
-A
Protoporphyrin

Heme
Ferrochelatase ( Lead poisoning )

iheme -» T ALA synthase activity

T heme -» l ALA synthase activity
402 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY

Iron poisoning High mortality rate with accidental ingestion by children (adult iron tablets may look like candy).
MECHANISM Cell death due to peroxidation of membrane lipids.
SYMPTOMS/SIGNS Nausea, vomiting, gastric bleeding, lethargy, scarring leading to GI obstruction.
TREATMENT Chelation (eg, IV deferoxamine, oral deferasirox) and dialysis.

Coagulation disorders
—
PT— tests function of common and extrinsic pathway (factors I, II, V, VII, and X ). Defect t PT.
INR (international normalized ratio) — calculated from PT. 1 = normal, > 1 = prolonged. Most
common test used to follow patients on warfarin.
PIT— tests function of common and intrinsic pathway (all factors except VII and XIII). Defect
-
t PTT. _
Coagulation disorders can be due to clotting factor deficiencies or acquired inhibitors. Diagnose
with a mixing study, where normal plasma is added to patient ’s plasma. Clotting factor
deficiencies are corrected, whereas factor inhibitors are not corrected.
DISORDER _PT PTT MECHANISM AND COMMENTS
Hemophilia A , B, or C — t Intrinsic pathway coagulation defect.

——
A: deficiency of factor VIII t PTT; X-linked recessive.
B: deficiency of factor IX t PTT; X-linked recessive.
* C: deficiency of factor XI — t PTT; autosomal recessive.
Macrohemorrhage in hemophilia — hemarthroses (bleeding into joints, such
as knee Q), easy bruising, bleeding after trauma or surgery (eg, dental
procedures).
Treatment: desmopressin + factor VIII concentrate (A); factor IX concentrate
(B); factor XI concentrate (C).
Vitamin K deficiency t t General coagulation defect. Bleeding time normal.
I activity of factors II, VII, IX, X, protein C, protein S.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 403

Platelet disorders

DISORDER
—
Defects in platelet plug formation t bleeding time ( BT ).
Platelet abnormalities -* microhemorrhage: mucous membrane bleeding, epistaxis, petechiae ,
purpura , t bleeding time, possibly decreased platelet count ( PC).
PC BT MECHANISM AND COMMENTS
Bernard -Soulier -H t Defect in platelet plug formation . Large platelets.
syndrome
Glanzmann
thrombasthenia
t
1 Gplb -*• defect in platelet-to-vWF adhesion.

—
Defect in platelet integrin (XmJT (GpIIb/ IIIa ) defect in platelet-to-platelet
aggregation , and therefore platelet plug formation!
"

fl^abs: blood smear shows no platelet clumping.

Hemolytic- uremic 1 t Characterized by thrombocytopenia , microangiopathic hemolytic anemia , and
syndrome acute renal failure.
Typical HUS is seen in children, accompanied by diarrhea and commonly
caused by Enterohemorrhagic E coli ( EHEC| ) (eg, 0157: H 7 ). HLJS in adults
does not present with diarrhea; EHECj infection not required .
Same spectrum as TIP, with a similar clinical presentation and same initial

Immune
thrombocytopenia
i t
treatment of plasmapheresis.

—
Anti-GpIIb/ IIIa antibodies splenic macrophage consumption of
platelet-antibodv complex. May be primary disorder or secondary to
autoimmune disorder, viral illness, malignancy, or drug reaction!
Labs: t megakaryocytes on bone marrow biopsy.
Treatment: steroids, IVIG , splenectomy (for refractory ITP).

—
Thrombotic 1 t Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease)
thrombocytopenic
purpura
-* 1 degradation of vWF multimers.
aggregation and thrombosis.
Labs: schistocytes, t LDII .
—
Pathogenesis: t large vWF multimers t platelet adhesion t platelet

Symptoms: pentad of neurologic and renal symptoms, fever, thrombocytopenia,

and microangiopathic hemolytic anemia .
Treatment: plasmapheresis, steroids.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 405

Blood transfusion therapy

COMPONENT DOSAGE EFFECT CLINICAL USE
Packed RBCs t Hb and 07 carrying capacity Acute blood loss, severe anemia
Platelets t platelet count ( t ~ 5000/mmVunit) Stop significant bleeding (thrombocytopenia ,
qualitative platelet defects)
Fresh frozen plasma / t coagulation factor levels DIC, cirrhosis, immediate warfarin reversal
prothrombin complex
concentrate)
Cryoprecipitate Contains fibrinogen , factor VIII , factor XIII, Coagulation factor deficiencies involving
vWF, and fibronectin fibrinogen and factor VIII
Blood transfusion risks include infection transmission ( low ), transfusion reactions, iron overload ( may lead to 2°
hemochromatosis), hypocalcemia ( citrate is a Ca -+ chelator), and hyperkalemia ( RBCs may lyse in old blood units).

Leukemia vs lymphoma
Leukemia Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are
usually found in peripheral blood.
Lymphoma Discrete tumor mass arising from lymph nodes. Presentations often blur definitions.

Hodgkin vs Hodgkin Non - Hodgkin

non - Hodgkin Localized, single group of nodes; contiguous
lymphoma spread (stage is strongest predictor of
prognosis ). Many patients have a relatively
good prognosis.
Characterized by Reed-Sternberg cells.
Bimodal distribution-young adulthood and
> 55 years; more common in men except for
nodular sclerosing type.
Associated with EBV.
Constitutional (“ B” ) signs/symptoms: low-grade
fever, night sweats, w eight loss]
Multiple lymph nodes involved ; extranodal
involvement common; noncontiguous spread.
Majority involve B cells; a few are of T-cell
lineage.
Can occur in children and adults.
May be associated with HIV and autoimmune
diseases.
May present with constitutional ( “ B” ) signs/
symptoms]

Hodqkin lymphomal
^
Contains Reed-Sternberg cells: distinctive tumor giant cells; binucleate or bilobec with the 2 halves
as mirror images ( “ owl eyes” Q). 2 owl eyes x 15 = 30. RS cells are CD15+ and CD30+ B -cell
origin. Necessary but not sufficient for a diagnosis of Hodgkin lymphoma.

• *
SUBTYPE NOTES
if Nodular sclerosis Most common
I riC A Lymphocyte-rich Best prognosis

. . -4 Mixed cellularity

Lymphocyte depleted
Eosinophilia , seen in immunocompromised
patients
Seen in immunocompromised patients
406 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY

LONG PAGE - Edit to fit?

Non-Hodgkin lymphoma
TYPE OCCURS IN GENETICS COMMENTS

Neoplasms of mature B cells

Burkitt lymphoma Adolescents or young t(8;14) — translocation “ Starry sky” appearance, sheets of lymphocytes
adults of c-myc (8) and with interspersed “ tingible body” macrophages
heavy-chain Ig ( 14) (arrows in Q).
Associated with EBV.
Jaw lesion [j] in endemic form in Africa; pelvis
or abdomen in sporadic form.
Diffuse large B- cell Usually older adults, Alterations in Bcl-2, Most common type of non-Hodgkin lymphoma
lymphoma but 20% in children Bcl-6 in adults.
Follicular lymphoma Adults t(14;18) — translocation Indolent course; Bcl-2 inhibits apoptosis.
of heavy-chain Ig ( 14) Presents with painless “waxing and waning”
and BCL-2 (18) lymphadenopathv. Follicular architecture:
small cleaved cells ( grade 1), large cells ( grade
3), or mixture ( grade 2).
Mantle cell lymphoma Adult males t ( 11;14) — translocation Very aggressive, patients typically present with
of cyclin D1 ( 11) and late-stage disease.
heavy-chain Ig ( 14), _
CD 5+
Marqinal cell Adults tf 11,18) Associated with chronic inflammatorv diseases
lymphoma ( Sjogren syndrome, chronic gastritis [ MALT
lymphoma]).
Primary central Adults Most commonly Considered an AIDS-defining illness. Variable
nervous system associated with HIV/ presentation: confusion, memory loss,
lymphoma AIDS; pathogenesis seizures. Mass lesion(s) on MRI, needs to be
involves EBV distinguished from toxoplasmosis via CSF
infection analysis or other lab tests.
Neoplasms of mature T cells
Adult T- cell lymphoma Adults Caused by HTLV Adults present with cutaneous lesions; especially
(associated with IV affects populations in Japan, West Africa, and
drug abuse) the Caribbean.
Lytic bone lesions, hypercalcemia.
Mycosis fungoides/ Adults Mycosis fungoides presents with skin patches 0/
Sezary syndrome plaques (cutaneous T-cell lymphoma),
characterized by atypical CD4+ cells with
“cerebriform” nuclei and intraepidermal
aggregates of neoplastic cells ( Pautrier
microabscess). May progress to Sezary
syndrome (T-cell leukemia).

fc
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 407

Multiple myeloma Monoclonal plasma cell (“ fried egg" Think CRAB:

appearance) cancer that arises in the marrow HyperCalcemia
M spike — ; and produces large amounts of IgG ( 55%) or Renal involvement
IgA ( 25%). Bone marrow > 10% monoclonal Anemia
plasma cells. Most common 1° tumor arising Bone lytic lesions/Back pain
within bone in people > 40-50 years old. Multiple Myeloma: Monoclonal M protein
Albumin q 02 P Y Associated with: spike
t susceptibility to infection Distinguish from Waldenstrom

0
Primary amyloidosis (AL)
Punched-out lytic bone lesions on x-ray Q
—
macroglobulinemia M spike = IgM
-*• hyperviscosity syndrome (eg, blurred vision,
M spike on serum protein electrophoresis Raynaud phenomenon); no “ CRAB” findings.
Ig light chains in urine ( Bence Jones
protein)
Rouleaux formation Q ( RBCs stacked like
poker chips in blood smear)
Numerous plasma cells Q with “clock-face”
chromatin and intracytoplasmic inclusions
containing immunoglobulin.
Monoclonal gammopathy of undetermined
significance (MGUS) — monoclonal expansion
of plasma cells (bone marrow < 10%
monoclonal plasma cells), asymptomatic,
may lead to multiple myeloma. No “ CRAB”
findings. Patients with MGUS develop
multiple myeloma at a rate of 1-2% per year.

& n

. Ar/\
o

<
•
Myelodysplastic Stem-cell disorders involving ineffective Pseudo-Pelger-Huet anomaly — neutrophils
syndromes hematopoiesis -* defects in cell maturation of with bilobed nuclei. Typically seen after
all nonlymphoid lineages. Caused by de novo chemotherapy,
mutations or environmental exposure (eg,
radiation, benzene, chemotherapy). Risk of
transformation to AML .
408 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY
Leukemias Unregulated growth and differentiation of WBCs in bone marrow -* marrow failure -*• anemia
( A RBCs), infections ( 1 mature WBCs), and hemorrhage ( 1 platelets). Usually presents with
t circulating WBCs ( malignant leukocytes in blood ); rare cases present with normal /1 WBCs.
Leukemic cell infiltration of liver, spleen, lymph nodes, and skin ( leukemia cutis) possible.
TYPE NOTES
Lymphoid neoplasms
Acute lymphoblastic Most frequently occurs in children; less common in adults (worse prognosis). T-cell ALL can
leukemia / lymphoma present as mediastinal mass ( presenting as SVC-like syndrome). Associated with Down syndrome.
Peripheral blood and bone marrow have 111 lymphoblasts Q.
TdT+ ( marker of pre-T and pre- B cells), CD10 + ( marker of pre- B cells).
Most responsive to therapy.
May spread to CNS and testes.
t (12;21) better prognosis.
Chronic lymphocytic Age: > 60 years. Most common adult leukemia. CCD20 +, CD2 > 4 j CD 5+ B-cell neoplasm .
leukemia /small Often asymptomatic, progresses slowly; smudge cells Q in peripheral blood smear; autoimmune
lymphocytic hemolytic anemia. CLL = Crushed Little Lymphocytes (smudge cells).
lymphoma —
Richter transformation SLL /CLL transformation into an aggressive lymphoma , most commonly
diffuse large B-cell lymphoma ( DLBCL).
Hairy cell leukemia Age: Adult males. Mature B-cell tumor. Cells have filamentous, hair-like projections
(fuzzy appearing on LM H ).
Causes marrow fibrosis -*• dry tap on aspiration . Patients usually present with massive splenomegaly
and pancytopenia!
Stains TRAP (tartrate-resistant acid phosphatase) ©. TRAP stain largely replaced with flow
cytometry.
Treatment: cladribine, pentostatin.
Myeloid neoplasms
Acute myelogenous Median onset 65 years. Auer rods 0; myeloperoxidase © cytoplasmic inclusions seen mostly in
leukemia
^ APL ( formerly M 3 AML); 111 circulating myeloblasts on peripheral smear; adults.
Risk factors: prior exposure to alkylating chemotherapy, radiation , myeloproliferative disorders,
Down syndrome. APL: t ( 15;17 ), responds to all-trans retinoic acid ( vitamin A ), inducing
differentiation of promyelocytes; D1C is a common presentation!
Chronic myelogenous Occurs across the age spectrum with peak incidence 45-85 years, median age at diagnosis 64 years ,

leukemia Defined by the Philadelphia chromosome (t[9;22], BCR-ABL ) and myeloid stem cell proliferation .
Presents with dysregulated production of mature and maturing granulocytes (eg, neutrophils,
metamyelocytes, myelocytes, basophils Q) and splenomegaly. May accelerate and transform to
AML or ALL (“ blast crisis” ).
Very low LAP as a result of low activity in malignant neutrophils (vs benign neutrophilia
[ leukemoid reaction], in which LAP is t ).
Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib).

m La?0 §
9
:

< ^ 4 I
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY SECTION III 409

Chronic The myeloproliferative disorders (polycythemia vera, essential thrombocythemia, myelofibrosis, and
myeloproliferative CML) are malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell
disorders lines. Associated with V617F JAK 2 mutation.
Polycythemia vera A form of 1° polycythemia. Disorder of t hematocrit. May present as intense itching after
hot shower. Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue
coloration) due to episodic blood clots in vessels of the extremities Q. J
1 EPO (vs 2° polycythemia, which presents with endogenous or artificially t EPO). Treatment is
phlebotomy, hydroxyurea, ruxolitinib ( JAK 1/ 2 inhibitor).
Essential Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include
thrombocythemia bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may
be large or otherwise abnormally formed Q. Erythromelalgia may occur.
Myelofibrosis Obliteration of bone marrow with fibrosis H due to t fibroblast activity. Often associated with
massive splenomegaly and “ teardrop” RBCs Q. “ Bone marrow is crying because it’s fibrosed and
is a dry tap.”
RBCs WBCs PLATELETS PHILADELPHIA CHROMOSOME M2 MUTATIONS
Polycythemia vera t t t e ©
Essential - - t e © ( 30-50%)
thrombocythemia
Myelofibrosis t Variable Variable e © ( 30-50%)
CML i t t © ©
r
r«o
^ 9
1 P
9G
^
— a

Polycythemia
PLASMA VOLUME RBCMASS 02 SATURATION EPO LEVELS ASSOCIATIONS

Relative i - - - Dehydration, burns.

Appropriate absolute - t i t Lung disease, congenital heart
disease, high altitude.
Inappropriate absolute - t t Malignancy (eg, renal cell
carcinoma, hepatocellular
carcinoma), hydronephrosis.
Due to ectopic EPO
secretion.
Polycythemia vera t tt EPO i in PCV due to negative
feedback suppressing renal
EPO production.
410 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PATHOLOGY
Chromosomal translocations
TRANSLOCATION ASSOCIATED DISORDER
t(8;14) Burkitt lymphoma (c-tnyc activation )
t (9;22) (Philadelphia CML ( BCR-ABL hybrid ), ALL ( less common , Philadelphia CreaML cheese.
chromosome) poor prognostic factor! The Ig heavy chain genes on chromosome 14
are constitutivelv expressed. When other
genes (eg, c-myc and BCL-2 ) are translocated
next to this heavy chain gene region , they are
overexpressed .
t( ll;14) Mantle cell lymphoma (cyclin D1 activation )
t(14;18) Follicular lymphoma ( BCL-2 activation )
t(15;17 ) APL ( M 3 type of AML) Responds to all-frans retinoic acid .

Maliqnant cell surface DISEASE SURFACE MARKERS

markers ALL CD 10
CLL CD 5, 19, 20, 23
AML CD 13. 15, 64
CML
Hodgkin Lymphoma CD 15. 30
Non - Hodgkin Lymphoma .
CD 5 (Mantlet CD 20

Langerhans cell Collective group of proliferative disorders of

g&at
.
A

am
histiocytosis dendritic ( Langerhans) cells. Presents in a
child as lytic bone lesions Q and skin rash or
as recurrent otitis media with a mass involving ' MS
* F

the mastoid bone. Cells are functionally

immature and do not effectively stimulate m
v
V i
'
primary T cells via antigen presentation .
Cells express S-100 (mesodermal origin ) and
CDla. Birbeck granules (“ tennis rackets” or
fcfsjfi i3

rod shaped on EM ) are characteristic Q.

 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY SECTION III 411

HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY

Heparin
MECHANISM Lowers the activity of thrombin and factor Xa . Short half-life.
CLINICAL USE Immediate anticoagulation for pulmonary embolism ( PE ), acute coronary syndrome, MI, deep
venous thrombosis ( DVT ). Used during pregnancy (does not cross placenta ). Follow FIT.
ADVERSE EFFECTS Bleeding, thrombocytopenia ( HIT ), osteoporosis, drug-drug interactions. For rapid reversal
(antidote), use protamine sulfate ( positively charged molecule that binds negatively charged
heparin ).
NOTES Low-molecular-weight heparins (eg, enoxaparin , dalteparin ) act predominantly on factor Xa .
Fondaparinux acts only on factor Xa . Both have better bioavailabilitv, and 2-4 times longer half
life; car!be administered subcutaneously and without laboratory monitoring. Not easily reversible .
—
—
Heparin - induced thrombocytopenia ( HIT ) development of IgG antibodies against heparin
bound platelet factor 4 ( PF4). Antibody-heparin -PF4 complex activates platelets thrombosis and
thrombocytopenia .
-

Direct thrombin Bivalirudin ( related to hirudin , the anticoagulant used by leeches), dabigatran , argatrobanj
inhibitors
MECHANISM Directly inhibits activity of free and clot-associated thrombin .
CLINICAL USE Venous thromboembolism, atrial fibrillation. Can be used in HIT. Does not require lab
monitoring.
ADVERSE EFFECTS Bleeding; reverse dabigatran with idaruci /. umab. Can attempt to use activated prothrombin
complex concentrates ( PCC ) and/or antifibrinolytics (eg, tranexamic acid ) if no reversal agent
available!
412 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY

Warfarin
MECHANISM Interferes with y-carboxylation of vitamin In¬
The EX-PresidenT went to war(farin).
dependent clotting factors II, VII, IX, and X,
and proteins C and S. Metabolism affected
by polymorphisms in the gene for vitamin
K epoxide reductase complex (VKORC1).
In laboratory assay, has effect on EXtrinsic
pathway and t PT. Long half-life.
CLINICAL USE Chronic anticoagulation (eg, venous
thromboembolism prophylaxis, and prevention
of stroke in atrial fibrillation). Not used in
pregnant women ( because warfarin, unlike
heparin, crosses placenta). Follow PT/INR.
ADVERSE EFFECTS Bleeding, teratogenic, skin/tissue necrosis Q, For reversal of warfarin, give vitamin K.
drug-drug interactions. Proteins C and S have For rapid reversal, give fresh frozen plasma or
shorter half-lives than clotting factors II,
VII, IX, and X, resulting in early transient
prothrombin complex concentrate
^
Heparin “ bridging”: heparin frequently used
hypercoagulability with warfarin use. Skin / when starting warfarin. Ileparin s activation of
tissue necrosis within first few days of large antithrombin enables anticoagulation during

/ doses believed to be due to small vessel

microthromboses.
initial, transient hypercoagulable state caused
by warfarin. Initial heparin therapy reduces
risk of recurrent venous thromboembolism
and skin/tissue necrosis.

Heparin vs warfarin
Heparin Warfarin
ROUTE OF ADMINISTRATION Parenteral (IV, SC) Oral
SITE OF ACTION Blood Liver
ONSET OF ACTION Rapid (seconds) Slow, limited by half-lives of normal clotting
factors
MECHANISM OF ACTION Activates antithrombin, which 1 the action of Impairs synthesis of vitamin K-dependent
Ila (thrombin) and factor Xa clotting factors II, VII, IX, and X, and anti
¬

clotting proteins C and S

DURATION OF ACTION Hoursj Dayj
AGENTS FOR REVERSAL Protamine sulfate Vitamin K, fresh frozen plasma, prothrombin
complex concentrate
MONITORING PTT (intrinsic pathway) PT/INR (extrinsic pathway)
CROSSES PLACENTA No Yes (teratogenic)
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY SECTION III 413

Direct factor Xa ApiXaban, rivaroXaban.

inhibitors
MECHANISM Bind to and directly inhibit factor Xa.
CLINICAL USE Treatment and prophylaxis for DVT and PEj stroke prophylaxis in patients with atrial fibrillation.
Oral agents do not usually require coagulation monitoring.
ADVERSE EFFECTS Bleeding. Not easily reversible. Experimental reversal agents (eg, andexanet alfa) in development

Thrombolytics Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA).

MECHANISM Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
clots t PT, t PIT,' no change in platelet count .
,

CLINICAL USE Early MI, early ischemic stroke, direct thrombolysis of severe PE.
ADVERSE EFFECTS Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding,
recent surgery, known bleeding diatheses, or severe hypertension. Reverse with antifibrinolvtics
( eg, aminocaproic acid, tranexamic acid ), platelet transfusions, and factor corrections ( eg,
crvopreeipitate, fresh frozen plasma, prothrombin complex concentrate). No specific reversal
agent

ADP receptor inhibitors Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine.

MECHANISM Inhibit platelet aggregation bv irreversibly blocking ADP ( P2Yn) receptot Prevent expression of
glycoproteins Ilb/IIIa on platelet surface.
CLINICAL USE Acute coronary syndrome; coronary stenting. 1 incidence or recurrence of thrombotic stroke.
ADVERSE EFFECTS Neutropenia (ticlopidine). TTP may be seen.

Cilostazol, dipyridamole
Phosphodiesterase inhibitor ; t cAMP in platelets, resulting in inhibition of platelet aggregation;
MECHANISM
vasodilators. ^
CLINICAL USE Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with
aspiring
ADVERSE EFFECTS Nausea, headache, facial flushing, hypotension, abdominal pain.

Glycoprotein Ilb/ IIIa Abciximab, eptifibatide, tirofiban.

inhibitors
MECHANISM Bind to the glycoprotein receptor Ilb/IIIa on activated platelets, preventing aggregation. Abciximab
is made from monoclonal antibody Fab fragments.
CLINICAL USE Unstable angina, percutaneous transluminal coronary angioplasty.
ADVERSE EFFECTS Bleeding, thrombocytopenia.
 NEUROLOGY AND SPECIAL SENSES
Movement disorders
DISORDER PRESENTATION
Akathisial Restlessness and intense urge
to movq
Asterixis Extension of wrists causes
“ flapping” motion
Athetosis Slow, writhing movements;
especially seen in fingers
Chorea Sudden, jerky, purposeless
movements
Dystonia Sustained, involuntary muscle
contractions
Essential tremor High-frequency tremor
with sustained posture
(eg, outstretched arms),
worsened with movement or
when anxious
Hemiballismus Sudden, wild flailing of 1 arm
+/— ipsilateral leg
Intention tremor Slow, zigzag motion when
pointing/extending toward a
target
Myoclonus Sudden, brief, uncontrolled
muscle contraction
Resting tremor Uncontrolled movement of distal Parkinson disease
appendages (most noticeable
in hands); tremor alleviated by
intentional movement
NEUROLOGY — PATHOLOGY
CHARACTERISTIC LESION
1 Can be seen with neuroleptic
Basal ganglia (eg, Huntington)
Basal ganglia (eg, Huntington)
Contralateral subthalamic
nucleus (eg, lacunar stroke)
Cerebellar dysfunction
SECTION III 487
NOTES
use or in Parkinson disease !
Associated with hepatic
encephalopathy, Wilsons
disease, and other metabolic
derangements.
Writhing, snake-like
movement.
Chorea = dancing. _
Svndenham chorea seen in
acute rheumatic fever.
Writer’s cramp; blepharospasm;
!
torticollis
Often familial. Patients often
self-medicate with alcohol,
which 1 tremor amplitude.
Treatment: nonselective
P-blockers (eg, propranolol ),
primidone.
Pronounce “Half-of-body
ballistic."
Contralateral lesion.
Jerks; hiccups; common in
metabolic abnormalities such
as renal and liver failure.
Occurs at rest; “pill-rolling
tremor ” of Parkinson disease. _
When vou park your car, it is
at rest.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY
Antimetabolites
DRUG MECHANISM3
Azathioprine, Purine (thiol) analogs
6- mercaptopurine -* 1 de novo purine synthesis.
Activated by HGPRT.
Azathioprine is metabolized
into 6-MP.
Cladribine Purine analog -*• multiple
mechanisms (eg, inhibition
of DNA polymerase, DNA
strand breaks).
Cytarabine
(arabinofuranosyl of DNA polymerase.
—
Pyrimidine analog inhibition Leukemias (AML), lymphomas. Mvelosuppression with
cytidine)
5 - fluorouracil Pyrimidine analog bioactivated
to 5-FdUMP, which
covalently complexes folic
acid. Capecitabine is a
prodrug with similar activity
This complex inhibits
thymidylate synthase
- .-i dTMP
synthesis
1 DNA
Methotrexate Folic acid analog that
competitively inhibits
dihydrofolate reductase
- 1 dTMP
synthesis.
- 1 DNA
aAll arc S-phase specific.
CLINICAL USE
Preventing organ rejection,
rheumatoid arthritis, IBD,
SLE; used to wean patients
off steroids in chronic disease
and to treat steroid-refractor}'
chronic disease.
Hairy cell leukemia.
megaloblastic anemia.
Colon cancer, pancreatic
cancer, basal cell carcinoma
( topical).
Effects enhanced with the
addition of leucovorin.
Cancers: leukemias
(ALL), lymphomas,
choriocarcinoma, sarcomas.
Non-neoplastic: ectopic
pregnancy, medical
abortion (with misoprostol),
rheumatoid arthritis, psoriasis,
IBD, vasculitis.
SECTION III 415
ADVERSE EFFECTS
Mvelosuppression, GI, liver.
Azathioprine and 6-MP are
metabolized by xanthine
oxidase; thus both have
t toxicity with allopurinol or
febuxostat.
Mvelosuppression,
nephrotoxicity, and
neurotoxicity.
CYTarabine causes
panCYTopenia.
Mvelosuppression, palmar-
plantar ervthrodvsesthesial
Mvelosuppression, which is
reversible with leucovorin
“rescue.”
Hepatotoxicity.
Mucositis (eg, mouth ulcers).
Pulmonary fibrosis.
416 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY
Antitumor antibiotics
DRUG MECHANISM CLINICAL USE ADVERSE EFFECTS
Bleomycin Induces free radical formation Testicular cancer, Hodgkin Pulmonary fibrosis, skin
-*• breaks in DNA strands. lymphoma. hyperpigmentation . Minimal
mvelosuppression.
Dactinomycin Intercalates in DNA. Wilms tumor, Ewing sarcoma , Myelosuppression .
(actinomycin D) rhabdomyosarcoma . Used for
childhood tumors (“ children
act out ” ).
Doxorubicin , Generate free radicals. Solid tumors, leukemias, Cardiotoxicity (dilated
daunorubicin Intercalate in DNA -* breaks in lymphomas. cardiomyopathy),
DNA -* 1 replication .
• myelosuppression, alopecia.
Dexrazoxane ( iron chelating
agent), used to prevent
cardiotoxicity.

Alkylating agents
DRUG MECHANISM CLINICAL USE ADVERSE EFFECTS
Busulfan Cross-links DNA. CML . Also used to ablate Severe myelosuppression ( in
patient’s bone marrow before almost all cases), pulmonary
bone marrow transplantation . fibrosis, hyperpigmentation .
Cyclophosphamide, Nitrogen mustard; cross-link Solid tumors, leukemia , Myelosuppression; hemorrhagic
ifosfamide DNA at guanine N-7. Require lymphomas. cystitis, prevented with
bioactivation bv livei mesna (thiol group of mesna
binds toxic metabolites) or
N-acetylcvsteine .
Nitrosoureas Require bioactivation . Brain tumors ( including CNS toxicity (convulsions,
(Carmustine, Cross blood-brain barrier glioblastoma multiforme). dizziness, ataxia).
lomustine,
semustine,
- -
CNS. Cross link DNA.

streptozotocini
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY SECTION III 417

Microtubule inhibitors
DRUG MECHANISM CLINICAL USE ADVERSE EFFECTS
Paclitaxel, other taxols Hyperstabilize polymerized Ovarian and breast carcinomas. Mvelosuppression , neuropathy,
microtubules in M phase so hypersensitivity.
that mitotic spindle cannot
break down (anaphase cannot
occur).
Vincristine, vinblastine Vinca alkaloids that bind Solid tumors, leukemias, Vincristine: neurotoxicity
p-tubulin and inhibit Hodgkin (vinblastine) and (areflexia , peripheral neuritis),
its polymerization into non-Hodgkin ( vincristine) constipation ( including
microtubules -*• prevent lymphomas. paralytic ileus).
mitotic spindle formation
( M-phase arrest).

Cisplatin, carboplatin
MECHANISM Cross-link DNA.
CLINICAL USE Testicular, bladder, ovary, and lung carcinomas.
ADVERSE EFFECTS Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free
radical scavenger) and chloride (saline) diuresis.

Etoposide, teniposide
MECHANISM

CLINICAL USE
ADVERSE EFFECTS
—
Etoposide inhibits topoisomerase II t DNA degradation .
Solid tumors ( particularly testicular and small cell lung cancer ), leukemias, lymphomas.
Mvelosuppression , alopecia .

Irinotecan, topotecan
MECHANISM Inhibit topoisomerase I and prevent DNA unwinding and replication .
CLINICAL USE Colon cancer (irinotecan ); ovarian and small cell lung cancers (topotecan ).
ADVERSE EFFECTS Severe mvelosuppression , diarrhea.

Hydroxyurea
MECHANISM

CLINICAL USE

ADVERSE EFFECTS
Inhibits ribonucleotide reductase
— -
1 DNA Synthesis (S phase specific).
Melanoma , myeloproliferative syndromes (eg, CML, polvcvthemia vera ), sickle cell ( T HbF ) j
Severe mvelosuppression .
418 SECTION III HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY
Prednisone, prednisolone
MECHANISM Various; bind intracvtoplasmic steroid receptor; alter gene transcription .
CLINICAL USE Most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin
lymphoma ( part of combination chemotherapy regimen ). Also used as immunosuppressants (eg,
in autoimmune diseases).
ADVERSE EFFECTS Cushing-like symptoms; weight gain , central obesity, muscle breakdown , cataracts, acne,
osteoporosis, hypertension , peptic ulcers, hyperglycemia , psychosis.

Bevacizumab
MECHANISM Monoclonal antibody against VEGF. Inhibits angiogenesis.
CLINICAL USE Solid tumors (colorectal cancer, renal cell carcinoma ).
ADVERSE EFFECTS Hemorrhage, blood clots, and impaired wound healing.

Erlotinib
MECHANISM EGFR tyrosine kinase inhibitor.
CLINICAL USE Non-small cell lung carcinoma .
ADVERSE EFFECTS Rash .

Cetuximab
MECHANISM Monoclonal antibody against EGFR .
CLINICAL USE Stage IV colorectal cancer ( wild-type KRAS ) , head and neck cancer.
ADVERSE EFFECTS Rash , elevated LFTs, diarrhea.

Imatinib
MECHANISM -
Tyrosine kinase inhibitor of BCR ABL ( Philadelphia chromosome fusion gene in CML) and c-kit
(common in GI stromal tumors).
CLINICAL USE CML, GI stromal tumors (GIST j
ADVERSE EFFECTS Fluid retention .

Rituximab
MECHANISM Monoclonal antibody against CD20, which is found on most B -cell neoplasms.
CLINICAL USE Non- Hodgkin lymphoma , CLL , ITP, rheumatoid arthritis,
ADVERSE EFFECTS t risk of progressive multifocal leukoencephalopathy.
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHARMACOLOGY SECTION III 419

Tamoxifen, raloxifene
MECHANISM Selective estrogen receptor modulators (SERMs) — receptor antagonists in breast and agonists in
bone. Block the binding of estrogen to ER ® cells.
CLINICAL USE Breast cancer treatment ( tamoxifen only) and prevention. Raloxifene also useful to prevent
osteoporosis.
ADVERSE EFFECTS
—
Tamoxifen partial agonist in endometrium, which t the risk of endometrial cancer; “ hot flashes.”
Raloxifene — no t in endometrial carcinoma because it is an estrogen receptor antagonist in
endometrial tissue.
Both t risk of thromboembolic events (eg, DVT, PE ).

Trastuzumab ( Herceptin )
MECHANISM Monoclonal antibody against HER-2 (c-erbB2 ), a tyrosine kinase receptor. Helps kill cancer cells
that overexpress HER-2 , through inhibition of HER 2-initiated cellular signaling and antibody-
dependent cytotoxicity.
CLINICAL USE HER-2 ® breast cancer and gastric cancer (trasZzumab).
ADVERSE EFFECTS Cardiotoxicity. “ Heartceptin” damages the heart.

Vemurafenib
MECHANISM Small molecule inhibitor of BRAF oncogene ® melanoma. VEmuRAF-enib is for V600E-
mutated BRAF inhibition .
CLINICAL USE Metastatic melanoma.

Common
chemotoxicities
Cisplatin /Carboplatin
nephrotoxicity) — ototoxicity (and

!
1
w
Vincristine
— —
peripheral neuropathy
Bleomycin , Busulfan pulmonary fibrosis

——
* Doxorubicin -* cardiotoxicity
Trastuzumab ( Herceptin ) cardiotoxicity
Cisplatin /Carboplatin nephrotoxic (and
ototoxicity

CYclophosphamide

-
—
5 FU -* myelosuppression
•

6-MP -* myelosuppression
hemorrhagic cystitis

—
Hydroxyurea -» myelosuppression
Methotrexate myelosuppression
HIGH- YI E LD SYSTEMS

Musculoskeletal, Skin,
and Connective Tissue

“ Rigid , the skeleton of habit alone upholds the human frame.” Anatomy and
— Virginia Woolf Physiology 422

“ Beauty may be skin deep , but ugly goes clear to the bone." Pathology 433
— Redd Foxx
Dermatology 443
“ The function of muscle is to pull and not to push, except in the case of
the genitals and the tongue .” Pharmacology 453
— Leonardo da Vinci
“ To thrive in life you need three bones. A wishbone. A backbone. And a
tunny bone.”
— Reba McEntire

421
422 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE- ANATOMY AND PHYSIOLOGY

Knee exam ACL: extends from lateral femoral condyle to

—
Femur «
anterior tibia. Lateral — v
^
Medial

PCL: extends from medial femoral condyle to

condyle \ condyle

-^-
ACL PCL
posterior tibia.
Perform knee exam with patient supine.
LCL
Lateral
meniscus
Fibula
—
— •
V-MCL
Medial
meniscus
Tibia gg

TEST PROCEDURE

Anterior drawer sign Bending knee at 90° angle, t anterior gliding

of tibia due to ACL injury. Lachman test is ACL tear
Antenor drawer sign
similar, but at 30° angle.
Posterior drawer sign Bending knee at 90° angle, t posterior gliding of
tibia due to PCL injury.
PCL tear
Posterior drawer sign

Abnormal passive Knee either extended or at ~ 30° angle, lateral

Abduction
abduction (valgus) force -» medial space widening of (valgus)
MCL tear

tibia -* MCL injury. force

Abnormal passive Knee either extended or at ~ 30° angle, medial

adduction

— LCL injury.
—
(varus) force lateral space widening of tibia Adduction
(varus)
force
LCL tear

McMurray test During flexion and extension of knee with

External
rotation of tibia /foot: rotation Medial tear
Pain, “popping” on external rotation
-* medial meniscal tear ' P'
Pain, “popping” on internal rotation
Internal r Lateral tear

— lateral meniscal tear

rotation
0

Common fractures
Boxer 's fracture Striking hard object with a closed fist
-*• metacarpal neck fracture of 3th digit
Greenstick fracture Bending force
radius
— compression fracture of distal

Torus fracture Axial force applied to immature bone -* simple ART GOES HERE — FPO
buckle fracture of cortex
424 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

Overuse injuries of the elbow

Medial epicondylitis
(golfer 's elbow )
Repetitive flexion (forehand shots) or idiopathic — pain near medial epicondyle.

Lateral epicondylitis
(tennis elbow )
Repetitive extension ( backhand shots) or idiopathic
— pain near lateral epicondyle.

Wrist bones Scaphoid, Lunate, Triquetrum,

Pisiform, Hamate, Capitate, Trapezoid,
Trapezium Q. (So Long To Pinky, Here
Comes The Thumb).
Scaphoid ( palpated in anatomic snuffbox ) is
the most commonly fractured carpal bone,
typically due to a fall on an outstretched hand.
Complications of proximal scaphoid fractures
include avascular necrosis and nonunion
owing to retrograde blood supply
Dislocation of lunate may cause acute carpal

Carpal tunnel
tunnel syndrome
^ —
Entrapment of median nerve in carpal tunnel; nerve compression paresthesia, pain, and
syndrome numbness in distribution of median nerve ( thenar eminence atrophies but sensation spared,
because palmar cutaneous branch enters the hand external to carpal tunnel). Associated with
pregnancy ( due to edema!rheumatoid arthritis, hypothyroidism, diabetes, acromegaly dialysis-
related amyloidosis; may be associated with repetitive use. Tinel sign ( on percussion) and Phalen
maneuver (on 90° flexion) of wrist produces tingling.
Guyon canal Compression of ulnar nerve at wrist or hand. Classically seen in cyclists due to pressure from
syndrome handlebars.
 MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY SECTION III 425

Upper extremity nerves

NERVE CAUSES OF INJURY PRESENTATION
Axillary ( C5-C6) Fractured surgical neck of humerus; anterior Flattened deltoid
dislocation of humerus Loss of arm abduction at shoulder (> 15 j)
Loss of sensation over deltoid muscle and lateral
arm
Musculocutaneous Upper trunk compression Loss of forearm flexion and supination
(C5-C7 ) Loss of sensation over lateral forearm
Radial (C 5-T1) Midshaft fracture of humerus; compression of Wrist drop: loss of elbow, wrist, and finger
axilla , eg, due to crutches or sleeping with arm extension
over chair (“ Saturday night palsy” ) i grip strength (wrist extension necessary for
maximal action of flexors)
Loss of sensation over posterior arm /forearm and
dorsal hand
Median (C5-T1) Supracondylar fracture of humerus ( proximal “ Apehand ” and “ Pope’s blessing”
lesion ); carpal tunnel syndrome and wrist Loss of wrist flexion, flexion of lateral fingers,
laceration (distal lesion ) thumb opposition , lumbricals of 2nd and 3rd
digits
Loss of sensation over thenar eminence and
dorsal and palmar aspects of lateral 3 /2 fingers
with proximal lesionf
Ulnar (C8-T1) Fracture of medial epicondyle of humerus “ Ulnar claw” on digit extension
“ funny bone” ( proximal lesion ); fractured Radial deviation of w rist upon flexion ( proximal
hook of hamate (distal lesion ) from fall on lesion )
outstretched hancfl Loss of w rist flexion , flexion of medial fingers,
abduction and adduction of fingers ( interossei),
actions of medial 2 lumbrical muscles
Loss of sensation over medial IV2 fingers
including hypothenar eminence
Recurrent branch of Superficial laceration of palm “ Apehand ”
median nerve (C5-T1) Loss of thenar muscle group: opposition ,
abduction , and flexion of thumb
No loss of sensation

Axillary nerve

^4 CB

Axillary nerve
Median nerve

Musculocutaneous nerve
. Intercostobrachial
Ulnar nerve
Radial nerve S nerve

^— cutaneous nerve
Radial nerve Radial nerve
Medial brachial
, Palm of hand

—
Median nerve Ulnar nerve
Musculocutaneous nerve Medial antebrachial

Radial nerve
I
I " cutaneous nerve Median nerve u
Ulnar nerve

— J
Recurrent branch Radial nerve
of median nerve Radial nerve
^
% Dorsum of hand

0
426 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

Brachial plexus lesions

O Erb palsy ('waiter's tip") C5 Upper Lateral Randy
0 Klumpke palsy (claw hand) o 0 Musculocutaneous Travis
0 Wrist drop C6 Drinks
Axillary
O Winged scapula Middle Posterior 0 Cold
© Deltoid paralysis C7 0 (Extensors) O Median (flexors)
© “ Saturday night palsy’(wrist drop) o Beer
Radial
0 Difficulty flexing elbow, variable C8
sensory loss Lower Medial
© Decreased thumb function, 0 Q Ulnar
'Pope's blessing' T1 —
1 i—
Trunks
1 1— — 1 1— i—
i
Divisions Cords
1
Branches
© Intrinsic muscles of hand,
claw hand
o
Long thoracic

L J
Roots 0

CONDITION INJURY CAUSES MUSCLE DEFICIT FUNCTIONAL DEFICIT PRESENTATION

Erb palsy (“ waiter 's Traction or Infants — lateral Deltoid, Abduction (arm
tip") tear of upper traction on neck supraspinatus hangs by side)
(“ Erb-er ” ) trunk: during delivery Infraspinatus Lateral rotation (arm
C 5 -C6 roots Adults — trauma medially rotated)
Biceps brachii Flexion, supination
(arm extended and
pronated)

Klumpke palsy Traction or tear Infants — upward Intrinsic hand Total claw hand:
of lower trunk: force on arm muscles: lumbricals normally
C8-T1 root during delivery lumbricals, flex MCP joints and
Adults — trauma interossei, extend DIP and PIP
(eg, grabbing a thenar, joints
tree branch to hypothenar
break a fall)
Thoracic outlet Compression Cervical rib Same as Klumpke Atrophy of intrinsic
syndrome of lower trunk (arrows in Hi palsy hand muscles;
and subclavian Pancoast tumor ischemia, pain,
vessels and edema
due to vascular
compression
Winged scapula Lesion of long Axillary node Serratus anterior Inability to anchor
thoracic nerve dissection after scapula to thoracic
mastectomy,
stab wounds
—
cage cannot
abduct arm above
horizontal position
428 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE
Lower extremity nerves
NERVE INNERVATION
lliohypoqastric Sensory — suprapubic region
(T12-L1) Motor — transversus abdominis
and internal oblique
Genitofemoral nerve Sensory — scrotum /labia
(L1-L2) majora, medial thigh
Motor — cremaster
Lateral femoral Sensory: anterior and lateral
cutaneous (L2-L3 ) thigh
Obturator (L 2- L4) Sensory — medial thigh
Motor — obturator externus.
adductor longus, adductor
brevis, gracilis, pectineus.
adductor magnus
Femoral (L 2- L4) Sensory — anterior thigh.
medial leg
Motor — quadriceps, iliopsoas.
pectineus, sartorius
Sciatic ( L4-S3 ) Sensory — posterior thigh
Motor — semitendinosus.
semimembranosus, biceps
femoris, adductor magnus
Common peroneal Sensory — dorsum of foot
(L4- S2) Motor — biceps femoris, tibialis
anterior, extensor muscles
Tibial (L4-S3) Sensory — sole of foot
Motor — triceps surae, plantaris,
popliteus, flexor muscles
CAUSE OF INJURY
Abdominal surgery
Laparoscopic surgery
Tight clothing, obesity .
pregnancy
Pelvic surgery
Pelvic fracture
Herniated disc
Trauma or compression of
lateral aspect of leg, fibular
neck fracture
Knee trauma, Baker cyst
( proximal lesion); tarsal
tunnel syndrome (distal
lesion)
ANATOMY AND PHYSIOLOGY
PRESENTATION/COMMENTS
Burning or tingling pain in
surgical incision site radiating
to inguinal and suprapubic
region
i anterior thigh sensation
beneath inguinal ligament;
absent cremasteric reflex
i thigh sensation (anterior and
lateral)
i thigh sensation (medial) and
adduction
1 thigh flexion and leg
extension.
Splits into common peroneal
and tibial nerves
PED = Peroneal Everts and
Dorsiflexes; if injured, foot
dropPED
Foot drop — inverted and
plantarflexed at rest, loss of
eversion and dorsiflexion;
“ steppage gait ”; loss of
sensation on dorsum of foot
TIP = Tibial Inverts and
Plantarflexes; if injured, can’t
stand on TIPtoes
Inability to curl toes and loss of
sensation on sole; in proximal
lesions, foot everted at rest
with loss of inversion and
plantar flexion
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY SECTION III 429

Lower extremity nerves ( continued )

NERVE INNERVATION CAUSE OF INJURY PRESENTATION/COMMENTS
Superior qluteal ( L4- Motor — gluteus medius, gluteus Iatrogenic injury during Trendelenburg sign /gait —
§11 minimus, tensor fascia latae intramuscular injection to pelvis tilts because weight-
upper medial gluteal region bearing leg cannot maintain
Normal Trendelenburg sign
alignment of pelvis through
hip abduction

1f.
Inferior qluteal ( L 5 - S2)
Pudendal (S 2- S 4)
Lesion is contralateral to the
side of the hip that drops,
ipsilateral to extremity' on
which the patient stands
Choose superolateral gluteal
quadrant as intramuscular
injection site to avoid nerve
injury
Motor — gluteus maximus Posterior hip dislocation Difficulty climbing stairs, rising
from seated position; loss of
hip extension
Sensory — perineum Stretch injury during childbirth 1 sensation in perineum and
Motor — urethral and anal genital area; can cause fecal
sphincters or urinary incontinence
Can be blocked with local
anesthetic during childbirth
using ischial spine as a
landmark for injection

Hip muscles
ACTION MUSCLES
Abductors Gluteus medius, gluteus minimus
Adductors Adductor magnus, adductor longus, adductor brevis
Extensors .
Gluteus maximus semitendinosi, semimembranosus
Flexors Iliopsoas, rectus femoris, tensor fascia lata, pectineus
Internal rotation Gluteus medius, gluteus minimus, tensor fascia latae
External rotation Iliopsoas, gluteus maximus, piriformis, obturator
430 SECTION III MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

Signs of lumbosacral Paresthesia and weakness related to specific Intervertebral discs generally herniate
radiculopathy lumbosacral spinal nerves. Usually, the posterolaterally, due to the thin posterior
intervertebral disc herniates into the central longitudinal ligament and thicker anterior
canal , affecting the inferior nerves (eg, longitudinal ligament along the midline of the
herniation of L 3/4 disc affects L4 spinal nerve, vertebral bodies.
but not L3) j
DISC LEVEL FINDINGS
L3-L4 Weakness of knee extension , 1 patellar reflex
L4-L 5 Weakness of dorsiflexion , difficulty in heel-
walking
L 5-S1 Weakness of plantar flexion, difficult}’ in toe¬
walking, i Achilles reflex

Neurovascular pairing Nerves and arteries are frequently named together by the bones/regions with which they are
associated . The following are exceptions to this naming convention .
LOCATION NERVE ARTERY
Axilla /lateral thorax Long thoracic Lateral thoracic
Surgical neck of Axillary Posterior circumflex
humerus
Midshaft of humerus Radial Deep brachial
Distal humerus/ Median Brachial
cubital fossa
Popliteal fossa Tibial Popliteal

Posterior to medial Tibial Posterior tibial

malleolus
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY SECTION III 431

Muscle conduction to T-tubules are extensions of plasma membrane juxtaposed with terminal cisternae of the
contraction sarcoplasmic reticulum, allowing for coordinated contraction of musclej
Dihydropyridine receptor In skeletal muscle, 1 T-tubule + 2 terminal cisternae = triad.
T-tubule membrane In cardiac muscle, 1 T-tubule + 1 terminal cisterna = dyad.
[Revised Exterior
| Figure | Cvtosol
1. Action potential depolarization opens presynaptic voltage-gated Ca2+ channels, inducing
neurotransmitter release.
8$ 2. Postsvnaptic ligand binding leads to muscle cell depolarization in the motor end plate.
Ryanodine Sarcoplasmic 3. Depolarization travels along muscle cell and down the T-tubule.
receptor reticulum 3 4. Depolarization of the voltage-sensitive dihydropyridine receptor, mechanically coupled to the
ryanodine receptor on the sarcoplasmic reticulum, induces a conformational change in both
receptors, causing Ca-+ release from sarcoplasmic reticulum.
5. Released Ca-+ binds to troponin C, causing a conformational change that moves tropomyosin
out of the myosin-binding groove on actin filaments.
—
6. Myosin releases bound ADP and P| displacement of myosin on the actin filament (power
stroke). Contraction results in shortening of H and I bands and between Z lines (IlIZ
shrinkage), but the A band remains the same length (A band is Always the same length) .
7. Binding of a new ATP molecule causes detachment of myosin head from actin filament.
—
Hydrolysis of bound ATP ADP, myosin head adopts high-energy position (“cocked") for the
next contraction cycle.

T- tubule
Actin Myosin

li

Mitochondrion M line

| A band || I band |

U
H band

Types of muscle fibers

Type 1 muscle Slow twitch; red fibers resulting from Think “1 slow red ox.”
t mitochondria and myoglobin concentration
( t oxidative phosphorylation) -*• sustained
contraction. Proportion t after endurance
training.
Type 2 muscle Fast twitch; white fibers resulting from
i mitochondria and myoglobin concentration
(t anaerobic glycolysis). Proportion t after
weight /resistance training, sprinting
432 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

Smooth muscle contraction

Agonist Acetylcholine
bradykinin, etc
Endothelial cells

o-
|_
- —
Receptor

Ca 2
i
*

L-arginine *
NO synthase
NO

L-type voltage v ^ Smooth muscle cell NO diffusion

gated Ca2‘
channel
Action
potential - TCa;* NO .
I
+
+* * *
TCa - calmodulin
complex
GTP - 4 cGMP
Myosin
+ actin
I
4
Myosin-light -chain Myosin-light-chain
kinase phosphatase
(MLCK ) Myosin-P ( MLCP)
+ actin
CONTRACTION RELAXATION

T Ca2 ’- CONTRACTION Nitric oXide - RELAXATION

Bone formation
Endochondral Bones of axial skeleton, appendicular skeleton, and base of skull. Cartilaginous model of bone is
ossification first made by chondrocytes. Osteoclasts and osteoblasts later replace with woven bone and then
remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease.
Defective in achondroplasia.
Membranous Bones of calvarium and facial bones. Woven bone formed directly without cartilage. Later
ossification remodeled to lamellar bone.

Cell biology of bone

Osteoblast Builds bone by secreting collagen and catalyzing mineralization in alkaline environment via ALP.
Differentiates from mesenchymal stem cells in periosteum. Osteoblastic activity measured by
bone ALP, osteocalcin, propeptides of type I procollagen.
Osteoclast Dissolves bone by secreting H+ and collagenases. Differentiates from a fusion of monocyte /
macrophage lineage precursors.
Parathyroid hormone At low, intermittent levels, exerts anabolic effects ( building bone) on osteoblasts and osteoclasts
(indirect). Chronically t PTH levels (1° hyperparathyroidism) cause catabolic effects (osteitis
fibrosa cystica).
Estrogen Inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts.
Causes closure of the epiphyseal plate during puberty. Estrogen deficiency (surgical or
postmenopausal), excess cycles of remodeling, and bone resorption lead to osteoporosis.
432 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY

Smooth muscle contraction

Agonist Acetylcholine
bradykinin, etc
Endothelial cells

o-
|_
- —
Receptor

Ca 2
i
*

L-arginine *
NO synthase
NO

L-type voltage v ^ Smooth muscle cell NO diffusion

gated Ca2‘
channel
Action
potential - TCa;* NO .
I
+
+* * *
TCa - calmodulin
complex
GTP - 4 cGMP
Myosin
+ actin
I
4
Myosin-light -chain Myosin-light-chain
kinase phosphatase
(MLCK ) Myosin-P ( MLCP)
+ actin
CONTRACTION RELAXATION

T Ca2 ’- CONTRACTION Nitric oXide - RELAXATION

Bone formation
Endochondral Bones of axial skeleton, appendicular skeleton, and base of skull. Cartilaginous model of bone is
ossification first made by chondrocytes. Osteoclasts and osteoblasts later replace with woven bone and then
remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease.
Defective in achondroplasia.
Membranous Bones of calvarium and facial bones. Woven bone formed directly without cartilage. Later
ossification remodeled to lamellar bone.

Cell biology of bone

Osteoblast Builds bone by secreting collagen and catalyzing mineralization in alkaline environment via ALP.
Differentiates from mesenchymal stem cells in periosteum. Osteoblastic activity measured by
bone ALP, osteocalcin, propeptides of type I procollagen.
Osteoclast Dissolves bone by secreting H+ and collagenases. Differentiates from a fusion of monocyte /
macrophage lineage precursors.
Parathyroid hormone At low, intermittent levels, exerts anabolic effects ( building bone) on osteoblasts and osteoclasts
(indirect). Chronically t PTH levels (1° hyperparathyroidism) cause catabolic effects (osteitis
fibrosa cystica).
Estrogen Inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts.
Causes closure of the epiphyseal plate during puberty. Estrogen deficiency (surgical or
postmenopausal), excess cycles of remodeling, and bone resorption lead to osteoporosis.
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE
MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE- PATHOLOGY
Achondroplasia
Osteoporosis
Normal vertebrae
Mild compression fracture
Osteopetrosis ( marble
bone disease, Albers-
Schonberq disease )!
A
PATHOLOGY SECTION III 433
—
Failure of longitudinal bone growth (endochondral ossification) short limbs. Membranous
ossification is not affected -* large head relative to limbs. Constitutive activation of fibroblast
growth factor receptor (FGFR 3 ) actually inhibits chondrocyte proliferation. > 85% of mutations
occur sporadically; autosomal dominant with full penetrance (homozygosity is lethal). Most
common cause of dwarfism.
Trabecular (spongy) and cortical bone lose mass Can lead to vertebral compression fractures ( ,
and interconnections despite normal bone small arrows; large arrows show normal-for-age
-
mineralization and lab values (serum Ca + and vertebral body height for comparison) — acute
P04'-). back pain, loss of height, kyphosis. Also can
Most commonly due to t bone resorption present with fractures of femoral neck, distal
related to i estrogen levels and old age. radius (Colles fracture).
Can be secondary to drugs (eg, steroids,
alcohol, anticonvulsants, anticoagulants,
thyroid replacement therapy) or other
medical conditions (eg, hyperparathyroidism,
hyperthyroidism, multiple myeloma,
malabsorption syndromes).
Diagnosed by a bone mineral density scan
(dual-energy x-ray absorptiome [DEXAp with
a|T-score of < — 2.5 or by a fragility fracture of
hip or vertebra. Screening recommended in
women > 65 years olcjj
Prophylaxis: regular weight-bearing exercise
and adequate Ca~+ and vitamin D intake
throughout adulthood.
Treatment: bisphosphonates, teriparatide,
SERMs, rarely calcitonin; denosumab
(monoclonal antibody against RANKL).
—
Failure of normal bone resorption due to defective osteoclasts thickened, dense bones that are
prone to fracture. Defective osteoclasts cause overgrowth and sclerosis of cortical bone. Bone fillj
marrow space -* pancytopenia, extramedullary hematopoiesis. Mutations (eg, carbonic anhydrase
II) impair ability of osteoclast to generate acidic environment necessary for bone resorption.
X-rays show bone-in-bone ('‘stone” bone) appearance Q. Can result in cranial nerve impingement
and palsies as a result of narrowed foramina. Bone marrow transplant is potentially curative as
osteoclasts are derived from monocytes.
434 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY

m'
Osteomalacia / rickets Defective mineralization of osteoid
(osteomalacia) or cartilaginous growth plates

A1
(rickets, only in children). Most commonly due
to vitamin D deficiency.
X-rays show osteopenia and “ Looser zones”
(pseudofractures) in osteomalacia, epiphyseal
widening and metaphyseal cupping/fraying in
rickets. Children with rickets have pathological
boujlegs , bead-like costochondral junctions
(rachitic rosary), craniotabes (soft skull).
f
—— —
1 vitamin D 1 serum Ca2+ t PTH
secretion i serum
Hyperactivity of osteoblasts — t ALP.

Paget disease of bone Common, localized disorder of bone
( osteitis deformans) remodeling caused by t osteoclastic activity
followed by t osteoblastic activity that forms
poor-quality bone. Serum Ca ~+, phosphorus,
and PTH levels are normal, t ALP. Mosaic
pattern of woven and lamellar bone (osteocytes
within!lacunae in chaotic juxtapositions); long
bone chalk-stick fractures, t blood flow from
t arteriovenous shunts may cause high-output
heart failure, t risk of osteogenic sarcoma.
Hat size can be increased due to skull
thickening ; hearing loss is common due to
auditory foramen narrowing.
Stages of Paget disease:
Lytic — osteoclasts
Mixed — osteoclasts + osteoblasts
a
Sclerotic — osteoblasts
Quiescent — minimal osteoclast /osteoblast
activity.
Treatment: bisphosphonates, calcitonin.

Osteonecrosis Infarction of bone and marrow, usually very cerstKM

( avascular necrosis) painful. Most common site is femoral
D ’: -v : \- 0'
zone infarcted
obturator artery
head Q (due to insufficiency of medial
circumflex femoral artery). Causes include
Corticosteroids, Alcoholism, Sickle cell Media femoral
disease, Trauma, “ the Bends” (caisson / circumflex artery

decompression disease), LEgg-Calve-Perthes Lateral femoral

* ,j disease (idiopathic), Gaucher disease, Slipped circumflex artery
capital femoral epiphysis — CAST Bent LEGS.
436 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY

Primary bone tumors

TUMOR TYPE EPIDEMIOLOGY/LOCATION CHARACTERISTICS
Benign tumors
Osteochondroma Most common benign bone tumor. Bony exostosis with cartilaginous (chondroid)
Males < 25 years old. capQ.
Rarely transforms to chondrosarcoma.
Giant cell tumor 20-40 years old. Locally aggressive benign tumor.
Epiphyseal end of long bones. Arises most “ Soap bubble” appearance on x-ray Q.
commonly at distal femur and proximal tibia! Multinucleated giant cells that express RANKLj
“ Osteoclastoma.”
Malignant tumors
Osteosarcoma Most common 1° malignant bone tumoj Codman triangle (from elevation of periosteum)
(osteogenic sarcoma) Bimodal distribution: 10-20 years old (1°), > 65 or sunburst pattern on x-ray.
(2°). Aggressive. Treat with surgical en bloc resection
Predisposing factors: Paget disease of bone, bone (with limb salvage) and chemotherapy.
infarcts, radiation, familial retinoblastoma,
Li-Frauineni syndrome (germline pS 3
mutation).
Metaphysis of long bones, often around knee Q.
Ewing sarcoma Boys < 15 years old. Anaplastic small blue cell malignant tumor QJ.
Commonly appears in diaphysis of long bones, Extremely aggressive with early metastases, but
pelvis, scapula, ribs. responsive to chemotherapy.
“ Onion skin” periosteal reaction in bone.
Associated with t(l1;22) translocation causing
fusion protein EWS-FLI 1.
11 + 22 = 33 (Patrick Ewings jersey number).

f
r
Round cell lesions
Ewing sarcoma
.£ Myeloma
f<
C5
,
Fibrous dysplasia

Osteoid osteoma
( nighttime pan central nidusl
\
V
Simple bone cyst

- hi
&4 \ tti rn

*»
7,
Osteosarcoma
Osteochondroma 1
Physis

I{ Giant cell tumor

a
>-

J
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY SECTION III 437

Osteoarthritis and rheumatoid arthritis

Osteoarthritis Rheumatoid arthritis
PATHOGENESIS Mechanical — wear and tear destroys articular Autoimmune — inflammatory cytokines and
cartilage ( DID ) and causes inflammation with cells induce pannus (proliferative granulation
inadequate repair. Chondrocytes mediate tissue) formation, which erodes articular
degradation and inadequate repaid cartilage and bone.
PREDISPOSING FACTORS Age, female, obesity, joint trauma. Female, HLA-DR4, smoking, silica exposure.
© rheumatoid factor ( IgM antibody that
targets IgC Fc rcgioij in 80%), anti-cyclic
citrullinated peptide antibody (more specific).
PRESENTATION Pain in weight-bearing joints after use (eg, Pain, swelling, and morning stiffness lasting
at the end of the day), improving with rest. > 1 hour, improving with use. Symmetric
Asymmetric joint involvement. Knee cartilage joint involvement. Systemic symptoms
loss begins medially (“ bowlegged” ). No (fever, fatigue, weight loss). Extraarticular
systemic symptoms. manifestations common.*
JOINT FINDINGS Osteophytes (bone spurs), joint space narrowing, Erosions, juxtaarticular osteopenia, soft tissue
subchondral sclerosis and cysts. Synovial swelling, subchondral cysts, joint space
fluid non-inflammatory ( WBC < 2000/mm5). narrowing ( more prominent as disease
progresses Deformities include cervical
Involves DIP (Heberden nodes Q) and PIP
( Bouchard nodes), and 1st CMC; not MCP. ^
subluxatiorj fingers with ulnar deviation,
sw an neck Q, and boutonniere. Synovial fluid
inflammatory ( WBC > 2000/mm5). Involves
MCP, PIP, wrist; not DIP or 1st CMC.
TREATMENT Acetaminophen, NSAIDs, intra-articular NSAIDs, glucocorticoids, disease-modifying
glucocorticoids. agents (methotrexate, sulfasalazine,
hydroxychloroquine, leflunomide), biologic
agents (eg, TNF-a inhibitors).
^ Extraarticular manifestations
include rheumatoid nodules (fibrinoid necrosis with palisading histiocytes) in subcutaneous
tissue and lung (+ pneumoconiosis -*• Caplan syndrome), interstitial lung disease, pleuritis, pericarditis, anemia of chronic
disease, neutropenia + splenomegaly (Felty syndrome), AA amyloidosis, Sjogren syndrome, scleritis, carpal tunnel syndrome.
Normal Osteoarthritis Normal

f
Rheumatoid
arthritis
Thickened
capsule Bone and
/I*0® ® cartilage
Joint capsule —.
« - \ slight synovial
nypertrophy Joint capsule —\ v erosion
and synovial
lining
\ Osteophyte
and synovial
lining
i creased
Synovial U cerated Synovial synovial fluid
cavity
Cartilage 3^::- sclerotic bone
Joint space
narrowing
cavity
Cartilage
Pannus
formation
Revised
Figure

sulxhondiai
bone cyst
438 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY

Gout
FINDINGS Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in
joints Q. More common in males. Associated with hyperuricemia, which can be caused by:
31
Underexcretion of uric acid (90% of patients) — largely idiopathic, potentiated by renal failure!;
can be exacerbated by certain medications (eg, thiazide diuretics).
•
Overproduction of uric acid ( 10% of patients) — Lesch-Nyhan syndrome, PRPP excess, t cell
turnover (eg, tumor lysis syndrome), von Gierke disease.
Crystals are needle shaped and © birefringent under polarized light (yellow under parallel light,
blue under perpendicular light Q).
SYMPTOMS Asymmetric joint distribution. Joint is swollen, red, and painful. Classic manifestation is painful
MTP joint of big toe (podagra). Tophus formation Q (often on external ear, olecranon bursa, or
Achilles tendon). Acute attack tends to occur after a large meal with foods rich in purines (eg, red
meat, seafood) or alcohol consumption!(alcohol metabolites compete for same excretion sites in

TREATMENT
—
kidney as uric acid 1 uric acid secretion and subsequent buildup in blood).
Acute: NSAIDs (eg, indomethacin), glucocorticoids, colchicine.
Chronic ( preventive): xanthine oxidase inhibitors (eg, allopurinol, febuxostat).

u
-J

'
.
5
*
Q
r to-

Calcium Deposition of calcium pyrophosphate crystals within the joint space. Occurs in patients > 50 years
pyrophosphate old; both sexes affected equally. Usually idiopathic, sometimes associated with hemochromatosis,
deposition disease hyperparathyroidism, joint trauma.
Pain and swelling with acute inflammation ( pseudogout) and/or chronic degeneration ( pseudo ¬

osteoarthritis). Knee most commonly affected joint.

Chondrocalcinosis (cartilage calcification) on x-ray.
Crystals are rhomboid and weakly © birefringent under polarized light (blue when parallel to
light) .

— Acute treatment: NSAIDs, colchicine, glucocorticoids.

Prophylaxis: colchicine.
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY SECTION III 439

Sjogren syndrome Autoimmune disorder characterized by A common 1° disorder or a 2° syndrome

a- #
szaerir
destruction of exocrine glands (especially
lacrimal and salivary) by lymphocytic
infiltrates Q. Predominantly affects females
associated with other autoimmune disorders
(eg, rheumatoid arthritis, SLE, systemic
sclerosis).
40-60 years old. Complications: dental caries; mucosa-associated
Findings: lymphoid tissue (MALT) lymphoma (may
2 rA Inflammatory joint pain present as parotid enlargement)
^
Keratoconjunctivitis sicca (1 tear production Salivarygland biopsy can be used to confirm
and subsequent corneal damage) diagnosis.
a
Xerostomia (1 saliva production)
Presence of antinuclear antibodies,
rheumatoid factor (can be in the absence of
rheumatoid arthritis), antiribonucleoprotein
antibodies: SS-A ( anti-Ro) and/or SS-B ( anti-
Laj
Bilateral parotid enlargement

Septic arthritis S aureus, Streptococcus, and Neisseria gonorrhoeae are common causes. Affected joint is swollen ,
red, and painful. Synovial fluid purulent ( WBC > 50,000/mm ). *
Gonococcal arthritis — STI that presents as either purulent arthritis (eg, knee) or triad of
polyarthralgias, tenosynovitis (eg, hand), dermatitis (eg, pustules).
440 SECTION III MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE PATHOLOGY

Seronegative Arthritis without rheumatoid factor ( no anti-IgG antibody). Strong association with HLA-B27
spondyloarthritis ( MHC class I serotype). Subtypes ( PAIR) share variable occurrence of inflammatory back
pain (associated with morning stiffness, improves with exercise), peripheral arthritis, enthesitis
( inflamed insertion sites of tendons, eg, Achilles), dactylitis (“ sausage fingers” ), uveitis.
Psoriatic arthritis Associated with skin psoriasis and nail lesions. Seen in fewer than lA of patients with psoriasis.
Asymmetric and patch}' involvement Q.
Dactylitis and “ pencil-in-cup” deformity of
DIP on x-ray Q.
Ankylosing
spondylitis
—
Symmetric involvement of spine and sacroiliac
joints ankylosis ( joint fusion ), uveitis, aortic
regurgitation .
-
Bamboo spine (vertebral fusion ) H Can cause
restrictive lung disease due to limited chest wall
expansion .
More common in males.
Inflammatory bowel Crohn disease and ulcerative colitis are often
disease associated with spondyloarthritis.
Reactive arthritis Formerly known as Reiter syndrome. “ Can’ t see, can’ t pee, can’ t bend my knee.”
Classic triad : Post-GI ( Shigella , Salmonella, Yersinia ,
Conjunctivitis Campylobacter ) or Chlamydia infections.
Urethritis
Arthritis

f
r I (r

Wt
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PATHOLOGY SECTION III 441

Systemic lupus erythematosus

SYMPTOMS Classic presentation: rash, joint pain, and fever, RASH OR PAIN:
most commonly in a female of reproductive Rash (malar Q or discoid )
age and African-American descent. Arthritis (nonerosive)
A Libman-Sacks Endocarditis — nonbacterial, Serositis
m verrucous thrombi usually on mitral or aortic
valve and can be present on either surface of
Hematologic disorders (eg, cvtopenias)
Oral/nasopharyngeal ulcers
the valvdfLSE in SLE). Renal disease
Lupus nephritis ( glomerular deposition of anti- Photosensitivity
RU
DNA immune complexes) can be nephritic Antinuclear antibodies
or nephrotic ( hematuria or proteinuria). Immunologic disorder (anti-dsDNA, anti-Sm,
Most common and severe type is diffuse antiphospholipid)
proliferative. Neurologic disorders (eg, seizures, psychosis)
Common causes of death in SLE:
Cardiovascular disease
* Infections
Renal disease
FINDINGS Antinuclear antibodies (ANA) Sensitive, not specific
Anti-dsDNA antibodies Specific, poor prognosis (renal disease)
Anti-Smith antibodies Specific, not prognostic (directed against
snRNPs)
Antihistone antibodies Sensitive for drug-induced lupus (eg,
hydralazine, procainamide)
i C3, C4, and CH50 due to immune complex
formation.
TREATMENT NSAIDs, steroids, immunosuppressants,
hydroxychloroquine.

Antiphospholipid 1° or 2° autoimmune disorder (most commonly Anticardiolipin antibodies can cause false ¬

syndrome in SLE). positive VDRL/RPR, and lupus anticoagulant

Diagnose based on clinical criteria including can cause prolonged PTT, which is not
history of thrombosis (arterial or venous) corrected by the addition of normal platelet-
or spontaneous abortion along with free plasmaj
laboratory findings of lupus anticoagulant,
anticardiolipin, anti-Pi glycoprotein antibodies.
Treat with systemic anticoagulation.

Mixed connective Features of SLE, systemic sclerosis, and/or polymyositis. Associated with anti-Ul RNP antibodies
tissue disease (speckled ANA).
442 SECTION III MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE PATHOLOGY

Sarcoidosis -
Characterized by immune mediated, widespread noncaseating granulomas Q, elevated serum
ACE levels, and elevated CD4+ /CD8+ ratio in bronchoalveolar lavage fluid . More common in
African-American females. Often asymptomatic except for enlarged lymph nodes. Findings on
CXR of bilateral adenopathy and coarse reticular opacities Q; CT of the chest better demonstrates
the extensive hilar and mediastinal adenopathy Q.
Associated with restrictive lung disease (interstitial fibrosis), erythema nodosum , lupus pernio (skin
lesions on face resembling lupus), Bell palsy, epithelioid granulomas containing microscopic
Schaumann and asteroid bodies, uveitis, hypercalcemia ( due to t la-hydroxylase-mediated
vitamin D activation in macrophages).
Treatment: steroids (if symptomatic).

V
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Polymyalgia rheumatica
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SYMPTOMS Pain and stiffness in shoulders and hips, often with fever, malaise, weight loss. Does not cause
muscular weakness. More common in women > 50 years old ; associated with giant cell (temporal )
arteritis.
FINDINGS t ESR, t CRP, normal CK.
TREATMENT Rapid response to low-dose corticosteroids.

Fibromyalqia Most commonly seen in females 20-50 years old. Chronic, widespread musculoskeletal pain
( central sensitization associated with stiffness , paresthesias, poor sleep, fatigue, cognitive disturbance ( “ fibro fog” ).
svndromeL Treatment: regular exercise, antidepressants (TCAs, SNRIs), anticonvulsants.
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE DERMATOLOGY SECTION III 443

Polymyositis / t CK, ® ANA, ® anti-Jo-1, © anti-SRP, © anti-Mi-2 antibodies. Treatment: steroids followed by
dermatomyositis long-term immunosuppressant therapy (eg, methotrexate).
Polymyositis Progressive symmetric proximal muscle weakness, characterized by endomvsial inflammation with
CD8+ T cells. Most often involves shoulders.
Dermatomyositis Similar to polymyositis, but also involves malar rash (similar to SLE), Gottron papules Q,
heliotrope (erythematous periorbital) rash Q, “shawl and face” rash Q, “mechanics hands.” t risk
of occult malignancy. Perimysial inflammation and atrophy with CD4+ T cells.

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Neuromuscular junction diseases

Myasthenia gravis Lambert-Eaton myasthenic syndrome
FREQUENCY Most common NMJ disorder Uncommon
PATHOPHYSIOLOGY Autoantibodies to postsynaptic ACh receptor Autoantibodies to presynaptic Ca~^ channel
-*• 1 ACh release
CLINICAL Ptosis, diplopia, weakness Proximal muscle weakness, autonomic
Worsens with muscle use_ symptoms (dry mouth, impotence)
Improvement after edrophonium ( tensilon) test Improves with muscle use
ASSOCIATED WITH Thymoma, thymic hyperplasia Small cell lung cancer
AChE INHIBITOR ADMINISTRATION Reverses symptoms (edrophonium to diagnose, Minimal effect
pyridostigmine to treat)
444 SECTION III MUSCULOSKELETAL, SKIN , AND CONNECTIVE TISSUE DERMATOLOGY

Scleroderma ( systemic Triad of autoimmunity, noninflammatory vasculopathy, and collagen deposition with fibrosis,
sclerosis) Commonly sclerosis of skin, manifesting as puffy, taut skin Q without wrinkles, fingertip pitting
Q- Also sclerosis of renal, pulmonary (most common cause of death), cardiovascular, GI systems.
75% female. 2 major types:
Diffuse scleroderma — w idespread skin involvement, rapid progression, early visceral
involvement. Associated with anti-Scl-70 antibody (anti-DNA topoisomerase I antibody).
Limited scleroderma — limited skin involvement confined to fingers and face. Also with
CREST syndrome: Calcinosis/anti-Centromere antibody 0, Raynaud phenomenon,
Esophageal dysmotility, Sclerodactyly, and Telangiectasia. More benign clinical cours4
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Raynaud phenomenon 1 blood flow to the skin due to arteriolar (small vessel) vasospasm in response to cold or stress:
color change from white (ischemia) to blue (hypoxia) to red (reperfusion). Most often in the
fingers Q and toes. Called Raynaud disease when 1° (idiopathic), Raynaud syndrome when 2°
to a disease process such as mixed connective tissue disease, SLE, or CREST (limited form of
systemic sclerosis) syndrome. Digital ulceration (critical ischemia) seen in 2° Raynaud syndrome.
Treat with Ca-+ channel blockers.

MUSCULOSKELETAL, SKIN , ARP CONNECTIVE TISSUE- DERMATOLOGY

Skin layers Skin has 3 layers: epidermis, dermis, Californians Like Girls in String Bikinis.
subcutaneous fat (hypodermis, subcutis).
Epidermis layers from surface to base Q:
0
Stratum Corneum (keratin)

'
p0
sSPermis
- .. * <
Stratum Lucidum
Stratum Granulosum
Stratum Spinosum (desmosomes)
Stratum Basale (stem cell site)
. '; [3
446 SECTION III MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE DERMATOLOGY

Dermatologic microscopic terms

LESION CHARACTERISTICS EXAMPLES
Hyperkeratosis t thickness of stratum corneum Psoriasis, calluses
Parakeratosis Hyperkeratosis with retention of nuclei in Psoriasis
stratum corneum
Hypergranulosis t thickness of stratum granulosum Lichen planus
Spongiosis Epidermal accumulation of edematous fluid in Eczematous dermatitis
intercellular spaces
Acantholysis Separation of epidermal cells Pemphigus vulgaris
Acanthosis Epidermal hyperplasia ( t spinosum) Acanthosis nigricans, psoriasis

Pigmented skin disorders

Albinism Normal melanocyte number with 4 melanin production Q due to 4 tyrosinase activity or defective
tyrosine transport , t risk of skin cancer.
Melasma (chloasma ) Hyperpigmentation associated with pregnancy ( “ mask of pregnancy” Q) or OCP use.
Vitiligo Irregular areas of complete depigmentation H- Caused by autoimmune destruction of melanocytes.

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 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE DERMATOLOGY SECTION III 447

Common skin disorders

Acne Multifactorial etiology — t sebum ( T androgens) production, abnormal keratinocvte desquamation,
Propionibacterium acnes colonization of the pilosebaceous unit, ( comedones), and inflammation
( papules /pustules , nodules, cysts). Treatment includes retinoids, benzoyl peroxide, and antibiotics!

Atopic dermatitis Pruritic eruption, commonly on skin flexures. Often associated with other atopic diseases (asthma,
(eczema) allergic rhinitis, food allergies); t serum IgE. Usually appears on face in infancy Q and then
antecubital fossalH when older.
Allergic contact Type IV hypersensitivity reaction that follows exposure to allergen. Lesions occur at site of contact
dermatitis (eg, nickel 0, poison ivy, neomycin Q).
Melanocytic nevus Common mole. Benign, but melanoma can arise in congenital or atypical moles. Intradermal nevi
are papular Q. Junctional nevi are flat macules 0.
Pseudofolliculitis Foreign body inflammatory facial skin disorder characterized by firm, hyperpigmented papules and
barbae pustules that are painful and pruritic . Located on cheeks, jawline, and neck. Commonly occurs as
a result of shaving (“ razor bumps”), primarily affects African American males.
Psoriasis Papules and plaques w ith silvery scaling Q, especially on knees and elbow s. Acanthosis with
parakeratotic scaling (nuclei still in stratum corneum), Munro microabscesses, t stratum
spinosum, \ stratum granulosum. Auspitz sign (arrow in Q) — pinpoint bleeding spots from
exposure of dermal papillae w hen scales are scraped off. Can be associated w ith nail pitting and
psoriatic arthritis.
Rosacea Inflammatory facial skin disorder characterized by erythematous papules and pustules Q, but no
comedones. May be associated with facial flushing in response to external stimuli (eg, alcohol,
heat). Phymatous rosacea can cause rhinophvma ( bulbous deformation of nose).
Seborrheic keratosis Flat, greasy, pigmented squamous epithelial proliferation with keratin-filled cysts ( horn cysts) Q.
Looks “stuck on.” Lesions occur on head, trunk, and extremities. Common benign neoplasm of
older persons.
Leser-Trelat sign D — sudden appearance of multiple seborrheic keratoses, indicating an underlying
malignancy (eg, GI, lymphoid).
Verrucae Warts; caused by HPV. Soft, tan-colored, cauliflower-like papules G3. Epidermal hyperplasia,
hyperkeratosis, koilocvtosis. Condyloma acuminatum on genitals 0.
Urticaria Hives. Pruritic wheals that form after mast cell degranulation 0. Characterized by superficial
dermal edema and lymphatic channel dilation.

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 MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE DERMATOLOGY SECTION III 449

Skin infections
Bacterial infections
Impetigo Very superficial skin infection . Usually from S aureus or S pyogenes. Highly contagious. Honey-
colored crusting Q.
Bullous impetigo Q has bullae and is usually caused by S aureus .
Erysipelas Infection involving upper dermis and superficial lymphatics, usually from S pyogenes. Presents with
well-defined demarcation between infected and normal skin Q-
Cellulitis Acute, painful , spreading infection of deeper dermis and subcutaneous tissues. Usually from
S pyogenes or S aureus . Often starts with a break in skin from trauma or another infection 0.
Abscess Collection of pus from a walled-off infection within deeper layers of skin Q. Offending organism is
almost always S aureus.
Necrotizing fasciitis Deeper tissue injury, usually from anaerobic bacteria or S pyogenes. Pain may be out of proportion
to exam . Results in crepitus from methane and CO, production . “ Flesh-eating bacteria .” Causes
bullae and a purple color to the skin Q-
Staphylococcal scalded Exotoxin destroys keratinocvte attachments in stratum granulosum only (vs toxic epidermal
skin syndrome necrolysis, which destroys epidermal-dermal junction ). Characterized by fever and generalized
erythematous rash with sloughing of the upper layers of the epidermis 0 that heals completely.
® Nikolsky sign. Seen in newborns and children, adults with renal insufficiency.
Viral infections
Herpes Herpes virus infections ( HSV1 and HSV2 ) of skin can occur anywhere from mucosal surfaces to
normal skin . These include herpes labialis, herpes genitalis, herpetic whitlow Q (finger ).
Molluscum Umbilicated papules Q caused by a poxvirus. While frequently seen in children, it may be sexually
contagiosum transmitted in adults.
Varicella zoster virus Causes varicella (chickenpox) and zoster (shingles). Varicella presents with multiple crops of
lesions in various stages from vesicles to crusts. Zoster is a reactivation of the virus in dermatomal
distribution (unless it is disseminated ).
Hairy leukoplakia Irregular, white, painless plaques on lateral tongue that cannot be scraped off Q. EBV mediated .
Occurs in HIV-positive patients, organ transplant recipients. Contrast with thrush (scrapable) and
leukoplakia ( precancerous).

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450 SECTION III MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE DERMATOLOGY

Blistering skin disorders

Pemphigus vulgaris Potentially fatal autoimmune skin disorder with IgG antibody against desmoglein (component of
desmosomes).
Flaccid intraepidermal bullae Q caused by acantholvsis ( keratinocytes in stratum spinosum are
connected bv desmosomes, resembling a “ row of tombstones ” ); oral mucosa is also involved . Type

^
II hypersensitivity reaction
Immunofluorescence reveals antibodies around epidermal cells in a reticular ( net-like ) pattern Q.
Nikolsky sign ® (separation of epidermis upon manual stroking of skin ).
Bullous pemphigoid Less severe than pemphigus vulgaris. Involves IgG antibod} against hemidesmosomes (epidermal
7

basement membrane; antibodies are “ bullow” the epidermis).

Tense blisters H containing eosinophils affect skin but spare oral mucosa.
Immunofluorescence reveals linear pattern at epidermal-dermal junction 0.
Nikolsky sign ©.
Dermatitis Pruritic papules, vesicles, and bullae (often found on elbows) Q- Deposits of IgA at tips of dermal
herpetiformis papillae. Associated with celiac disease. Treatment: dapsone, gluten-free diet .
Erythema multiforme Associated with infections (eg, Mycoplasma pneumoniae. IISV ), drugs (eg, sulfa drugs, P-lactams,
phenytoin), cancers, autoimmune disease . Presents with multiple types of lesions — macules,
papules, vesicles, target lesions ( look like targets with multiple rings and dusky center showing
epithelial disruption ) Q-
Stevens-Johnson Characterized by fever, bullae formation and necrosis, sloughing of skin at dermal -epidermal
syndrome junction , high mortality rate. Typically 2 mucous membranes are involved 0 Q, and targetoid
skin lesions may appear, as seen in erythema multiforme. Usually associated with adverse drug
reaction . A more severe form of Stevens-Johnson syndrome (SJS) with > 30 % of the body surface
area involved is toxic epidermal necrolysis Q Q (TEN ). 10-30 % involvement denotes SJS-TEN .

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 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE DERMATOLOGY SECTION III 451

Miscellaneous skin disorders

Acanthosis nigricans Epidermal hyperplasia causing symmetric, hyperpigmented thickening of skin, especially in axilla
or on neck Q El- Associated with insulin resistance (eg, diabetes, obesity, Cushing syndrome),
visceral malignancy (eg, gastric adenocarcinoma).
Actinic keratosis Premalignant lesions caused by sun exposure. Small, rough, erythematous or brownish papules or
plaques Q 0. Risk of squamous cell carcinoma is proportional to degree of epithelial dysplasia.
Erythema nodosum Painful raised inflammatory lesions of subcutaneous fat ( panniculitis), usualhjon anterior shins.
Often idiopathic, but can be associated with sarcoidosis, coccidioidomycosis, histoplasmosis, TB,
streptococcal infections Q, leprosy Q, inflammatory bowel disease.
Lichen Planus Pruritic, Purple, Polygonal Planar Papules and Plaques are the 6 P’s of lichen Planus 0 Q.
Mucosal involvement manifests as Wickham striae (reticular white lines) and hvpergranulosis.
Sawtooth infiltrate of lymphocytes at dermal-epidermal junction. Associated with hepatitis C.
Pityriasis rosea “ Herald patch” Q followed days later by other scaly erythematous plaques, often in a “ Christmas
tree” distribution on trunk Q. Multiple plaques with collarette scale. Self-resolving in 6-8 weeks.
Sunburn Acute cutaneous inflammatory reaction due to excessive UV irradiation. Causes DNA mutations,
inducing apoptosis of keratinocytes. UVB is dominant in sunBurn, UVA in tAnning and
photoAging. Exposure to UVA and UVB increase the risk of skin cancer. Can lead to impetigo,
skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma).

25
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452 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE DERMATOLOGY

Skin cancer
Basal cell carcinoma Most common skin cancer. Found in sun-exposed areas of body (eg, face). Locally invasive, but
rarely metastasizes. Waxv, pink, pearly nodules, commonhjwith telangiectasias, rolled borders,
central crusting or ulceration Q. BCCs also appear as nonhealing ulcers with infiltrating growth
Q or as a scaling plaque (superficial BCC ) Q. Basal cell tumors have “palisading” nuclei 0-

Squamous cell Second most common skin cancer. Associated with excessive exposure to sunlight,
carcinoma immunosuppression, chronically draining sinuses, and occasionalhiarsenic exposure. Commonly
appears on face Q, lower lip Q, ears, hands. Locally invasive, may spread to lymph nodes,
and will rarely metastasize. Ulcerative red lesions with frequent scale. ( listopathology: keratin
_
“pearls” 0.
Actinic keratosis, a scaly plaque, is a precursor to squamous cell carcinoma.
Keratoacanthoma is a variant that grows rapidly (4-6 weeks) and may regress spontaneously over
months 0.

m
% M
•T

Melanoma Common tumor with significant risk of metastasis. S-100 tumor marker. Associated with sunlight
exposure and dysplastic nevi; fair-skinned persons are at t risk. Depth of tumor correlates with risk
of metastasis. Look for the ABCDEs: Asymmetry, Border irregularity, Color variation, Diameter
> 6 mm, and Evolution over time. At least 4 different types of melanoma, including superficial
.
spreading Q, nodular Q, lentigo maligna Q, and acral lentiginous Q Often driven by activating
mutation in BRAF kinase. Primary treatment is excision with appropriately wide margins.
Metastatic or unresectable melanoma in patients with BRAF V600E mutation may benefit from
vemurafenib, a BRAF kinase inhibitor.

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454 SECTION III MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PHARMACOLOGY

Aspirin
MECHANISM NSAID that irreversibly inhibits cyclooxygenase ( both COX-1 and COX-2) by covalent acetylation
— 1 synthesis of TXA 7 and prostaglandins, t bleeding time. No effect on PT, PTT. Effect lasts
until new platelets are produced.
CLINICAL USE Low dose (< 300 mg/day): 1 platelet aggregation. Intermediate dose ( 300-2400 mg/day): antipyretic
and analgesic. High dose ( 2400-4000 mg/day): anti-inflammatory.
ADVERSE EFFECTS Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial
nephritis, GI bleeding. Risk of Reve syndrome in children treated with aspirin for viral infection.
Causes respiratory alkalosis early, but transitions to mixed metabolic acidosis-respiratory alkalosis.

Celecoxib
MECHANISM the cyclooxygenase (COX ) isoform 2 (“ Selecoxib ” ), which!is found
Reversibly inhibits selectively
in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares
COX-1, which helps maintain gastric mucosa. Thus, does not have the corrosive effects of other
NSAIDs on the GI lining. Spares platelet function as TXA -, production is dependent on COX-1.
CLINICAL USE Rheumatoid arthritis, osteoarthritis.
ADVERSE EFFECTS t risk of thrombosis. Sulfa allergy.

Nonsteroidal Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac, meloxicam, piroxicam.

anti-inflammatory
druqs ( NSAIDsL
MECHANISM Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin synthesis.
CLINICAL USE Antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA.
ADVERSE EFFECTS Interstitial nephritis, gastric ulcer (prostaglandins protect gastric mucosa), renal ischemia
( prostaglandins vasodilate afferent arteriole), aplastic anemia.

Leflunomide
MECHANISM Reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis. Suppresses
T-cell proliferation.
CLINICAL USE Rheumatoid arthritis, psoriatic arthritis.
ADVERSE EFFECTS Diarrhea, hypertension, hepatotoxicity, teratogenicity.

Bisphosphonates Alendronate, ibandronate, risedronate, zoledronate.

MECHANISM Pyrophosphate analogs; bind hydroxyapatite in bone, inhibiting osteoclast activity.
CLINICAL USE Osteoporosis, hypercalcemia, Paget disease of bone, metastatic bone disease, osteogenesis
imperfecta.
ADVERSE EFFECTS Esophagitis (if taken orally, patients are advised to take with water and remain upright for 30
minutes), osteonecro sis of jaw, atypical stress fractures.
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE PHARMACOLOGY SECTION III 455

Teriparatide
MECHANISM Recombinant PTH analog given subcutaneously daily, t osteoblastic activity.
CLINICAL USE Osteoporosis. Causes t bone growth compared to antiresorptive therapies (eg, bisphosphonates).
ADVERSE EFFECTS t risk of osteosarcoma ( avoid use in patients with Paget disease of the bone or unexplained
elevation of alkaline phosphatase).
Transient hypercalcemia.

Gout drugs
Chronic gout drugs (preventive)
Allopurinol Competitive inhibitor of xanthine oxidase , Diet Purines Nucleic acids
i conversion of hypoxanthine and xanthine to
urate. Also used in lymphoma and leukemia
Hypoxanthine
to prevent tumor lvsis-associated urate
I Xanthine
nephropathy, t concentrations of azathioprine 1 oxidase
and 6-MP ( both normally metabolized by Allopurinol,
Xanthine
xanthine oxidase). I Xanthine
febuxostat

Febuxostat Inhibits xanthine oxidase. I oxidase

Plasma Urate crystals - Gout
Pegloticase Recombinant uricase that catalyzes metabolism
uric acid deposited
of uric acid to allantoin (a more water-soluble in joints
product).
Probenecid Inhibits reabsorption of uric acid in proximal Tubular
convoluted tubule (also inhibits secretion of reabsorption
penicillin). Can precipitate uric acid calculi.
$
Probenecid and
high -dose salicylates
Acute gout drugs
NSAIDs Naproxen, indomethacin.
Avoid salicylates; all but the highest doses
depress uric acid clearance. Other NSAIDs are
Urine
r
Diuretics and
low -dose salicylates
Tubular
secretion

better tolerated]
Glucocorticoids Oral, intra-articular, or parenteral.
Colchicine Binds and stabilizes tubulin to inhibit
microtubule polymerization, impairing
neutrophil chemotaxis and degranulation.
Acute and prophylactic value. GI side effects.

TNF-a inhibitors All TNF-a inhibitors predispose to infection, including reactivation of latent TB, since TNF is
important in granuloma formation and stabilization.
DRUG MECHANISM CLINICAL USE
Etanercept Fusion protein (receptor for TNF-a + IgGj Fc), Rheumatoid arthritis, psoriasis, ankylosing
produced by recombinant DNA. spondylitis
Etanercept is a TNF decoy receptor.
Infliximab, Anti-TNF-a monoclonal antibody. Inflammatory bowel disease, rheumatoid arthritis,
adalimumab, ankylosing spondylitis, psoriasis
certolizumabj
HIGH - YI E LD SYSTEMS

Neurology and
Special Senses

“ Estimated amount of glucose used by an adult human brain each day, Embryology 458
expressed in M & Ms: 250.”
— Harper’s Index Anatomy and
Physiology 461
“ Anything’s possible if you’ve got enough nerve.”
— J.K. Rowling Harry Potter and the Order of the Phoenix
, Pathology 479

“ I like nonsense ; it wakes up the brain cells.” Otology 500

— Dr. Seuss
Ophthalmology 502
“I believe in an open mind , but not so olren that your brains fall out.”
— Arthur Hays Sulzberger Pharmacology 512
“ The chief junction of the body is to earn the brain around ."
— Thomas Edison

457
458 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — EMBRYOLOGY

NEUROLOGY — EMBRYOLOGY

Neural development Notochord induces overlying ectoderm to differentiate into neuroectoderm and form neural plate.
Neural plate Neural plate gives rise to neural tube and neural crest cells.
Day 18 Notochord becomes nucleus pulposus of intervertebral disc in adults.
'-Notochord Alar plate (dorsal): sensory
Neural fold
Basal plate (ventral): motor J Same orientation as spinal cord.

Neural tube
Neural

Day 21

Regional specification of developing brain

Three primary Five secondary Adult derivatives of:
vesicles vesicles Walls Cavities

Telencephalon Cerebral Lateral

Wall Cavity hemispheres ventricles

Forebrain Diencephalon Thalamus, Third

(prosencephalon)
Hypothalamus ventricle

Midbrain Mesencephalon Midbrain Aqueduct

(mesencephalon)

Rons Upper part of

fourth ventricle
Metencephalon
Hindbrain Cerebellum
(rhombencephalon)
Myelencephalon
Medulla Lower part of
fourth ventricle

Spinal cord 113

CNS /PNS origins Neuroepithelia in neural tubcj— CNS neurons, ependymal cells ( inner lining of ventricles, make
CSF), oligodendroglia, astrocytes.
Neural crest — PNS neurons, Schwann cells.
Mesoderm — Microglia ( like Macrophages).
 MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE ANATOMY AND PHYSIOLOGY SECTION III 423

Common knee conditions

"Unhappy triad" Common injury in contact sports due to lateral force applied to a planted leg. Classically, consists
of damage to the ACL Q, MCL, and medial meniscus (attached to MCL); however, lateral
meniscus injury is more common. Presents with acute knee pain and signs of joint injury/
instability.
Prepatellar bursitis Inflammation of the prepatellar bursa over the kneecaptp. Can be caused by repeated trauma or
("housemaid's knee" )j pressure from excessive kneeling.
Baker cyst Popliteal fluid collection in gastrocnemius-semimembranous bursa Q commonly communicating
with synovial space and related to chronic joint disease.

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Rotator cuff muscles Shoulder muscles that form the rotator cuff: SItS (small t is for teres minor).
a
Supraspinatus (suprascapular nerve) — Acromion Supraspinatus
abducts arm initially ( before the action Coracoid
of the deltoid); most common rotator cuff
Biceps tendon
injury Q (trauma or degeneration and
—
Infraspinatus
impingement tendinopathy or tear), - Subscapularis
assessed by “ empty/full can” test.
Teres minor
%
1
Infraspinatus (suprascapular nerve) — laterally Posterior Anterior
rotates arm; pitching injury.
teres minor (axillary nerve) — adducts and
laterally rotates arm.
1
Subscapularis (upper and lower subscapular
nerves) — medially rotates and adducts arm.
Innervated primarily by C 5 -C6.

Arm abduction
DEGREE MUSCLE NERVE
New 0°-15° Supraspinatus Suprascapular
I Fact 1 15°-100° Deltoid .Axillary-

> 100° Serratus anterior Long thoracic

 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — EMBRYOLOGY SECTION III 459

Neural tube defects Neuropores fail to fuse (4th week) -*• persistent connection between amniotic cavity and spinal
canal . Associated with maternal diabetes as well asjlow folic acid intake before conception and
during pregnancy, t a-fetoprotein (AFP ) in amniotic fluid and maternal serum (except spina
bifida occulta ) t acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test (fetal
,

Anencephaly

Spina bifida occulta

polyhydramnios ( no swallowing center in brain ) . —
AChE in CSF flows through defect into amniotic fluid ).
Failure of rostral neuropore to close no forebrain, open calvarium . Clinical findings: t AFP,

Failure of caudal neuroporejto close, but no herniation. Usually seen at lower vertebral levels. Dura
is intact . Associated with tuft of hair or skin dimple at level of bony defect. Normal AFP
Meningocele
Meningomyelocele
Meninges ( but no neural tissue) herniate through bony defect . Associated with spina bifida cystic
Meninges and neural tissue (eg, cauda equina ) herniate through bony defect .
^
f /- Tuft of hair Skin defect/thinning - Skin thin or absent
Skin +/- Skin dimple
subarachnoid
—- spai e
Jjia

Leptomeninges
J
-j
Spinal Transverse
cord

Normal Spina bifida occulta Meningocele Meningomyelocele

(most common)

Holoprosencephaly Failure of left and right hemispheres to separate; usually occurs during weeks 5-6. May be related
to mutations in sonic hedgehog signaling pathway. Moderate form has cleft lip/palate, most severe
form results in cyclopia . Seen in Patau syndrome and fetal alcohol syndrome.
 RENAL RENAL — EMBRYOLOGY SECTION III 547

Horseshoe kidney Inferior poles of both kidneys fuse

•Aorta abnormally Q. As they ascend from pelvis
Horseshoe /

m
during fetal development, horseshoe kidneys
kidney
/ Renalartery
get trapped under inferior mesenteric
artery and remain low in the abdomen.
Kidneys function normally. Associated
with hydronephrosis (eg, ureteropelvic
Ureteral ^'CMnfeno
mesenteric junction obstruction), renal stones, infection,
artery ,
chromosomal aneuploidv syndromes (eg,
Turner syndrome; trisomies 13, 18, 21), and
rarely renal cancer.

Unilateral renal Ureteric bud fails to develop and induce differentiation of metanephric mesenchyme -* complete
agenesis absence of kidney and ureter. Often diagnosed prenatally via ultrasound.

Multicystic dysplastic Predominantly non-hereditarv condition where ureteric bud fails to induce differentiation of
kidney
—
metanephric mesenchvmet nonfunctional kidney consisting of cysts and connective tissue.
Often diagnosed prenatally via ultrasound.

Duplex collecting Bifurcation of ureteric bud before it enters the metanephric blastema creates a Y-shaped bifid
system ureter. Duplex collecting system can alternatively occur through two ureteric buds reaching and
interacting with metanephric blastema. Strongly associated with vesicoureteral reflux and/or
ureteral obstruction, t risk for UTIs.

Congenital solitary Condition of being born with only one functioning kidney. Majority asymptomatic with
functioning kidney compensator}’ hypertrophy of contralateral kidney, but anomalies in contralateral kidney are
common.

New Posterior urethral Membrane obstructs the urethra due to abnormal development in utero. Found only in males. Can
Fact valves be diagnosed prenatally by hydronephrosis and dilated bladder on ultrasound. Most common
cause of urinary obstruction in male infants.
460 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — EMBRYOLOGY

Posterior fossa malformations

Chiari I malformation! Ectopia of cerebellar tonsils ( 1 structure ) > 3-5 mm; congenital, usually asymptomatic in
childhood, manifests in adulthood with headaches and cerebellar symptoms. Associated with
spinal cavitations ( eg, syringomyelia ) , i
Chiari II malformation Herniation of low-lying cerebellar vermis and tonsils ( 2 structures) through foramen
magnum )] with aqueductal stenosis
—
hydrocephalus. Usually associated with lumbosacral
meningomyelocele (may present as paralysis/sensory loss at and below the level of the lesion ) .
Dandy-Walker Agenesis of cerebellar vermis with cvstic enlargement of 4th ventricle ( red arrow in ), fills the
syndrome| enlarged posterior fossa. Associated with noncommunicating hydrocephalus, spina bifidaj

u
£

B=
New
y wan
*
r#vV
*
f

Image X

t
*

Syringomyelia Cystic cavity (syrinx) within central canal Syrinx = tube, as in syringe.
of spinal cord ( yellow arrow in Q). Fibers
crossing in anterior white commissure
(spinothalamic tract) are typically damaged
Most common at C8-T1
^
first. Results in a “cape-like,” bilateral loss
of pain and temperature sensation in upper
extremities (fine touch sensation is preserved).
Associated with Chiari malformations (red
arrow in EJ), trauma, and tumors.
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 461

Tongue development 1st and 2nd branchial arches form anterior 2A Taste — CN VII, IX, X (solitary nucleus).
Anterior tongue (thus sensation via CN V,, taste via CN VII). „
Pain-CN V IX, X.
Arches
land 2
3rd and 4th branchial arches form posterior A
(thus sensation and taste mainly via CN IX,
‘ Motor-CN X, XII.

Sensation extreme posterior via CN X ).

vnaV ,
Taste Motor innervation is via CN XII to hyoglossus
via VII
(retracts and depresses tongue), genioglossus
Revised
(protrudes tongue), and styloglossus (draws
Figure |
sides of tongue upward to create a trough for
swallowing).
Sensation
and taste
via IX a cues Motor innervation is via CN X to palatoglossus
Sand 4
Sensation
and taste
(elevates posterior tongue during swallowing).
Posterior tongue

NEUROLOGY — ANATOMY AND PHYSIOLOGY

Neurons Signal-transmitting cells of the nervous system. Permanent cells — do not divide in adulthood.
Signal-relaying cells with dendrites (receive input), cell bodies, and axons (send output). Cell bodies
and dendrites can be seen on Nissl staining (stains RER). RER is not present in the axon.
—
Injury to axon Wallerian degeneration — degeneration distal to injury and axonal retraction
proximally; allows for potential regeneration of axon (if in PNS).

Astrocytes Physical support, repair, buffers extracellular K4! removal of excess neurotransmitter, component
of blood-brain barrier, glycogen fuel reserve buffer. Reactive gliosis in response to neural injury.
Astrocyte marker: GFAP Derived from neuroectoderm.

Microglia Phagocytic scavenger cells of CNS HIV-infected microglia fuse to form

(mesodermal, mononuclear origin). Activated multinucleated giant cells in CNS.
in response to tissue damage. Not readily
discernible by Nissl stain.
462 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY

Myelin t conduction velocity of signals transmitted Wraps and insulates axons (red arrow in H):

m —
down axons saltatory conduction of action
potential at the nodes of Ranvier, where there ^
t pace constant and t conduction velocity,

are high concentrations of Na+ channels.

CNS — oligodendrocytes; PNS — Schwann
cells.

Schwann cells Each Schwann cell myelinates only 1 PNS axon. May be injured in Guillain-Barre syndromeJ
Nucleus -v Node of Ranvier Also promote axonal regeneration. Derived

v
1 from neural crest
^
I
Myelin sheath -* V Schwann cell

Oligodendroglia Myelinates axons of neurons in CNS. Each Derived from neuroectoderm.

oligodendrocyte can myelinate many axons “ Fried egg” appearance histologically.
-Node of Ranvier (~ 50). Predominant type of glial cell in white Injured in multiple sclerosis, progressive
Axon matter. multifocal leukoencephalopathy (PML),
leukodystrophies.

Sensory receptors
RECEPTOR TYPE SENSORY NEURON FIBER TYPE LOCATION SENSES

Free nerve endings C — slow, unmyelinated fibers
A8 — fast, myelinated fibers
Meissner corpuscles Large, myelinated fibers; adapt
quickly
Pacinian corpuscles Large, myelinated fibers; adapt
quickly
Merkel discs Large, myelinated fibers; adapt
slowly
Ruffini corpuscles Dendritic endings with
capsule; adapt slowly
All skin, epidermis, some
viscera
Glabrous (hairless) skin
Deep skin layers, ligaments,
joints
Finger tips, superficial skin
Finger tips, joints
Pain, temperature
Dynamic, fine/light touch,
position sense
Vibration, pressure
Pressure, deep static touch (eg,
shapes, edges), position sense
Pressure, slippage of objects
along surface of skin, joint
angle change
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 463

Peripheral nerve Endoneurium — invests single nerve fiber layers Endo = inner.
Nerve trunk (inflammatory infiltrate in Guillain-Barre Peri = around.
syndrome). Epi = outer.
- Epineurium
Perineurium ( blood-nerve Permeability
Perineurium
Endoneurium
barrier) — surrounds a fascicle of nerve fibers.
Nerve fibers Must be rejoined in microsurgery for limb
reattachment.
Epineurium — dense connective tissue that
surrounds entire nerve (fascicles and blood
vessels).

Chromatolysis Reaction of neuronal cell body to axonal injury. Changes reflect t protein synthesis in effort to
repair the damaged axon. Characterized bv:
Round cellular swelling H
Displacement of the nucleus to the periphery
' . Dispersion ofNissl substance throughout cytoplasm

***
-
m Concurrent with Wallerian degeneration — degeneration of axon distal to site of injury.
Macrophages remove debris and mvelin.

:
Neurotransmitter changes with disease!
LOCATION OF ANXIETY DEPRESSION SCHIZOPHRENIA ALZHEIMER HUNTINGTON PARKINSON
SYNTHESIS DISEASE DISEASE DISEASE
Acetylcholine Basal nucleus i t
of Meynert
*
Dopamine Ventral i t t i
tegmentum,
SNj
GABA Nucleus i i
accumbens
Norepinephrine Locus ceruleus t i
Serotonin Raphe nucleus * i
464 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY

Blood-brain barrier Prevents circulating blood substances A few specialized brain regions with fenestrated
(eg, bacteria, drugs) from reaching the CSF/ capillaries and no blood-brain barrier allow
processes CNS. Formed by 3 structures: molecules in blood to affect brain function (eg,
° Tight junctions between nonfenestrated area postrema — vomiting after chemo; OVLT
-4' ll
r
.i' y '

capillary endothelial cellsw [organum vasculosum laminar terminalisl —

light osmotijsensing) or neurosecretory products to
Sasement “ Basement membrane
membrane
Astrocyte foot processes enter circulation (eg, neurohypophysis — ADH
Glucose and amino acids cross slowly by carrier- release).
mediated transport mechanisms. Infarction and/or neoplasm destroys endothelial
Nonpolar /1ipid-soluble substances cross rapidly
via diffusion.
—
cell tight junctions vasogenic edema.
Other notable barriers include:
Blood-testis barrier
* Maternal-fetal blood barrier of placenta

Hypothalamus The hypothalamus wears TAN HATS — Thirst and water balance, Adenohypophysis control
(regulates anterior pituitary), Neurohypophysis releases hormones produced in the hypothalamus .
Hunger, Autonomic regulation, Temperature regulation, Sexual urges.
Inputs (areas not protected by blood-brain barrier): OVLlt senses change in osmolarity), area
postrema (found in medulla, responds to emetics)]
Lateral area
—
Hunger. Destruction anorexia, failure
to thrive (infants). Stimulated by ghrelin,
If you zap your lateral area, you shrink laterally.

inhibited by leptin.
Ventromedial area Satiety. Destruction (eg, craniopharyngioma)
hyperphagia. Stimulated by leptin.
— • If you zap your ventromedial area, you grow
ventrally and medially.
7

Anterior Cooling, parasympathetic. Anterior nucleus = cool off (cooling,

hypothalamus pArasympathetic). A /C = anterior cooling.
Posterior Heating, sympathetic. Posterior nucleus = get fired up (heating,
hypothalamus sympathetic). If you zap your posterior
hypothalamus, you become a poikilotherm
(cold-blooded, like a snake).
Suprachiasmatic Circadian rhythm. You need sleep to be charismatic (chiasmatic).
nucleus
Supraoptic nucleus Releases ADI 1 ADH and oxvtoxin are carried by neurophvsins
Paraventricular Releases oxvtocin down axons to posterior pituitary , where they arc
nucleus stored and released.
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 465

Sleep physiology Sleep cycle is regulated by the circadian rhythm, which is driven by suprachiasmatic nucleus (SCN)
of hypothalamus. Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin,
— — —
norepinephrine: SCN norepinephrine release pineal gland melatonin. SCN is regulated
by environment (eg, light).
Two stages: rapid-eve movement (REM) and non-REM|
Alcohol, benzodiazepines, and barbiturates are associated with l REM sleep and delta wave sleep;
norepinephrine also i REM sleep.
Oral desmopressin ( ADI 1 analog) is useful in treatment of bedwetting (sleep enuresis) j preferred over
imipramine because of the latter’s adverse effects.
Benzodiazepines are useful for night terrors and sleepwalking by decreasing N3 and REM sleep!
SLEEP STAGE (% OF TOTAL SLEEP DESCRIPTION EEG WAVEFORM
TIME IN YOUNG ADULTS)
Awake (eyes open) Alert, active mental concentration Beta ( highest frequency, lowest amplitude)
Awake (eyes closed) Alpha
Non- REM sleep
Stage N1 (5%) Light sleep Theta
Stage N2 (45%) Deeper sleep; when bruxism occurs Sleep spindles and K complexes
Stage N3 (25%) Deepest non-REM sleep (slow -wave sleep); Delta (lowest frequency, highest amplitude)
when sleepwalking, night terrors, and
bedwetting occur
REM sleep (25%) Loss of motor tone, t brain O-, use, t and Beta
variable pulse and blood pressure; when At night, BATS Drink Blood
dreaming, nightmares, and penile/clitoral
tumescence occur; may serve memory
processing function. Depression increases total
REM sleep but decreases REM latencvi
Extraocular movements due to activity of PPRF
( paramedian pontine reticular formation /
conjugate gaze center)
Occurs every 90 minutes, and duration
t through the night
t ACh in REM
466 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY

Thalamus Major relay for all ascending sensory information except olfaction.
NUCLEUS INPUT SENSES DESTINATION MNEMONIC
Ventral Spinothalamic and dorsal columns/ Vibration, Pain, 1° somatosensory-
FJpstero- medial lemniscus Pressure, cortex
Ljateral Proprioception,
nucleus Light touch,
temperature!
Ventral Trigeminal and gustatory pathway Face sensation, 1° somatosensory - Makeup goes on
postero- taste cortex the face (VPM)
Medial
nucleus
Lateral CN II Vision Calcarine sulcus Lateral = Light
geniculate
nucleus
Medial Superior olive and inferior colliculus of Hearing Auditory cortex of Medial = Music
geniculate tectum temporal lobe
nucleus
Ventral lateral Basal ganglia, cerebellum Motor Motor cortex
nucleus

Limbic system Collection of neural structures involved in The famous 5 F’s.

emotion, long-term memory, olfaction,
behavior modulation, ANS function.
jiCpA The Pape / circuit consists of the following
,

structures: hippocampus ( red arrows in H),

- v;
mammillary bodies, anterior thalamic nuclei,

; j cingulate gyrus ( yellow arrows in D),

entorhinal cortex ]Responsible for Feeding,
Fleeing, Fighting, Feeling, and Sex.
*

Dopaminergic Commonly altered by drugs (eg, antipsychotics) and movement disorders (eg, Parkinson disease).
pathways
PATHWAY SYMPTOMS OF ALTERED ACTIVITY NOTES
Mesocortical 1 activity
—
“negative” symptoms (eg, anergia,
apathy, lack of spontaneity!).
Antipsychotic drugs have limited effect.

Mesolimblc t activity -*• “positive” symptoms (eg, delusions, Primary therapeutic target of antipsychotic drugs
hallucinations). -* 1 positive symptoms (eg, in schizophrenia).
Nigrostriatal
—
1 activity extrapyramidal symptoms
(eg, dystonia, akathisia, parkinsonism, tardive
Major dopaminergic pathway in brain.
Significantly affected by movement disorders
dyskinesia). and antipsychotic drugs.
Tuberoinfundibular 1 activity -*• t prolactin
—
1 libido, sexual
dysfunction, galactorrhea, gynecomastia (in
men).
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 467

Cerebellum Modulates movement; aids in coordination and
balance.
Input:
° Contralateral cortex via middle cerebellar
peduncle.
Ipsilateral proprioceptive information via
inferior cerebellar peduncle from spinal
cord.
Output:
The only output of cerebellar cortex =
Purkinje cells (always inhibitorydeep
Lateral lesions — affect voluntary movement of
extremities ( Limbst when injured, propensity
to fall toward injured (ipsilateral) side.
Medial lesions — involvement of Mjjdline
structures (vermal cortex, fastigial nuclei)
—
and/or flocculonodular lobe truncal ataxia
(wide-based cerebellar gait), nystagmus, head
tilting. Generally result in bilateral motor
deficits affecting axial and proximal limb
musculature.

—
nuclei of cerebellum contralateral cortex
via superior cerebellar peduncle.
Deep nuclei (lateral -* medial) — Dentate,
Emboliform, Globose, Fastigial (“ Don’t Eat
Greasy Foods” ).
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 469

Cerebral cortex functions

Premotor Central sulcus Somatosensory

Re ¬ cortex association cortex
located
Fact Frontal eye
held

Prefronl 3
Frontal
'
ibc 0i
T
Broca area Wernicke area
Occipital
mpo
Temporal lobe
lobe Primary
Sylvian fissure visual cortex

Limbic Primary
association area auditory cortex

Homunculus Topographic representation of motor (shown )

Re - and sensory areas in the cerebral cortex.
oooo0
located ^
Fact
-,x
fV i %
Distorted appearance is due to certain body
regions being more richly innervated and thus
having t cortical representation .

</
'
W
— 11
Tongue
Swallowing
—— — 4

Medial Lateral
 470 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY

Re -
located
Fact
Cerebral perfusion Brain perfusion relies on tight autoregulation .
Cerebral perfusion is primarily driven by
Pco7 ( Po2 also modulates perfusion in severe
hypoxia).
Cerebral perfusion relies on a pressure gradient
— — —
Therapeutic hyperventilation 1 Pco?
-*• vasoconstriction i cerebral blood flow
1 intracranial pressure ( ICP) . May be used
to treat acute cerebral edema (eg, 2° to stroke )
unresponsive to other interventions.
between mean arterial pressure ( MAP) and
ICP. i blood pressure or t ICP -* 1 cerebral
perfusion pressure ( CPP ). —
CPP = MAP - ICP. If CPP = 0, there is no
cerebral perfusion brain death .

Cerebral perfusion
pressure * Pco2 until
1 Normal
normal Po2
--02
Pco2 > 90 mm Hg
2
Hypoxemia increases
cerebral perfusion pressure
I
only when Po2 < 50 mm Hg
Normal
normal Pco2

50 100 ISO 40 80 120

Arterial gas pressure (mm Hg ) Arterial gas pressure 1mm Hg)

Re -
—
located Cerebral arteries cortical distribution
Fact
Anterior cerebral artery (supplies anteromedial surface )
[ j Middle cerebral artery (supplies lateral surface)
| | Posterior cerebral artery (supplies posterior and inferior surfaces)
A

?T
A

Watershed zones Between anterior cerebral /middle cerebral , posterior cerebral /middle cerebral arteries. Damage by
severe hypotension -*• upper leg /upper arm weakness, defects in higher-order visual processing.
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — ANATOMY AND PHYSIOLOGY SECTION III 471

Circle of Willis System of anastomoses between anterior and posterior blood supplies to brain.
Re -
located ACom I Anterior
Fact communicating Optic chiasm

4
Anterior
ACA
cerebral Internal carotid | ICA
ACA
Anterior CIRCLE

AT
Middle CA
circulation
ACA
MCA
zerebi ri ft PCA
ICA OF
MCA WILLIS
PCom
communicating -ni
Posterior
circulation : •
— BA
9T- PCom
Posterior
PCA
: erebi il CA

I rr A Superior Ht
GCA
I/A

cerebellar

: cephalic

1 f

if ^
Anterior inferior
AICA
cerebellar - Basilar | BA Aorta

^
PICA
Posterior inferior - Vertebral | VA
INFERIOR VIEW
. -
-
> I i . l .TI OBLIQUE- LATERAL VIEW

Anterior spinal | ASA

0

Dural venous sinuses Large venous channels that run through the dura. Drain blood from cerebral veins and receive CSF
from arachnoid granulations. Empty into internal jugular vein.
Venous sinus thrombosis — presents with signs/symptoms of t ICP (eg, headache, seizures, focal
neurologic deficits). May lead to venous hemorrhage. Associated with hypercoagulable states (eg,
pregnancy, OCP use, factor V Leiden).

Superior sagittal sinus

(main location of CSF return
via arachnoid granulations )

Inferior sagittal sinus

Great cerebral vein of Galen Superior ophthalmic vein

Sphenoparietal sinus
Straight sinus
Cavernous sinus
Confluence of the sinuses
Sigmoid sinus
Occipital sinus
Jugular foramen
^
Transverse sinus
S Internal jugular vein
0
 NEUROLOGY AND SPECIAL SENSES NEUROLOGY — PATHOLOGY SECTION III 483

Effects of strokes ( continued )

ARTERY AREA OF LESION SYMPTOMS NOTES
Basilar artery Pons, medulla , lower niidbrain RAS spared , therefore preserved “ Locked-in syndrome.”
consciousness
Corticospinal and corticobulbar Quadriplegia; loss of voluntary
tracts facial , mouth , and tongue
movements
Ocular cranial nerve nuclei, Loss of horizontal, but not vertical ,
paramedian pontine reticular eye movements
formation
Posterior Occipital cortex, visual cortex. Contralateral hemianopia with
cerebral macular sparing.
artery
a
I New I
llmaqel
\

r
 514 SECTION III NEUROLOGY AND SPECIAL SENSES NEUROLOGY — PHARMACOLOGY
Suvorexant
MECHANISM Hvpocretin (orexin) receptor antagonist.
I NeW I CLINICAL USE
| Fact |
Insomnia.
ADVERSE EFFECTS CNS depression , headache, dizziness, abnormal dreams, upper respiratory tract infection .
Contraindicated in patients with narcolepsy. Not recommended in patients with liver disease.

Triptans Sumatriptan
MECHANISM 5- HT|B/1 p agonists. Inhibit trigeminal nerve A SUMo wrestler TRIPs ANd falls on your
activation ; prevent vasoactive peptide release; head ,

induce vasoconstriction .
CLINICAL USE Acute migraine, cluster headache attacks.
ADVERSE EFFECTS Coronary vasospasm (contraindicated in
patients with CAD or Prinzmetal angina),
mild paresthesia , serotonin syndrome ( in
combination with other 5 - HT agonists).
HIGH- YIELD PRINCIPLES IN

Psychiatry

“ A Freudian slip is when you say one thing but mean your mother.” Psychology 522
— Anonymous
Pathology 524
“ Men will always be mad , and those who think they can cure them are the
maddest of all.” Pharmacology 539
— Voltaire

“ Anyone who goes to a psychiatrist ought to have his head examined ."
— Samuel Goldwyn

“ Words of comfort , skillfully administered , are the oldest therapy known to

man.”
— Louis Nizer

This chapter has been updated with PSM- 5 criteria .

521
522 SECTION III PSYCHIATRY PSYCHIATRY — PSYCHOLOGY

PSYCHIATRY — PSYCHOLOGY

Classical conditioning Learning in which a natural response
(salivation) is elicited by a conditioned,
or learned, stimulus (bell) that previously
was presented in conjunction with an
unconditioned stimulus (food).
Usually deals with involuntary responses.
Pavlovs classical experiments with dogs —
ringing the bell provoked salivation.

Operant conditioning Learning in which a particular action is elicited because it produces a punishment or reward.
Usually deals with voluntary responses.
Reinforcement Target behavior (response) is followed by desired reward (positive reinforcement) or removal of
aversive stimulus (negative reinforcement).
Punishment Repeated application of aversive stimulus Skinner’s Operant Conditioning Quadrant
(positive punishment) or removal of desired
Decrease Behavior Increase Behavior
reward (negative punishment) to extinguish
unwanted behavior. 2 Positive Positive
< Punishment Reinforcement

I Negative
Punishment
Negative
Reinforcement

Extinction Discontinuation of reinforcement (positive or negative) eventually eliminates behavior. Can occur
in operant or classical conditioning.

Transference and countertransference

Transference Patient projects feelings about formative or other important persons onto physician (eg, psychiatrist
is seen as parent).
Countertransference Doctor projects feelings about formative or other important persons onto patient (eg, patient
reminds physician of younger sibling).

Ego defenses Mental processes (unconscious or conscious) used to resolve conflict and prevent undesirable
feelings (eg, anxiety, depression).
IMMATURE DEFENSES DESCRIPTION EXAMPLE
Acting out Expressing unacceptable feelings and thoughts Tantrums.
through actions.
Denial Avoiding the awareness of some painful reality. A cancer patient plans a full-time work schedule
despite being warned of significant fatigue
during chemotherapy

Displacement Redirection of emotions or impulses to a neutral Mother yells at her child, because her husband
person or object (vs projection)! yelled at her.
Dissociation Temporary, drastic change in personality, Patient has incomplete or no memory of
memory, consciousness, or motor behavior traumatic event ]
to avoid emotional stress. Extreme forms can
result in dissociative identity disorder (multiple
personality disorder ]
 PSYCHIATRY PSYCHIATRY — PSYCHOLOGY
Ego defenses ( continued )
IMMATURE DEFENSES DESCRIPTION
Fixation Partially remaining at a more childish level of
development (vs regression).
Idealization Expressing extremely positive thoughts of self
and others while ignoring negative thoughts.
Identification Modeling behavior after another person who
is more powerful (though not necessarily
admired).
Intellectualization Using facts and logic to emotionally distance
oneself from a stressful situation.
Isolation (of affect) Separating feelings from ideas and events.
Passive aggression Project hostile feelings in a non-confrontational
manner ]
Projection Attributing an unacceptable internal impulse to
an external source (vs displacement).
Rationalization Proclaiming logical reasons for actions actually
performed for other reasons, usually to avoid
self-blame.
Reaction formation Replacing a warded-off idea or feeling by an
(unconsciously derived) emphasis on its
opposite (vs sublimation).
Regression Involuntarily turning back the maturational
clock and going back to earlier modes of
dealing with the world (vs fixation).
Repression Involuntarily withholding an idea or feeling
from conscious awareness (vs suppression).
Splitting Believing that people are either all good or
all bad at different times due to intolerance
of ambiguity. Commonly seen in borderline
personality disorder.
MATURE DEFENSES
Sublimation Replacing an unacceptable wish with a course
of action that is similar to the wish but does
not conflict with one's value system (vs
reaction formation).
Altruism Alleviating negative feelings via unsolicited
generosity.
Suppression Intentionally withholding an idea or feeling
from conscious awareness (vs repression);
temporary.
Humor Appreciating the amusing nature of an anxiety-
provoking or adverse situation.
Mature adults wear a SASH.
SECTION III 523
EXAMPLE
Adults that suck their thumbs (oral fixation!
A patient boasts about his physician and his
accomplishments while ignoring any flaws.
Abused child later becomes a child abuser.
In a therapy session, patient diagnosed with
cancer focuses only on rates of survival.
Describing murder in graphic detail with no
emotional response.
Disgruntled employee is repeatedly late to work.
A man who wants to cheat on his wife accuses
his wife of being unfaithful.
After getting fired, claiming that the job was not
important anyway.
A patient with libidinous thoughts enters a
monastery.
Seen in children under stress such as illness,
punishment, or birth of a new sibling (eg,
bedwetting in a previously toilet-trained child
when hospitalized).
A 20-vear-old does not remember going to
counseling during his parents’ divorce 10 years
earlier.
A patient says that all the nurses are cold and
insensitive but that the doctors are warm and
friendly.
Teenager’s aggression toward his father is
redirected to perform well in sports.
Mafia boss makes large donation to charity.
Choosing to not worry about the big game until
it is time to play.
Nervous medical student jokes about the boards.
524 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY

PSYCHIATRY — PATHOLOGY

Psychiatric genetics Both genetic and environmental factors are involved in development of most psychiatric disorders.
For example, in bipolar disorder and schizophrenia, lifetime risk in general population (~ 1%)
< parent or sibling of someone affected (~ 10%) < monozygotic twin of someone affected (~ 50%).

Infant deprivation Long-term deprivation of affection results in: (Deprivation for > 6 months can lead to
effects Failure to thrive irreversible changes.
Poor language/socialization skills Severe deprivation can result in infant death.
Lack of basic trust
Reactive attachment disorder (infant
withdrawn/unresponsive to comfort)

Child abuse
Physical abuse Sexual abuse
EVIDENCE Fractures (eg, ribs, long bone spiral, multiple Genital, anal, or oral trauma; STIs; UTIs.
in different stages of healing), bruises (eg,
trunk, ear, neck; in pattern of implement),
burns (eg, cigarette, buttocks/thighs), subdural
hematomas, retinal hemorrhages. During
exam, children often avoid eye contact.
ABUSER Usually biological mother. Known to victim, usually male.
EPIDEMIOLOGY 40% of deaths related to child abuse or neglect Peak incidence 9-12 years old.
occur in children < 1 year old ]

Child neglect Failure to provide a child with adequate food, shelter, supervision, education, and/or affection.
Most common form of child maltreatment. Evidence: poor hygiene, malnutrition, withdrawal,
impaired social/emotional development, failure to thrive.
As with child abuse, suspected child neglect must be reported to local child protective services.

Vulnerable child Parents perceive the child as especially susceptible to illness or injury. Usually follows a serious
syndrome illness or life-threatening event. Can result in missed school or overuse of medical services.
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 525

Childhood and early-onset disorders

Attention -deficit Onset before age 12. Limited attention span and poor impulse control. Characterized by
hyperactivity hyperactivity, impulsivity, and /or inattention in multiple settings (school , home, places of worship,
disorder etc). Normal intelligence, but commonly coexists with difficulties in school . Continues into
adulthood in as many as 50% of individuals. Treatment: stimulants (eg, methylphenidate) +/ —
cognitive behavioral therapy (CBT ) ; alternatives include atomoxetine, guanfacine, clonidine.
Autism spectrum Characterized by poor social interactions, social communication deficits, repetitive /ritualized
disorder behaviors, restricted interests. Must present in early childhood. May be accompanied by
intellectual disability; rarely accompanied by unusual abilities (savants). More common in boys.
Associated with t head/brain size.
Rett syndrome X-linked dominant disorder seen almost exclusively in girls (affected males die in utero or
—
shortly after birth ) . Symptoms usually become apparent around ages 1 4, including regression
characterized by loss of development , loss of verbal abilities, intellectual disability, ataxia ,
stereotyped hand-wringing.
Conduct disorder Repetitive and pervasive behavior violating the basic rights of others or societal norms (eg,
aggression to people and animals, destruction of property, theft ). After age 18, many of these
patients will meet criteria for diagnosis of antisocial personality disorder. Treatment for both:
psychotherapy such as CBT.
Oppositional defiant Enduring pattern of hostile, defiant behavior toward authority figures in the absence of serious
disorder violations of social norms. Treatment: psychotherapy such as CBT.
Separation anxiety Common onset at 7-9 years. Overwhelming fear of separation from home or loss of attachment
disorder figure. May lead to factitious physical complaints to avoid going to or staying at school . Treatment:
CBT, play therapy, family therapy.
Tourette syndrome Onset before age 18. Characterized by sudden , rapid , recurrent, nonrhythmic, stereotyped motor
and vocal tics that persist for > 1 year. Coprolalia ( involuntary obscene speech ) found in only
10-20% of patients. Associated with OCD and ADHD. Treatment: psychoeducation , behavioral
therapy. For intractable and distressing tics, high -potency antipsychotics (eg, fluphenazine,
pimozide), tetrabenazine, a,-agonists (eg , guanfacine and clonidine), or atypical antipsychotic
may be used. ^
Disruptive mood Onset before age 10. Severe and recurrent temper outbursts out of proportion to situation . Child
dysrequlation is constantly angry and irritable between outbursts. Treatment: psychostimulants, antipsychotics.
disorder behavioral therapy.

Orientation Patient’s ability to know who he or she is, where — —

Order of loss: 1st time; 2 nd place; last —
he or she is, and the date and time. person .
Common causes of loss of orientation : alcohol,
drugs, fluid /electrolyte imbalance, head
trauma , hypoglycemia , infection, nutritional
deficiencies.
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 527

Dementia I in intellectual function without affecting “ Dememtia ” is characterized by memory loss .

level of consciousness. Characterized by Usually irreversible.
memory deficits, apraxia, aphasia , agnosia , In elderly patients, depression and
loss of abstract thought , behavioral / personality hypothyroidism may present like dementia
changes, impaired judgment. A patient ( pseudodementia). Screen for depression ,
with dementia can develop delirium (eg, exclude neurosyphilis with RPR if high clinical
patient with Alzheimer disease who develops suspicion!and measure TSH , Bp levels.
pneumonia is at t risk for delirium ).
Irreversible causes: Alzheimer disease, Lewy
body dementia , Huntington disease, Pick
disease, cerebral infarct , Creutzfeldt-Jakob
disease, chronic substance abuse (due to
neurotoxicity of drugs).
Reversible causes: hypothyroidism, depression,
vitamin B ) 2 deficiency, normal pressure
hydrocephalus, neurosyphilis.
t incidence with age. EEG usually normal .

Psychosis Distorted perception of reality characterized by delusions, hallucinations, and/or disorganized

thought /speeclj Can occur in patients with medical illness, psychiatric illness, or both .
Delusions Unique, false beliefs that persist despite the facts, not typical of a patient ’s culture or religion ( eg,
thinking aliens are communicating with vouj Types include erotomanic, grandiose , jealous,
persecutory, somatic, mixed , and unspecified!
Disorganized thought Speech may be incoherent (“ word salad ” ), tangential , or derailed ( “ loose associations” ).
Hallucinations Perceptions in the absence of external stimuli (eg, seeing a light that is not actually present).
Contrast with illusions, misperceptions of real external stimuli. Types include:
a
—
Visual more commonly a feature of medical illness (eg, drug intoxication ) than psychiatric
illness.
—
Auditory more commonly a feature of psychiatric illness (eg, schizophrenia) than medical
illness.
—
Olfactory often occur as an aura of temporal lobe epilepsy (eg, burning rubber) and in brain
tumors.

——
Gustatory rare, but seen in epilepsy.
Tactile common in alcohol withdrawal and stimulant use (eg, cocaine, amphetamines),
delusional parasitosis, “ cocaine crawlies.”
9

——
Hypnagogic occurs while going to sleep. Sometimes seen in narcolepsy.
Hypnopompic occurs while waking from sleep ( “ pompous upon awakening” ). Sometimes
seen in narcolepsy.
528 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
Schizophrenia Chronic mental disorder with periods of Frequent cannabis use is associated with
psychosis, disturbed behavior and thought, psychosis/schizophrenia in teens.
and decline in functioning lasting > 6 Lifetime prevalence — 1.5% ( males = females,
months. Associated with t dopaminergic African Americans = Caucasians). Presents
activity, i dendritic branching. earlier in men ( late teens to early 20s vs late
Diagnosis requires at least 2 of the following, 20s to early 30s in women ). Patients are at t
and at least 1 of these should include 1-3 risk for suicide.
(first 4 are “ positive symptoms” ): Ventriculomegaly on brain imaging.
1 . Delusions Treatment: atypical antipsychotics (eg,
—
2 . Hallucinations often auditory risperidone) are first line.
3. Disorganized speech Negative symptoms often persist despite
4. Disorganized or catatonic behavior resolution of positive symptoms.
5. Negative symptoms (affective flattening,
avolition , anhedonia , asociality, alogia)
—
Brief psychotic disorder lasting < 1 month ,
usually stress related.
—
Schizophreniform disorder lasting 1-6
months.
—
Schizoaffective disorder Meets criteria for
schizophrenia in addition to major mood
disorder ( major depressive or bipolar ) . To
differentiate from a major mood disorder
with psychotic features, patient must have
> 2 weeks of hallucinations or delusions
without major mood episode

Delusional disorder Fixed , persistent, false belief system lasting > 1 month. Functioning otherwise not impaired
(eg, a woman who genuinely believes she is married to a celebrity when , in fact , she is not).
Can be shared by individuals in close relationships (folie a deux).

Mood disorder Characterized by an abnormal range of moods or internal emotional states and loss of control over
them . Severity of moods causes distress and impairment in social and occupational functioning.
Includes major depressive disorder, bipolar disorder, dysthymic disorder, and cyclothymic
disorder. Episodic superimposed psychotic features (delusions or hallucinations) may be present.

Manic episode Distinct period of abnormally and persistently elevated , expansive, or irritable mood and
abnormally and persistently t activity or energy lasting at least 1 week . Often disturbing to
patient .
Diagnosis requires hospitalization or at least 3 of the following ( manics DIG E\ST):
Distractibility
—
Irresponsibility seeks pleasure without 0
—
Flight of ideas racing thoughts
t in goal-directed Activity/psychomotor
regard to consequences ( hedonistic) Agitation
—
Grandiosity inflated self-esteem 3
1 need for Sleep
Talkativeness or pressured speech
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 529

Hypomanic episode Like a manic!episode except mood disturbance is not severe enough to cause marked impairment
in social and/or occupational functioning or to necessitate hospitalization. No psychotic features.
Lasts at least 4 consecutive days.

Bipolar disorder Bipolar I defined by presence of at least 1 manic episode +/— a hypomanic or depressive episode,
(manic depression ) Bipolar II defined by presence of a hypomanic and a depressive episode.
Patient s mood and functioning usually return to normal between episodes. Use of antidepressants
can precipitate mania. High suicide risk. Treatment: mood stabilizers (eg, lithium, valproic acid,
carbamazepine, lamotriginc!), atypical antipsychotics.

Cyclothymic disorder — milder form of bipolar disorder lasting at least 2 years, fluctuating
between mild depressive and hypomanic symptoms.

Major depressive Episodes characterized by at least 5 of the SIG E CAPS:

disorder 9 D+SIGECAPS symptoms for 2 or more " Depressed mood
weekj(symptoms must include patient- Sleep disturbance
reported depressed mood or anhedonia). 8
Loss of Interest (anhedonia)
Treatment: CBT and SSRIs are first line. Guilt or feelings of worthlessness
SNRIs, mirtazapine, bupropion can also be * Energy loss and fatigue
considered. Electroconvulsive therapy (ECT) Concentration problems
in select patients. • Appetite/weight changes
x Psychomotor retardation or
agitation
Persistent depressive disorder (dysthymia) —
Suicidal ideations
depression, often milder, lasting at least
Patients with depression typically have the
2 years. May be caused by low self- esteem.
following changes in their sleep stages:
c
1 slow-wave sleep
1 REM latency
t REM early in sleep cycle
t total REM sleep
Repeated nighttime awakenings
Earlv-morning awakening (terminal
insomnia)

Depression with pharacterized by mood reactivity ( being able to experience improved mood in response to positive
atypical features events, albeit briefly), “ reversed” vegetative symptoms ( hypersomnia, hyperphagia), leaden
paralysis ( heavy feeling in arms and legs), long-standing interpersonal rejection sensitivity. Most
common subtype of depression. Treatment: CBT and SSRIs are first line. MAO inhibitors are
effective but not first line because of their risk profile.
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 529

Hypomanic episode Like a manic!episode except mood disturbance is not severe enough to cause marked impairment
in social and/or occupational functioning or to necessitate hospitalization. No psychotic features.
Lasts at least 4 consecutive days.

Bipolar disorder Bipolar I defined by presence of at least 1 manic episode +/— a hypomanic or depressive episode,
(manic depression ) Bipolar II defined by presence of a hypomanic and a depressive episode.
Patient s mood and functioning usually return to normal between episodes. Use of antidepressants
can precipitate mania. High suicide risk. Treatment: mood stabilizers (eg, lithium, valproic acid,
carbamazepine, lamotriginc!), atypical antipsychotics.

Cyclothymic disorder — milder form of bipolar disorder lasting at least 2 years, fluctuating
between mild depressive and hypomanic symptoms.

Major depressive Episodes characterized by at least 5 of the SIG E CAPS:

disorder 9 D+SIGECAPS symptoms for 2 or more " Depressed mood
weekj(symptoms must include patient- Sleep disturbance
reported depressed mood or anhedonia). 8
Loss of Interest (anhedonia)
Treatment: CBT and SSRIs are first line. Guilt or feelings of worthlessness
SNRIs, mirtazapine, bupropion can also be * Energy loss and fatigue
considered. Electroconvulsive therapy (ECT) Concentration problems
in select patients. • Appetite/weight changes
x Psychomotor retardation or
agitation
Persistent depressive disorder (dysthymia) —
Suicidal ideations
depression, often milder, lasting at least
Patients with depression typically have the
2 years. May be caused by low self- esteem.
following changes in their sleep stages:
c
1 slow-wave sleep
1 REM latency
t REM early in sleep cycle
t total REM sleep
Repeated nighttime awakenings
Earlv-morning awakening (terminal
insomnia)

Depression with pharacterized by mood reactivity ( being able to experience improved mood in response to positive
atypical features events, albeit briefly), “ reversed” vegetative symptoms ( hypersomnia, hyperphagia), leaden
paralysis ( heavy feeling in arms and legs), long-standing interpersonal rejection sensitivity. Most
common subtype of depression. Treatment: CBT and SSRIs are first line. MAO inhibitors are
effective but not first line because of their risk profile.
530 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
Postpartum mood Onset within 4 weeks of delivery.
disturbances
Maternal 50-85% incidence rate. Characterized by depressed affect , tearfulness, and fatigue starting 2-3
( postpartum ) "blues" days after delivery. Usually resolves within 10 days. Treatment: supportive. Follow up to assess for
possible postpartum depression .
Postpartum 10-15% incidence rate. Characterized by depressed affect , anxiety, and poor concentration .
depression Treatment: CBT and SSRIs are first line.
Postpartum psychosis 0.1-0.2% incidence rate. Characterized by mood-congruent delusions, hallucinations, and
thoughts of harming the baby or self. Risk factors include history of bipolar or psychotic disorder,
first pregnancy, family history, recent discontinuation of psychotropic medication . Treatment:
hospitalization and initiation of atypical antipsychotic; if insufficient, ECT may be used .

Grief The five stages of grief are denial , anger, bargaining, depression , and acceptance, not necessarily
in that order. Other normal grief symptoms include shock, guilt , sadness, anxiety, yearning, and

^
somatic symptom Hallucinations of the deceased person are common . Duration varies widely;
usually < 6 months.
Pathologic grief is persistent and causes functional impairment . Can meet criteria for major
depressive episode.

Electroconvulsive Used mainly for treatment-refractory depression, depression with psychotic symptoms, and acutely
therapy suicidal patients. Produces grand mal seizure in an anesthetized patient . Adverse effects include
disorientation, temporary headache, partial anterograde /retrograde amnesia usually resolving in 6
months. Safe in pregnancy.

Risk factors for suicide Sex ( male) SAD PERSONS are more likely to complete
completion Age ( young adult or elderly) suicide.
Depression Most common method in US is firearms; access
Previous attempt ( highest risk factor!
) to guns t risk of suicide completion.
Ethanol or drug use Women try more often; men complete!more
Rational thinking loss ( psychosis) often.
Sickness (medical illness)
Organized plan
No spouse or other social support
Stated future intent

Anxiety disorder Inappropriate experience of fear/worry and its physical manifestations (anxiety) incongruent with
the magnitude of the perceived stressor. Symptoms interfere with daily functioning. Includes
panic disorder, phobias, generalized anxiety disorder, and selective mutism . Treatment: CBT,
SSRIs, SNRIs.
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 531

Panic disorder Defined by recurrent panic attacks ( periods PANICS ,

of intense fear and discomfort peaking in
10 minutes with at least 4 of the following):
Palpitations, Paresthesias, dePersonalization or
derealization, Abdominal distress or Nausea,
Intense fear of dying, Intense fear of losing
control or “going crazy,” light-headedness,
Chest pain, Chills, Choking, Sweating,
Shaking, Shortness of breath. Strong genetic
component t risk of suicide! Treatment:
,
Diagnosis requires attack followed by 1 month
(or more) of 1 (or more) of the following:
Persistent concern of additional attacks
Worrying about consequences of attack
Behavioral change related to attacks
Symptoms are the systemic manifestations of
fear.

CBT, SSRIs, and venlafaxine are first line.

Benzodiazepines occasionally used in acute
setting.

Specific phobia Severe, persistent (> 6 months) fear or anxiehidue to presence or anticipation of a specific object or
situation. Person recognizes fear is excessive. Can be treated with systematic desensitization.
Social anxiety disorder — exaggerated fear of embarrassment in social situations (eg, public
speaking, using public restrooms). Treatment: CBT, SSRIs, venlafaxine. For only occasional
anxiety-inducing situations, benzodiazepine or P-blocker.
Agoraphobia — exaggerated fear of open or enclosed places, using public transportation, being in
line or in crowds, or leaving home alone. Associated with panic disorder. Treatment: CBT, SSRI4

Generalized anxiety Anxiety lasting > 6 months unrelated to a specific person, situation, or event. Associated with
disorder restlessness, irritability, sleep disturbance, fatigue, muscle tension, difficulty concentrating.
Treatment: CBT, SSRIs, SNRIs are first line. Buspirone, TCAs, benzodiazepines are second line.
Adjustment disorder — emotional symptoms (anxiety, depression) causing impairment following
an identifiable psychosocial stressor (eg, divorce, illness) and lasting < 6 months (> 6 months in
presence of chronic stressor). Treatment: CBT, SSRIs.

Obsessive- compulsive Recurring intrusive thoughts, feelings, or sensations ( obsessions) that cause severe distress;
disorder relieved in part by the performance of repetitive actions (compulsions). Ego-dystonic : behavior
inconsistent with one’s own beliefs and attitudes (vs obsessive-compulsive personality disorder).
Associated with Tourette syndrome. Treatment : CBT, SSRIs, and clomipramine are first line.
Body dysmorphic disorder — preoccupation with minor or imagined defect in appearance
— significant emotional distress or impaired functioning; patients often repeatedly seek cosmetic
treatment. Treatment: CBT.

Post- traumatic stress Exposure to prior trauma (eg, witnessing death, experiencing serious injury or rape) -*• persistent
disorder .
Hyperarousal Avoidance of associated stimuli, intrusive Reexperiencing of the event ( nightmares,
.
flashbacks), changes in cognition or mood (fear, horror Distress! Disturbance lasts > 1 month
with significant distress or impaired social-occupational functioning. Treatment: CBT, SSRIs, and
venlafaxine are first line. Having PTSD is HARD!
Acute stress disorder — lasts between 3 days and 1 month. Treatment: CBT; pharmacotherapy is
usually not indicated.
532 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
DSM -5 Timinq Criteria
DISORDER DURATION OF SYMPTOMS FOR DIAGNOSIS
Brief psychotic < 1 month
disorder
Schizophreniform 1-6 months
disorder
Schizophrenia > 6 months
Schizoaffective > 2 weeks
disorder
Maior depressive > 2 weeks
disorder
Patholoqic qrief > 6 months
Dysthvmia , > 2 weeks
cyclothymia

Delusional disorder > 1 month

Generalized anxiety > 6 months
disorder .
Separation anxiety
disorder
Adjustment disorder < 6 months
(> 6 months if presence of chronic stressor )
Acute stress disorder 3 days-1 month
PTSD > 1 month

Malingering Patient consciously fakes, profoundly exaggerates, or claims to have a disorder in order to attain a
specific 2 ° (external ) gain (eg, avoiding work , obtaining compensation ). Poor compliance with
treatment or follow-up of diagnostic tests. Complaints cease after gain (vs factitious disorder).

Factitious disorders Patient consciously creates physical and/or psychological symptoms in order to assume “ sick role ”
and to set medical attention and sympathy (1° [ internal! gain ).
Factitious disorder Chronic factitious disorder with predominantly physical signs and symptoms. Characterized by
imposed on self a history of multiple hospital admissions and willingness to undergo invasive procedures. Often
( Munchausen
syndrome)
associated with healthcare worker
^
Factitious disorder Illness in a child or elderly patient is caused or fabricated by the caregiver. Motivation is to assume
imposed on another a sick role by proxy. Form of child /elder abuse.
( Munchausen
syndrome by proxy)
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 533

Somatic symptom and Category of disorders characterized by physical symptoms causing significant distress and
related disorders impairment . Both illness production and motivation are unconscious drives. Symptoms not
intentionally produced or feigned. More common in women.
Somatic symptom Variety of bodily complaints (eg, pain, fatigue) lasting for months to years. Associated with
disorder excessive, persistent thoughts and anxiety about symptoms. May co-occur with medical illness.

Conversion disorder
Treatment: Regular office visits with the same physician
^
Loss of sensory or motor function ( eg, paralysis, blindness, mutism), often following an acute
(functional stressor; patient is aware of but sometimes indifferent toward symptoms (“ la belle indifference” );
neurologic symptom more common in females, adolescents, and young adults.
disorder)
Illness anxiety Excessive preoccupation with acquiring or having a serious illness, often despite medical
disorder evaluation and reassurance; minimal somatic symptoms.
(Hypochondriasis|
]
Pseudocyesis False, nondelusional belief of being pregnant. May have signs and symptoms of pregnancy but is
not pregnant.

Personality
Personality trait An enduring, repetitive pattern of perceiving, relating to, and thinking about the environment and
oneself.
Personality disorder Inflexible, maladaptive, and rigidly pervasive pattern of behavior causing subjective distress
and/or impaired functioning; person is usually not aware of problem. Usually presents by early
adulthood.
Three clusters, A, B, and C; remember as Weird, Wild, and Worried based on symptoms.

Cluster A personality Odd or eccentric; inability to develop “ Weird” ( Accusatory, Aloof, Awkward),
disorders meaningful social relationships. No psychosis;
genetic association with schizophrenia.
Paranoid Pervasive distrust and suspiciousness; projection
is the major defense mechanism.
Schizoid Voluntary social withdrawal, limited emotional Schizoid = distant,
expression, content with social isolation (vs
avoidant).
Schizotypal Eccentric appearance, odd beliefs or magical Schizotypal = magical thinking ,

thinking, interpersonal awkwardness.

534 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
Cluster B personality Dramatic, emotional , or erratic; genetic "Wild ” ( Bad to the Bone).
disorders association with mood disorders and substance
abuse.
Antisocial Disregard for and violation of rights of others Antisocial = sociopath.
with lack of remorse, criminality, impulsivitw
males > females; must be > 18 years old and
have history of conduct disorder before age 15.
Conduct disorder if < 18 years old.
Borderline Unstable mood and interpersonal relationships, Treatment: dialectical behavior therapy.
impulsivity, self-mutilation , suicidality, sense
of emptiness; females > males; splitting is a
major defense mechanism.
Histrionic Excessive emotionality and excitability,
attention seeking, sexually provocative, overly
concerned with appearance.
Narcissistic Grandiosity, sense of entitlement ; lacks empathy
and requires excessive admiration ; often
demands the “ best ” and reacts to criticism
with rage.

Cluster C personality Anxious or fearful ; genetic association with “ Worried ” ( Cowardly, Compulsive, Clingy).
disorders anxiety disorders.
Avoidant Hypersensitive to rejection , socially inhibited ,
timid , feelings of inadequacy, desires
relationships with others (vs schizoid ).
Obsessive-compulsive Preoccupation with order, perfectionism , and
control ; ego-syntonic: behavior consistent with
one’s own beliefs and attitudes (vs OCD).
Dependent Submissive and cling); excessive need to be Patients often get stuck in abusive relationships.
taken care of, low self-confidence.
 PSYCHIATRY PSYCHIATRY — PATHOLOGY SECTION III 535

Eating disorders Most common in young females. Note that bupropion should be avoided for management of

Anorexia nervosa
depression
^
Excessive dieting, exercise, or binge eating/purging with BMI < 18.5 kg/m2; intense fear of gaining
weight; and distortion or overvaluation of body image. Associated with A bone density, severe
weight loss, metatarsal stress fractures, amenorrhea (due to loss of pulsatile GnRH secretion),
lanugo, anemia, electrolyte disturbances. Commonly coexists with depression. Psychotherapy
—
and nutritional rehabilitation are first line. Refeeding syndrome ( t insulin hypophosphatemia
-* cardiac complications) can occur in significantly malnourished patients.
Bulimia nervosa Binge eating with recurrent inappropriate compensatory behaviors (eg, self-induced vomiting,
using laxatives or diuretics, fasting, excessive exercise) occurring weekly for at least 3 months and
overvaluation of body image. Body weight often maintained within normal range. Associated with
parotitis, enamel erosion, electrolyte disturbances ( eg, hypokalemia, hvpochloremui metabolic

^
alkalosi dorsal hand calluses from induced vomiting ( Russell sign). Treatment: psychotherapy',
nutritional rehabilitation, antidepressants.
Binge eating disorder Regular episodes of excessive, uncontrollable eating without inappropriate compensatory behaviors,
t risk of diabetes. Treatment: psychotherapy such as CBT is first-line; SSRIs, lisdexamfetaminel

Gender dysphoria Strong, persistent cross-gender identification that leads to persistent discomfort with sex assigned at
birth, causing significant distress and/or impaired functioning. Transgender individuals may have
gender dysphoric disorder.
Transsexualism — desire to live as the opposite sex, often through surgery or hormone treatment.
Transvestism — paraphilia, not gender dysphoria. Wearing clothes (eg, vest) of the opposite sex
(cross-dressing).

Sexual dysfunction Includes sexual desire disorders ( hypoactive sexual desire or sexual aversion), sexual arousal
disorders (erectile dysfunction), orgasmic disorders (anorgasmia, premature ejaculation), sexual
pain disorders (dyspareunia, vaginismus).
Differential diagnosis includes:
Drugs (eg, antihypertensives, neuroleptics, SSRIs, ethanol)
0
Diseases (eg, depression, diabetes, STIs)
Psychological (eg, performance anxiety)

Sleep terror disorder Periods of terror with screaming in the middle of the night; occurs during slow-wave/deep (stage
N3) sleep. Most common in children . Occurs during non-REM sleep (no memory of arousal )
as opposed to nightmares that occur during REM sleep (memory of a scary dream). Cause
unknown, but triggers include emotional stress, fever, or lack of sleep. Usually self limited.
536 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
Narcolepsy Disordered regulation of sleep-wake cycles; 1°
characteristic is excessive daytime sleepiness
(awaken feeling rested ).
Caused by 1 hypocretin (orexin ) production in
lateral hypothalamus.
Also associated with: —
Hypnagogic going to sleep
" Hypnagogic ( just before sleep) or
hypnopompic ( just before awakening)
—
Hvpnopompic “ pompous upon awakening”

hallucinations.
° Nocturnal and narcoleptic sleep episodes
that start with REM sleep ( sleep paralysis!
e Cataplexy loss of all muscle tone following
(
strong emotional stimulus, such as laughter)
in some patients.
Strong genetic component . Treatment: daytime
stimulants (eg, amphetamines, modafinil ) and
nighttime sodium oxybate (GHB).

Substance use Maladaptive pattern of substance use defined as 2 or more of the following signs in 1 year related
disorder specifically to substance uset
—
Tolerance need more to achieve same effect
Withdrawal
Substance taken in larger amounts, or over longer time, than desired
Persistent desire or unsuccessful attempts to cut down
Significant energy spent obtaining, using, or recovering from substance
Important social, occupational , or recreational activities reduceq
Continued use despite knowing substance causes physical and /or psychological problems
Craving
Recurrent use in physically dangerous situations
Failure to fulfill major obligations at work, school , or homq
Social or interpersonal conflict
^
Stages of change in
overcoming substance —
—
1. Precontemplation not yet acknowledging that there is a problem
2. Contemplation acknowledging that there is a problem , but not yet ready or willing to make a
addiction change
—
3. Preparation /determination getting ready to change behaviors
—
4. Action/willpower changing behaviors
—
5. Maintenance maintaining the behavior changes
—
6. Relapse returning to old behaviors and abandoning new changes
538 SECTION III PSYCHIATRY PSYCHIATRY — PATHOLOGY
Psychoactive drug intoxication and withdrawal ( continued )
DRUG INTOXICATION WITHDRAWAL
Hallucinogens
Phencyclidine ( PCP, Violence, impulsivity, psychomotor agitation ,
anqel dustil nystagmus, tachycardia , hypertension ,
analgesia , psychosis, delirium , seizures.
Trauma is most common complication.
Treatment: benzodiazepines, rapid-acting
antipsychotic.
Lysergic acid Perceptual distortion (visual, auditory),
diethylamide ( LSD|
) depersonalization, anxiety, paranoia ,
psychosis, possible flashbacks.
Marijuana Euphoria , anxiety, paranoid delusions, Irritability, anxiety, depression, insomnia ,
(cannabinoid ) perception of slowed time, impaired judgment, restlessness, 1 appetite. Generally detectable in
social withdrawal, t appetite, dry mouth, urine for up to 1 month ,

conjunctival injection, hallucinations.

Pharmaceutical form is dronabinol
( tetrahydrocannabinol isomer): used as
antiemetic (chemotherapy) and appetite
stimulant ( in AIDS).
MDMA (ecstasy ) Hallucinogenic stimulant: euphoria , Depression , fatigue, change in appetite, difficulty
disinhibition , hy peractivity, distorted sensory concentrating, anxiety ,

and time perception , teeth clenching Life-

threatening effects include hypertension ,
tachycardia , hyperthermia , hyponatremia ,
serotonin syndrome.

Heroin addiction Users at t risk for hepatitis, HIV, abscesses, bacteremia , right-heart endocarditis. Treatment is
described below.
Methadone Long-acting oral opiate used for heroin detoxification or long-term maintenance.
Naloxone + Antagonist + partial agonist. Naloxone is not orally bioavailable, so withdrawal symptoms occur
buprenorphine only if injected (lower abuse potential ).
Naltrexone Long-acting opioid antagonist used for relapse prevention once detoxified .

Alcoholism Physiologic tolerance and dependence with symptoms of withdrawal ( tremor, tachycardia ,
hypertension , malaise, nausea , DTs) when intake is interrupted .
Complications: alcoholic cirrhosis, hepatitis, pancreatitis, peripheral neuropathy, testicular atrophy.
Treatment: disulfiram ( to condition the patient to abstain from alcohol use), acamprosate,
naltrexone, supportive care. Support groups such as Alcoholics Anonymous are helpful in
sustaining abstinence and supporting patient and family.
Wernicke- Korsakoff Caused by vitamin Bj (thiamine) deficiency. Triad of confusion , ophthalmoplegia , ataxia ( Wernicke
syndrome encephalopathy ). May progress to irreversible memory loss, confabulation , personality change
( Korsakoff syndrome) . Associated with periventricular hemorrhage /necrosis of mammillary
bodies. Treatment: IV vitamin Bj .
 PSYCHIATRY PSYCHIATRY — PHARMACOLOGY SECTION III 539

Delirium tremens Life-threatening alcohol withdrawal syndrome that peaks 2-4 days after last drink .
Characterized by autonomic hyperactivity (eg, tachycardia, tremors, anxiety, seizures). Classically
occurs in hospital setting (eg, 2-4 days postsurgery) in alcoholics not able to drink as inpatients.
Treatment: benzodiazepines ( eg, chlordiazepoxide, lorazepam , diazepam
^
Alcoholic hallucinosis is a distinct condition characterized by visual hallucinations 12-48 hours after
last drink . Treatment: benzodiazepines (eg, chlordiazepoxide, lorazepam , diazepam ).

PSYCHIATRY — PHARMACOLOGY
Preferred medications PSYCHIATRIC CONDITION PREFERRED DRUGS
for selected ADHD Stimulants ( methylphenidate, amphetamines)
psychiatric conditions
Alcohol withdrawal Benzodiazepines (eg, chlordiazepoxide,
lorazepam, diazepam )
Bipolar disorder Lithium , valproic acid , carbamazepine,
lamotrigine, aty pical antipsychotics
Bulimia nervosa SSRIs
Depression SSRIs
Generalized anxiety disorder SSRIs, SNRIs
Obsessive-compulsive disorder SSRIs, venlafaxine, clomipramine
Panic disorder SSRIs, venlafaxine, benzodiazepines
PTSD SSRIs, venlafaxine
Schizophrenia Atypical antipsychotics
Social anxiety disorder SSRIs, venlafaxine
Performance only: P-blockers, benzodiazepines
Tourette syndrome Antipsychotics (eg, fluphenazine, pimozide),
tetrabenazine

Central nervous system! Methylphenidate, dextroamphetamine, methamphetamine .

stimulants
MECHANISM t catecholamines in the synaptic cleft , especially norepinephrine and dopamine.
CLINICAL USE ADHD, narcolepsy, appetite control.
ADVERSE EFFECTS Nervousness, agitation , anxiety, insomnia , anorexia , tachycardia , hypertension .
540 SECTION III PSYCHIATRY PSYCHIATRY — PHARMACOLOGY
Antipsychotics Haloperidol , pimozide , trifluoperazine , fluphenazine , thioridazine, chlorpromazinej
( neuroleptics )
MECHANISM All typical antipsychotics block dopamine D2 High potency: Trifluoperazine , Fluphenazine ,
receptors ( t [cAMP] ). Haloperidol ( Try to Fly High) — neurologic
CLINICAL USE Schizophrenia ( primarily positive symptoms),
psychosis , bipolar disorder, delirium , Tourette
' ^
s dc c ec s
* extrapyramidal symptoms

syndrome, Huntington disease , OCD. Haloperidol — NMS, tardive dy skinesia .

ADVERSE EFFECTS Highly lipid soluble and stored in body fat; thus,
very slow to be removed from body.
Extrapvramidal system side effects (eg,
dyskinesias). Treatment: benztropine,
diphenhydramine , benzodiazepines.
Low potency: Chlorpromazine , Thioridazine
(Cheating Thieves are low) — non-neurologic
side effects (anticholinergic, antihistamine, and
arblockade effects).
Chlorpromazine - Comeal deposits;
rmal, , .1

—
Endocrine side effects (veg, dopamine
—
. . . .
v rrllnoridazine
I reI —
receptor antagonism hyperprolactinemia
galactorrhea , oligomenorrhea . Onset of EPS: ADAP 1
^
deposit

gynecomastia ) . * Hours to da> s: Acute Dystonia (muscle

Side effects arising from blocking muscarinic
,
(dry mouth , constipation ), a (orthostatic
-
sPasm’ stiffness ocul°§yric crisis)
* Da >’s to months: Akathisia (restlessness) and

hypotension ), and histamine (sedation) Parkinsonism ( bradykinesia ) .

tors " Months to years: Tardive dyskinesia
Can cause QT prolongation . For NMS> think FEVER :
Fever
OTHER TOXICITIES Neuroleptic malignant syndrome ( NMS) — Encephalopathy
rigidity, myoglobinuria , autonomic instability, \ jt fls unstable
hyperpyrexia Treatment: dantrolene, D‘
. , Enzymes t
agonists (eg. bromocriptme).
—
Tardive dyskinesia orofacial chorea as a result
of long-term antipsychotic use . ^
R of muscles

Atypical Aripiprazole , asenapine , clozapine , olanzapine , quetiapine , iloperidone , paliperidone , lurasidone,

antipsychotics risperidoneT ziprasidonej
MECHANISM Not completely understood . Most are D?
antagonists; aripiprazole is D-, partial agonist .
Varied effects on 5 -HT2, dopamine, and
a- and Hj-receptors.
CLINICAL USE Schizophrenia — both positive and negative Use clozapine for treatment-resistant
Also used for bipolar disorder,
symptoms . schizophrenia .
OCD, anxiety disorder, depression , mania ,
Tourette syndrome .
ADVERSE EFFECTS All — prolonged QT interval , fewer EPS and |
anticholinergic side effects than typical
antipsychotics.
“ - pines” — metabolic syndrome (weight gain ,
diabetes , hyperlipidemia ).
—
Clozapine agranulocytosis ( monitor WBC
w eekly) and seizures ( dose-relatedl) .
Olanzapine
— Obesity _
Must watch bone marrow clozely with clozapine ,

Risperidone — hyperprolactinemia (amenorrhea ,

galactorrhea , gynecomastia ).
 PSYCHIATRY PSYCHIATRY — PHARMACOLOGY SECTION III 541

Lithium
MECHANISM Not established; possibly related to inhibition of LiTHIUM:
phosphoinositol cascade. Low Thyroid ( hypothyroidism )
CLINICAL USE Mood stabilizer for bipolar disorder; blocks Heart ( Ebstein anomaly)
relapse and acute manic events. Insipidus ( nephrogenic diabetes insipidus )
Unwanted Movements ( tremor)
ADVERSE EFFECTS Tremor, hypothyroidism, polyuria (causes
nephrogenic diabetes insipidus), teratogenesis. I
Causes Ebstein anomaly in newborn if taken
by pregnant mother. Narrow therapeutic
window requires close monitoring of serum
levels. Almost exclusively excreted by kidneys;
most is reabsorbed at PCT with Na+. Thiazide
use is implicated in lithium toxicity in bipolar
patients.

Buspirone
MECHANISM Stimulates 5- HTJ A receptors. I’m always anxious if the bus will be on time, so
buspirone.
CLINICAL USE Generalized anxiety disorder. Does not cause
sedation , addiction, or tolerance. Takes 1-2
^
weeks to take effect. Does not interact with
alcohol (vs barbiturates, benzodiazepines).

Antidepressants

NORADRENERGIC SEROTONERGIC

AXON AXON
MAO inhibitors .
MAO Metabolites
Metabolites MAO

—
Bupropion

oc 5- HT

V* Oi 2 ( autoreceptor )

^
adrenergic
receptor
O
— 0—
/ V \
.
TCAs, SNRIs 1

4 NE reuptake J :>
Mirtazapme

V 5-HT reuptake k
-o- TCAs SSRis,
SNRIs, trazodone

V o
^o '
&S
NE receptor

h
POSTSYNAPTIC NEURON
542 SECTION III PSYCHIATRY PSYCHIATRY — PHARMACOLOGY

Selective serotonin Fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopramll

reuptake inhibitors
MECHANISM 5-HT-specific reuptake inhibitors. It normally takes 4-8 weeks for antidepressants
have an effect,
CLINICAL USE Depression, generalized anxiety disorder,
panic disorder, OCD, bulimia, social anxiety
*°
disorder, PTSD, premature ejaculation,
premenstrual dysphoric disorder.
ADVERSE EFFECTS Fewer than TCAs. GI distress, SIADH, sexual
dysfunction (anorgasmia, 1 libido).

Serotonin- Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran.

norepinephrine
reuptake inhibitors
MECHANISM Inhibit 5 -HT and norepinephrine reuptake.
CLINICAL USE Depression, general anxiety disorder, diabetic neuropathy. Venlafaxine is also indicated for social
anxiety disorder, panic disorder, PTSD, OCD. Duloxetine is also indicated for fibromyalgia!

ADVERSE EFFECTS t BP most common; also stimulant effects, sedation, nausea._

Serotonin syndrome — Can occur with any drug that t 5 -HT (eg, MAOIs, SSRIs, SNRIs, TCAs,
tramadol, ondansetron, triptans). Characterized by 3 As: neuromuscular hvperActivity (clonus,
.
hyperreflexia, hypertonia, tremor, seizure) Autonomic stimulation (hyperthermia, diaphoresis,
diarrhea), and Agitation. Treatment: cyproheptadine ( 5 -HT, receptor antagonist).

Tricyclic Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, amoxapine.

antidepressants
MECHANISM Block reuptake of norepinephrine and 5-HT.
CLINICAL USE Major depression, OCD (clomipramine), peripheral neuropathy, chronic pain, migraine
prophylaxis. Nocturnal enuresis (imipraminej
ADVERSE EFFECTS Sedation, (Xj-blocking effects including postural hypotension, and atropine-like (anticholinergic)
side effects (tachycardia, urinary retention, dry mouth). 3° TCAs (amitriptyline) have more
anticholinergic effects than 2° TCAs (nortriptyline). Can prolong QT interval.
Tri-C’s: Convulsions, Coma, Cardiotoxicity (arrhythmia due to Na+ channel inhibition);
also respiratory depression, hyperpyrexia. Confusion and hallucinations in elderly due to
anticholinergic side effects (nortriptyline better tolerated in the elderl . Treatment: NaHCO, to
prevent arrhythmia. ^
 PSYCHIATRY PSYCHIATRY — PHARMACOLOGY SECTION III 543

Monoamine oxidase Tranylcypromine, Phenelzine, Isocarboxazid, Selegiline (selective MAO-B inhibitor).

inhibitors (MAO Takes Pride In Shanghai).
MECHANISM Nonselective MAO inhibition t levels of amine neurotransmitters (norepinephrine, 5 -HT,
dopamine).
CLINICAL USE Atypical depression, anxiety. Parkinson disease (Selegiline!
ADVERSE EFFECTS Hypertensive crisis (most notably with ingestion of tyramine, which is found in many foods such
as aged cheese and wine); CNS stimulation. Contraindicated with SSRIs, TCAs, St. John’s wort,
meperidine, dextromethorphan (to prevent serotonin syndrome).
Wait 2 weeks after stopping MAO inhibitors before starting serotonergic drugs or stopping dietary
restrictions.

Atypical antidepressants
Bupropion t norepinephrine and dopamine via unknown mechanism. Also used for smoking cessation.
Known to cause weight losi Toxicity: stimulant effects (tachycardia, insomnia), headache,
seizures in anorexic /bulimic patients. May help alleviate sexual dvsfunctioli
Mirtazapine a-,-antagonist (t release of NE and 5-HT), potent 5-HT? and 5 -HT5 receptor antagonist and Hj
antagonist. Toxicity: sedation ( which may be desirable in depressed patients with insomnia),
t appetite, yveight gain (yvhich may be desirable in elderly or anorexic patients), dry mouth.
Trazodone ,
Primarily blocks 5 -HT-,, apadrenergic, and H receptors; also weakly inhibits 5 -HT reuptake. Used
primarily for insomnia, as high doses are needed for antidepressant effects. Toxicity: sedation,
nausea, priapism, postural hypotension. Called traZZZobone due to sedative and male-specific
side effects.
Varenicline Nicotinic ACh receptor partial agonist. Used for smoking cessation. Toxicity: sleep disturbance.

Tyramine Normally degraded by monoamine oxidase (MAO). Levels t in patients taking MAO inhibitors
who ingest tyramine-rich foods (eg, cheese, yvine). Excess tyramine enters presvnaptic vesicles and

——
displaces other neurotransmitters (eg, NE) t active presvnaptic neurotransmitters -* t diffusion
of neurotransmitters into synaptic cleft t sympathetic stimulation. Classically results in a
hypertensive crisis (treatment: phentolamine).

Placement of "Tyramine ' fact here OK ? Added per

1

comment ("pis delete Tyramine Fact here, moving

to Psych chapter") on page 243 in Pharmacology
chapter.
HIGH- YI E LD SYSTEMS

Renal

“ But I know all about love already. 1 know precious little still about Embryology 546
kidneys."
— Aldous Huxley, Antic Hay Anatomy 547

“ This too shall pass. Just like a kidney stone." Physiology 549
— Hunter Madsen
Pathology 560
“ I drink too much. The last time I gave a urine sample it had an olive
in it.” Pharmacology 572
— Rodney Dangerfield

545
 RENAL RENAL — PHYSIOLOGY SECTION III 549

RENAL — PHYSIOLOGY
Fluid compartments

r
Body mass: 70 kg
Total body water (TBW )
-
X Non water mass (NWM) 1
HIKIN': High K+ INtracellularly.
60-40-20 rule (% of body weight for average
60% of body mass = 42 kg = 42 L 40% of body mass * 28 kg
person ):
as 60% total body water
II 40% ICF
11 -
fit
Interstitial fluid - -
75% ECF 10.5 L 10.5 kg

-
1/ 3
20% ECF
ss Plasma volume can be measured by
?
J radiolabeling albumin .
- Extracellular volume can be measured by inulin
85 or mannitol .

2/ 3
Ij
1
Is
1 Normal HCT = 45%

HCT (%) ~ 3 x|Hbl in g/dL

Osmolality = 285-295 mOsm /kg H ^ O.

Glomerular filtration Responsible for filtration of plasma according to Charge barrier is lost in nephrotic syndrome
barrier size and charge selectivity -*• albuminuria , hypoproteinemia, generalized
Composed of: edema , hyperlipidemia .
e Fenestrated capillary endothelium (size

barrier)
Fused basement membrane with heparan
: sulfate ( negative charge and size barrier)
Epithelial layer consisting of podocvte foot
processes Q ( negative charge barrier)
if

Renal clearance Cx = UXV/PX = volume of plasma from which the Cx = clearance of X (mL/min).
substance is completely cleared per unit time. Ux = urine concentration of X (eg, mg/mL).
If Cx < GFR: net tubular reabsorption of X. Px = plasma concentration of X (eg, mg/mL).
If Cx > GFR: net tubular secretion of X. V = urine flow rate ( mL /min ).
If Cx = GFR: no net secretion or reabsorption .
 RENAL RENAL — PHYSIOLOGY SECTION III 551

Filtration Filtration fraction ( FF) = GFR / RPF. GFR can be estimated with creatinine
Normal FF = 20% . clearance.
Filtered load (mg/min) = GFR (mL/min ) RPF is best estimated with PAH clearance .
x plasma concentration ( mg/mL).
Prostaglandins preferentially
NSAIDs — ©— I dilate afferent arteriole Parietal layer of
( T RPF, T GFR, so noAFF) Bowman capsule

a ocuNmaf1 s space
%
%
% PS
Juxtaglomerular
cel :
* "
"i

Filtered Excreted
Macula densa
rP

Reabsorbed • Secreted
iecreie
Distal renal
Mb - e
'- capillary
Peritubular

Net filtration pressure

Endothelia ce Is (
PK + 7tas ) - (PBS + Tt^ )
Mesangial Basement
c e .l: membrane
Cerent arteriole
Angiotensin II preferentially
ACE inhibitors OH constricts efferent arteriole
.
(4 RPF, T GFR, so T FF) 0

Changes in glomerular dynamics

Effect GFR RPF FF (GFR/ RPF )
Afferent arteriole constriction l 1 —
Efferent arteriole constriction t l t
t plasma protein concentration i — t
i plasma protein concentration t — t
Constriction of ureter i — 1
Dehydration i a t

Calculation of Filtered load = GFR x . Px

reabsorption and Excretion rate = V x Ux.
secretion rate Reabsorption rate|= filtered - excreted .
Secretion rate|= excreted filtered . —
FENa = Na+ excreted/Na + filtered = V X UNa /GFR x PNa (GFR = UCr X V/PCr) =
PCr X UNi/UCr X FNa
554 SECTION III RENAL RENAL — PHYSIOLOGY
Renal tubular defects Fanconi syndrome is first ( PCT ), the rest are in alphabetic order.
Fanconi syndrome Generalized reabsorptive defect in PCT.
_
metabolic acidosis ( proximal renal tubular acidosis). ^
Associated with t excretion of nearly all amino acids, glucose, HCCX-, and PO . May result in

Causes include hereditary defects (eg, Wilson disease, tyrosinemia , glycogen storage disease,
cystinosis), ischemia, multiple myeloma , nephrotoxins/drugs (eg, ifosfamide, cisplatin, tenofovir,
expired tetracyclines), lead poisoning.
Bartter syndrome Reabsorptive defect in thick ascending loop of Henle . Affects Nai/ Ki/ 2C1- cotransporter. Results
in hypokalemia and metabolic alkalosis with hypercalciuria. Presents similarly to chronic loop

Gitelman syndrome
diuretic use. Autosomal recessive
^
Reabsorptive defect of NaCl in DCT. Leads to hypokalemia, hypomagnesemia, metabolic
alkalosis, hvpocalciuria. Similar to using lifelong thiazide diuretics. Autosomal recessive. Less

Liddle syndrome Gain of function mutation

—
severe than Bartter syndrome]
t Na+ reabsorption in collecting tubules ( t activity of epithelial Na+
channel ). Presents like hyperaldosteronism , but aldosterone is nearly undetectable.
Autosomal dominant . Results in hypertension , hypokalemia , metabolic alkalosis, i aldosterone.
Treatment: Amiloride.
Syndrome of Hereditary deficiency of HP-hydroxysteroid dehydrogenase, which normally converts cortisol (can
Apparent activate mineralocorticoid receptors) to cortisone (inactive on mineralocorticoid receptors ) in cells
Mineralocorticoid
Excess
—
containing mineralocorticoid receptors. Excess cortisol in these cells from enzyme deficiency
t mineralocorticoid receptor activity -*• hypertension, hypokalemia , metabolic alkalosis. Low
serum aldosterone levels. Can acquire disorder from glycvrrhetinic acid ( present in licorice),
which blocks activity of llp-hydroxysteroid dehydrogenase.

—
Treatment: corticosteroids (exogenous corticosteroids 1 endogenous cortisol production
1 mineralocorticoid receptor activation ).
Cortisol tries to be the SAME as aldosterone.
558 SECTION III RENAL RENAL — PHYSIOLOGY

Potassium shifts SHIFTS K + OUT OF CELL (CAUSING HYPERKALEMIA ) SHIFTS r INTO CELL (CAUSING HYPOKALEMIA )
Digitalis ( blocks Na + / K+ ATPase)
HyperOsmolarity Hypo-osmolarity
Lysis of cells (eg, crush injury, rhabdomyolysis,
tumor lysis syndrome)
Acidosis Alkalosis
P-blocker p-adrenergic agonist ( t Na+/K+ ATPase)
High blood Sugar ( insulin deficiency) Insulin ( t Na+ / K+ ATPase)
Patient with hyperkalemia? DO LApSj Insulin shifts K+ into cells

Electrolyte disturbances
ELECTROLYTE LOW SERUM CONCENTRATION HIGH SERUM CONCENTRATION
Na + Nausea and malaise, stupor, coma , seizures Irritability, stupor, coma
K* U waves and flattened T waves on ECG , Wide QRS and peaked T waves on ECG,
arrhythmias, muscle cramps, spasm , weakness arrhythmias, muscle weakness
Ca 2+ Tetany, seizures, QT prolongation , twitching Stones (renal ), bones ( pain ), groans (abdominal
(Chvostek sign ), spasm ( Trousseau sign ) pain), thrones ( t urinary frequency), psychiatric
overtones (anxiety, altered mental status), but
not necessarily calciuria
Mg2+ Tetanv, torsades de pointes, hypokalemia , 1 DTRs, lethargy, bradycardia, hypotension ,

PO 43-
hypocalcemia (when [ Mg 1 < 1.2 mg/dLi
—
Bone loss, osteomalacia (adults), rickets
cardiac arrest , hypocalcemia
Renal stones, metastatic calcifications,
(children ) hypocalcemia

Features of renal disorders

CONDITION BLOOD PRESSURE PLASMA RENIN ALDOSTERONE SERUM Mg2+ URINE Ca 2+
Bartter syndrome - t t t
Gitelman syndrome - t t 1 1
Liddle syndrome t i i
SIADH d i i
Primary t Ji II
hyperaldosteronism
(Conn syndrome)
-
Renin secreting tumor t t t
562 SECTION III RENAL RENAL — PATHOLOGY

Nephritic syndrome Nephritic syndrome = Inflammatory process. When it involves glomeruli, it leads to hematuria
and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention),
proteinuria.
Acute LM — glomeruli enlarged and hypercellular Q. Most frequently seen in children. Occurs
poststreptococcal IF— (“starry sky”) granular appearance ~ 2-4 weeks after group A streptococcal
glomerulonephritis (“ lumpy-bumpy”) due to IgG, IgM, and C 3 infection of pharynx or skin. Resolves
deposition along GBM and mesangium. spontaneously. Type III hypersensitivity-
EM — subepithelial immune complex (IC ) reaction.
humps. Presents with peripheral and periorbital edema,
cola-colored urine, hypertension.
Positive strep titers/serologies, i complement

Rapidly progressive LM and IF— crescent moon shape Q. Crescents

levels (C3) due to consumption
^
Poor prognosis. Rapidly deteriorating renal
(crescentic) consist of fibrin and plasma proteins (eg, C 3b) function (days to weeks).
glomerulonephritis with glomerular parietal cells, monocytes,
macrophages.
Several disease processes may result in this
pattern, in particular:
u
Goodpasture syndrome — type II Hematuria/hemoptysis.
hypersensitivity reactioij antibodies to Treatment: emergent plasmapheresis.
GBM and alveolar basement membrane

8
— JinearjF
Granulomatosis with polyangiitis (Wegener)
Microscopic ijplyangiitis
Diffuse proliferative Due to SLE or membranoproliferative
glomerulonephritis glomerulonephr itis.
LM — “ wire looping” of capillaries.
EM — subendothelial and sometimes
intramembranous IgG-based ICs often with
C3 deposition.
IF— granular.
IgA nephropathy LM— mesangial proliferation.
(Berger disease) EM — mesangial IC deposits.
IF— IgA-based IC deposits in mesangium.
Renal pathology of Henoeh-Schonlein purpura.
_ PR 3-ANCA/c-ANCA. Pauci-immune (no Ig/C3
deposition).
MPO-ANCA /p-ANCA. Pauci-immune (no Ig/C3
deposition).
A common cause of death in SLE (think “ wire
lupus” ). DPGN and MPGN often present as
nephrotic syndrome and nephritic syndrome
concurrently.
Episodic gross hematuria that occurs
concurrently with respiratory or GI tract
infections (IgA is secreted by mucosal linings).
Not to be confused with Buerger disease
(thromboangiitis obliterans).
562 SECTION III RENAL RENAL — PATHOLOGY

Nephritic syndrome Nephritic syndrome = Inflammatory process. When it involves glomeruli, it leads to hematuria
and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention),
proteinuria.
Acute LM — glomeruli enlarged and hypercellular Q. Most frequently seen in children. Occurs
poststreptococcal IF— (“starry sky”) granular appearance ~ 2-4 weeks after group A streptococcal
glomerulonephritis (“ lumpy-bumpy”) due to IgG, IgM, and C 3 infection of pharynx or skin. Resolves
deposition along GBM and mesangium. spontaneously. Type III hypersensitivity-
EM — subepithelial immune complex (IC ) reaction.
humps. Presents with peripheral and periorbital edema,
cola-colored urine, hypertension.
Positive strep titers/serologies, i complement

Rapidly progressive LM and IF— crescent moon shape Q. Crescents

levels (C3) due to consumption
^
Poor prognosis. Rapidly deteriorating renal
(crescentic) consist of fibrin and plasma proteins (eg, C 3b) function (days to weeks).
glomerulonephritis with glomerular parietal cells, monocytes,
macrophages.
Several disease processes may result in this
pattern, in particular:
u
Goodpasture syndrome — type II Hematuria/hemoptysis.
hypersensitivity reactioij antibodies to Treatment: emergent plasmapheresis.
GBM and alveolar basement membrane

8
— JinearjF
Granulomatosis with polyangiitis (Wegener)
Microscopic ijplyangiitis
Diffuse proliferative Due to SLE or membranoproliferative
glomerulonephritis glomerulonephr itis.
LM — “ wire looping” of capillaries.
EM — subendothelial and sometimes
intramembranous IgG-based ICs often with
C3 deposition.
IF— granular.
IgA nephropathy LM— mesangial proliferation.
(Berger disease) EM — mesangial IC deposits.
IF— IgA-based IC deposits in mesangium.
Renal pathology of Henoeh-Schonlein purpura.
_ PR 3-ANCA/c-ANCA. Pauci-immune (no Ig/C3
deposition).
MPO-ANCA /p-ANCA. Pauci-immune (no Ig/C3
deposition).
A common cause of death in SLE (think “ wire
lupus” ). DPGN and MPGN often present as
nephrotic syndrome and nephritic syndrome
concurrently.
Episodic gross hematuria that occurs
concurrently with respiratory or GI tract
infections (IgA is secreted by mucosal linings).
Not to be confused with Buerger disease
(thromboangiitis obliterans).
564 SECTION III RENAL RENAL — PATHOLOGY

Nephrotic syndrome —
NephrOtic syndrome massive prOteinuria (> 3.5 g/day) with hypoalbuminemia , resulting
edema , hyperlipidemia. Frothy urine with fatty casts. Due to podocyte damage disrupting
glomerular filtration charge barrier. May be 1° (eg, direct sclerosis of podocytes) or 2° (systemic
process [eg, diabetes) secondarily damages podocytes). Associated with hypercoagulable state (eg,
thromboembolism ) due to antithrombin ( AT) III loss in urine and t risk of infection (due to loss of
immunoglobulins in urine and soft tissue compromise by edema ).
Severe nephritic syndrome may present with nephrotic syndrome features (nephritic-nephrotic
syndrome) if damage to GBM is severe enough to damage charge barrier.
Minimal change LM — normal glomeruli ( lipid may be seen in Most common cause of nephrotic syndrome
disease ( lipoid PCT cells). in children . Often 1° (idiopathic) and may be
nephrosis) IF ©. triggered by recent infection , immunization,
—
EM effacement of foot processes Q. immune stimulus. Rarely, may be 2° to
lymphoma (eg, cytokine-mediated damage). 1°
disease has excellent response to corticosteroids.
Focal segmental LM — segmental sclerosis and hvalinosis Q. Most common cause of nephrotic syndrome in
glomerulosclerosis —
IF often ©, but may be © for nonspecific focal African Americans and Hispanics. Can be 1°
deposits of IgM, C3, Cl
^
EM — effacement of foot process similar to
minimal change disease.
( idiopathic ) or 2° to other conditions (eg, HIV7
infection, sickle cell disease, heroin abuse,
massive obesity, interferon treatment , chronic
kidney disease due to congenital malformations).
1° disease has inconsistent response to steroids.
May progress to chronic renal disease.
Membranous LM — diffuse capillary and GBM thickening Q. Most common cause of 1° nephrotic syndrome
nephropathy IF— granular as a result of immune complex in Caucasian adults. Can be 1° (eg, antibodies
( membranous deposition. Nephrotic presentation of SLE . to phospholipase A7 receptor) or 2° to drugs
glomerulonephritis) EM — “ spike and dome” appearance with (eg, NSAIDs, penicillamine, gold ), infections
subepithelial deposits.
^
(eg, HBV, I ICV, syphilis SLE , or solid tumors.
1° disease has poor response to steroids. May
progress to chronic renal disease.
Amyloidosis LM — Congo red stain shows apple-green Kidney is the most commonly involved organ
birefringence under polarized light due to (systemic amyloidosis). Associated with
amyloid deposition in the mesangium . chronic conditions that predispose to amyloid
deposition (eg, AL amyloid , AA amyloid ).
Diabetic glomerulo - LM — mesangial expansion , GBM thickening, Nonenzyinatic glycosylation of GBM
nephropathy eosinophilic nodular glomerulosclerosis - t permeability, thickening.
_
( Kimmelstiel -Wilson lesions, arrows in Q).
( hyaline arteriosclerosis )
expansion . — —
Nonenzyinatic glycosylation of efferent arterioles
t GFR mesangial

Most common cause of end -stage renal disease in

the United States.

rv
.
&
JI Vr £ m
I ’
v’4 ,
r- V:

1 Vr nmmssmiife:- <
*.
’
•

jtw
£
566 SECTION III RENAL RENAL — PATHOLOGY

Hydronephrosis Distention/dilation of renal pelvis and calyces Q. Usually caused by urinary tract obstruction (eg,
renal stones, BPH, cervical cancer, injury to ureter); other causes include retroperitoneal fibrosis,
vesicoureteral reflux. Dilation occurs proximal to site of pathology. Serum creatinine becomes
£ elevated only if obstruction is bilateral or if patient has only one kidney. Leads to compression and
possible atrophy of renal cortex and medulla.

Renal cell carcinoma

—
Originates from PCT cells polygonal clear
cells Q filled with accumulated lipids and
Most common 1° renal malignancy Q.
Associated with gene deletion on chromosome
carbohydrates. Often golden-yellow [] due to 5 (sporadic or inherited as von Hippel-Lindau
t lipid content. Most common in men 50-70 syndrome). RCC = 3 letters = chromosome 3.
years old. t incidence with smoking and Associated with paraneoplastic syndromes (eg,
obesity. Manifests clinically with hematuria, ectopic EPO, ACTH, PTHrP, renin).
palpable mass, 2° polycythemia, flank pain, “ Silent ” cancer because commonly presents as a
fever, weight loss. Invades renal vein (may metastatic neoplasm.
develop varicocele if left sided ) then IVCjand
spreads hematogenouslv; metastasizes to lung
and bone.
Treatment: resection if localized disease.
Immunotherapy (eg, aldesleukin) or targeted
therapy for advanced/metastatic disease.
Resistant to chemotherapy and radiation
therapy.

:•

SS;a
’M
J r .
*

Renal oncocytoma Benign epithelial cell tumor arising from

collecting ducts (arrows in Q point to well-
circumscribed mass with central scar).
Large eosinophilic cells with abundant
mitochondria without perinuclear clearing
P5 O (vs chromophobe renal cell carcinoma).
Presents with painless hematuria, flank pain,
abdominal mass.
Often resected to exclude malignancy (eg, renal
m- n
cell carcinoma).
 RENAL RENAL — PATHOLOGY SECTION III 567

Nephroblastoma Most common renal malignancy of early childhood (ages 2-4). Contains embryonic glomerular
( Wilms tumor ) j structures. Presents with large, palpable, unilateral flank mass Q and/or hematuria.
“ Loss of function ” mutations of tumor suppressor genes WTl or WT2 on chromosome 11 .
May be a part of several syndromes:
WAGR complex: Wilms tumor, Aniridia (absence of iris), Genitourinary malformations, mental
>r . Retardation /intellectual disability (WTl deletion )
* Denys-Drash : Wilms tumor, early- onset nephrotic syndrome, male pseudohermaphroditism

( WTl mutation )
-
Beckwith Wiedemann: Wilms tumor, macroglossia , organomegaly, hemihyperplasiaj ( WT2
mutation)

Transitional cell Most common tumor of urinary tract system Q 1

carcinoma (can occur in renal calyces, renal pelvis,

-
ureters, and bladder) Q EDI Painless hematuria
( no casts) suggests bladder cancer.
Associated with problems in your Pee SAC:
Phenacetin , Smoking, Aniline dyes, and
Cyclophosphamide.

5 \
m -
i in pillary turn
: ** *
\ .* # ' * <& mm .
S.'J*
tic urothelium ..
^
Squamous cell
carcinoma of the
bladder
carcinoma. —
Chronic irritation of urinary bladder -»• squamous metaplasia dysplasia and squamous cell

Risk factors include Schistosoma haematobium infection ( Middle East), chronic cystitis, smoking,
chronic nephrolithiasis. Presents with painless hematuria .

Urinary incontinence
Stress incontinence Outlet incompetence ( urethral hypermobility or intrinsic sphincteric deficiency) - leak with
t intra-abdominal pressure (eg, sneezing, lifting) t risk with obesity, vaginal delivery, prostate
,

surgery. © bladder stress test (directly observed leakage from urethra upon coughing or Valsalva
maneuver). Treatment: pelvic floor muscle strengthening ( Kegel ) exercises, weight loss, pessaries.
Urgency incontinence Overactive bladder (detrusor instability) -* leak with urge to void immediately. Treatment: Kegel
exercises, bladder training (timed voiding, distraction or relaxation techniques), antimuscarinics
(eg, oxybutynin).
Mixed incontinence Features of both stress and urgency incontinence.
Overflow Incomplete emptying (detrusor underactivity or outlet obstruction ) -*• leak with overfilling t post¬
,

incontinence void residual ( urinary retention ) on catheterization or ultrasound. Treatment: catheterization,

relieve obstruction (eg, a-blockers for BPH ).
568 SECTION III RENAL RENAL — PATHOLOGY

Urinary tract infection Inflammation of urinary bladder. Presents as suprapubic pain, dysuria , urinary frequency, urgency,
(acute bacterial Systemic signs (eg, high fever, chills) are usually absent .
cystitis) Risk factors include female gender (short urethra ), sexual intercourse (“ honeymoon cystitis” ),
indwelling catheter, diabetes mellitus, impaired bladder emptying.
Causes:
° E coli ( most common ).
—
Staphylococcus saprophyticus seen in sexually active young women (E coli is still more
common in this group ).
Klebsiella.
—
Proteus mirabilis urine has ammonia scent .
Lab findings: © leukocyte esterase. © nitrites (indicate gram © organisms, especially E coli ). Sterile
pyuria and © urine cultures suggest urethritis by Neisseria gotiorrhoeae or Chlamydia trachomatis .

Pyelonephritis
Acute pyelonephritis Neutrophils infiltrate renal interstitium Q. Affects cortex with relative sparing of glomeruli /vessels.
Presents with fevers, flank pain (costovertebral angle tenderness), nausea /vomiting, chills.
Causes include ascending UTI ( E coli is most common ), hematogenous spread to kidney. Presents
—
with WBCs in urine +/ WBC casts. CT would show striated parenchymal enhancement QJ.
Risk factors include indwelling urinary catheter, urinary tract obstruction , vesicoureteral reflux,
diabetes mellitus, pregnancy.
Complications include chronic pyelonephritis, renal papillary necrosis, perinephric abscess,
urosepsis.
Treatment: antibiotics.
Chronic The result of recurrent episodes of acute pyelonephritis. Typically requires predisposition to
pyelonephritis infection such as vesicoureteral reflux or chronically obstructing kidney stones.
Coarse, asymmetric corticomedullary scarring, blunted calyx. 7’ubules can contain eosinophilic
casts resembling thyroid tissue Q (thyroidization of kidney).
—
Xanthogranulomatous pyelonephritis rare; grossly orange nodules that can mimic tumor
nodules, characterized b\lwidespread kidney damage due to granulomatous tissue containing
foamy macrophages.
-5
>•
iV \
>
it m
> •V

.
1 .
Z

Diffuse cortical Acute generalized cortical infarction of both Associated with obstetric catastrophes (eg,
necrosis kidneys. Likely due to a combination of abruptio placentae), septic shock ,
vasospasm and DIC.
570 SECTION III RENAL RENAL — PATHOLOGY

Acute interstitial Acute interstitial renal inflammation. Pyuria Associated with fever, rash, hematuria, and
nephritis (classically eosinophils) and azotemia costovertebral angle tenderness, but can be
( tubulointerstitial occurring after administration of drugs that asymptomatic.
nephritis) act as haptens, inducing hypersensitivity (eg, Remember these P’s:
diuretics, penicillin derivatives, proton pump Pee (diuretics)
inhibitors, sulfonamides, rifampin, NSAIDs). u
Pain-free (NSAIDs)
Less commonly may be 2° to other processes Penicillins and cephalosporins
such as systemic infections (eg, mycoplasma) Proton pump inhibitors
autoimmune diseases (eg, Sjogren syndrome,
SLE, sarcoidosis).
- RifamPin

Acute tubular necrosis Most common cause of acute kidney injury- in hospitalized patients. Spontaneously resolves in
many cases. Can be fatal, especially during initial oliguric phase t FENa.
,

Key finding: granular (“muddy brown” ) casts Q.

3 stages:
1. Inciting event
2. Maintenance phase — oliguric; lasts 1-3 weeks; risk of hyperkalemia, metabolic acidosis,

• ;
. H P uremia
3. Recovery phase — polvuric; BUN and serum creatinine fall; risk of hypokalemia
Can be caused by ischemic or nephrotoxic injury:
° Ischemic — 2° to i renal blood flow (eg, hypotension, shock, sepsis, hemorrhage, HF). Results
in death of tubular cells that may slough into tubular lumen []] (PCT and thick ascending limb
are highly susceptible to injury).

\ Nephrotoxic — 2° to injury resulting from toxic substances (eg, aminoglycosides, radiocontrast

agents, lead, cisplatin, ethylene glycot. crush injury (myoglobinuria), hemoglobinuria. PCT is
particularly susceptible to injury.
A In
' iiMr \m 0 TTI i

Renal papillary
necrosis
—
Sloughing of necrotic renal papillae Q gross
hematuria and proteinuria. May be triggered
SAAD papa with papillary necrosis:
Sickle cell disease or trait

i
m by recent infection or immune stimulus.
Associated with sickle cell disease or trait,
acute pyelonephritis, NSAIDs, diabetes
mellitus.
Acute pyelonephritis
Analgesics (NSAIDs)
Diabetes mellitus

*
 RENAL RENAL — PATHOLOGY SECTION III 571

Renal cyst disorders

Autosomal dominant Numerous cysts in cortex and medulla Q causing bilateral enlarged kidneys ultimately destroy
polycystic kidney kidney parenchyma. Presents with flank pain, hematuria, hypertension, urinary infection,
disease progressive renal failure in ~ 50% of individuals.
Mutation in PKD1 ( 85% of cases, chromosome 16 ) or PKD2 ( 15% of cases, chromosome 4). Death
from complications of chronic kidney disease or hypertension (caused by t renin production).
Associated with berry aneurysms, mitral valve prolapse, benign hepatic cysts, diverticulosij
Treatment: ACE inhibitors or ARBs.
Autosomal recessive Cystic dilation of collecting ducts Q. Often presents in infancy. Associated with congenital
polycystic kidney hepatic fibrosis. Significant oliguric renal failure in utero can lead to Potter sequence. Concerns
disease beyond neonatal period include systemic hypertension, progressive renal insufficiency, and portal
hypertension from congenital hepatic fibrosis.
Medullary cystic Inherited disease causing tubulointerstitial fibrosis and progressive renal insufficiency with inability
disease to concentrate urine. Medullar}' cysts usually not visualized; shrunken kidneys on ultrasound.
Poor prognosis.
Simple vs complex Simple cysts are filled with ultrafiltrate (anechoic on ultrasound Q). Very common and account for
renal cysts majority of all renal masses. Found incidentally and typically asymptomatic.
Complex cysts, including those that are septated, enhanced, or have solid components on imaging
require follow-up or removal due to risk of renal cell carcinoma.

P'f “ s

,4.c. .

/
» i
*
»
- ra
-L .
 RENAL RENAL — PHARMACOLOGY SECTION III 573

Mannitol
MECHANISM Osmotic diuretic, t tubular fluid osmolarity
-* t urine flow, I intracranial /intraocular
pressure.
CLINICAL USE Drug overdose, elevated intracranial /intraocular

ADVERSE EFFECTS

Acetazolamide
MECHANISM
pressure.
Pulmonary edema , dehydration .
Contraindicated in anuria , HF.

Carbonic anhydrase inhibitor. Causes self¬

r
limited NaHCO, diuresis and i total body
.
HCO - stores.
CLINICAL USE Glaucoma , urinary alkalinization, metabolic
alkalosis, altitude sickness, pseudotumor
\ 0

cerebri .
ADVERSE EFFECTS Proximal renal tubular acidosis, paresthesias, “ ACID’ azolamide causes ACIDosis.
NFL toxicity, sulfa allergy; hypokalemial

Loop diuretics
Furosemide, bumetanide, torsemide
MECHANISM Sulfonamide loop diuretics. Inhibit cotransport
system ( Na + / K+ /2C1-) of thick ascending limb
of loop of Henle. Abolish hvpertonicity of
medulla , preventing concentration of urine.
Stimulate PGE release (vasodilatory effect

m
on afferent arteriole ); inhibited by NSAIDs.
t Ca 2+ excretion . Loops Lose Ca +. -
CLINICAL USE Edematous states ( HF, cirrhosis, nephrotic
syndrome, pulmonary edema), hypertension ,
hypercalcemia.
ft
ADVERSE EFFECTS Ototoxicity , Hypokalemia , Hy pomagnesemia, OHH DANG!
Dehydration , Allergy (sulfa ) /metabolic r -J
Alkalosis, Nephritis (interstitial ), Gout .
Ethacrynic acid
MECHANISM Nonsulfonamide inhibitor of cotransport system V 0
( Na +/ K+ /2C1 ~ ) of thick ascending limb of loop
of Henle.
CLINICAL USE Diuresis in patients allergic to sulfa drugs.
ADVERSE EFFECTS Similar to furosemide, but more ototoxic. Loop earrings hurt your ears.
 RENAL RENAL — PHARMACOLOGY SECTION III 575

Angiotensin ¬ Captopril, enalapril, lisinopril, ramipril.

converting enzyme
inhibitors
MECHANISM
- -
Inhibit ACE i AT II i GFR by preventing
constriction of efferent arterioles, t renin due
to loss of negative feedback. Inhibition of ACE
also prevents inactivation of bradvkinin, a
potent vasodilator.
CLINICAL USE Hypertension, HF (i mortality), proteinuria, In diabetic nephropathy, i intraglomerular
diabetic nephropathy. Prevent unfavorable pressure, slowing CBM thickening ,

heart remodeling as a result of chronic

hypertension.
ADVERSE EFFECTS Cough, Angioedema (due to t bradvkinin; Captopril's CATCHH.
contraindicated in Cl esterase inhibitor
deficiency), Teratogen (fetal renal
malformations), t Creatinine (1 GFR),
Hyperkalemia, and Hypotension. Used with
caution in bilateral renal artery stenosi
because ACE inhibitors will further 1 GFR^
— renal failure.

Angiotensin II receptor Losartan, candesartan, valsartan.

blockers
MECHANISM Selectively block binding of angiotensin II to ATj receptor. Effects similar to ACE inhibitors, but
ARBs do not increase bradvkinin.
CLINICAL USE Hypertension, HF, proteinuria, or diabetic nephropathy with intolerance to ACE inhibitors (eg,
cough, angioedema).
ADVERSE EFFECTS Hyperkalemia, i GFR, hypotension; teratogen.

Aliskiren
MECHANISM Direct renin inhibitor, blocks conversion of angiotensinogen to angiotensin I.
CLINICAL USE Hypertension.
ADVERSE EFFECTS
taking ACE inhibitors or ARBs. ^
Hyperkalemia, i GFR, hypotension, angioedema Relatively contraindicated in patients already
HIGH - YIELD SYSTEMS

Reproductive

“ Artificial insemination is when the farmer does it to the cow instead of the Embryology 578
bull.”
— Student essay Anatomy 589

“ Whoever called it necking was a poor judge of anatomy." Physiology 593

— Groucho Marx
Pathology 601
“ See , the problem is that Cod gives men a brain and a penis, and only
enough blood to run one at a time.” Pharmacology 616
—
Robin Williams

“ I think you can say that life is a system in which proteins and nucleic
acids interact in ways that allow the structure to grow and reproduce. It’ s
that growth and reproduction , the ability to make more of yourself , that’s
important.”
— Andrew H . Knolli

577
578 SECTION III REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY
REPRODUCTIVE — EMBRYOLOGY
Important genes of embryogenesis
Sonic hedgehog gene Produced at base of limbs in zone of polarizing activity. Involved in patterning along
anteroposterior axis and CNS development; mutation can cause holoprosencephaly.
Wnt -7 gene Produced at apical ectodermal ridge (thickened ectoderm at distal end of each developing limb ).
Necessary for proper organization along dorsal-ventral axis.
FGF gene Produced at apical ectodermal ridge. Stimulates mitosis of underlying mesoderm, providing for
lengthening of limbs.
Homeobox ( Hox )
genes

Early fetal development

—
Involved in segmental organization of embryo in a craniocaudal direction . Code for transcription
factors. Hox mutations appendages in wrong locations.

Early embryonic
development
DAY 1

©, ©
Faun ' i i n

mo .

Degenerated
DMoping corpus litojm
-
follicle v

f
r
1
DAY 4
Morula

DAY 5
Blastocyst

*
2 oocyte
En kxneb uni

Within week 1 hCG secretion begins around the time of Blastocyst “ sticks” at day 6:
implantation of blastocyst.
Within week 2 Bilaminar disc (epiblast , hypoblast). 2 weeks = 2 layers.
Within week 3 Gastrulation forms trilaminar embryonic disc. 3 weeks = 3 layers.
Cells from epiblast invaginate -*• primitive
streak -*• endoderm , mesoderm , ectoderm.
Notochord arises from midline mesoderm ;
overlying ectoderm becomes neural plate.
Weeks 3-8 Neural tube formed by neuroectoderm and Extremely susceptible to teratogens.
(embryonic period ) closes by week 4.
Organogenesis.
Week 4 Heart begins to beat . 4 weeks = 4 limbs and 4 heart chambers.
Upper and lower limb buds begin to form .
Week 6 Fetal cardiac activity visible by transvaginal
ultrasound .
Week 8 Fetal movements start . Gait at week 8.
Week 10 Genitalia have male /female characteristics. TENitalia
 REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY SECTION III 579

Embryologic derivatives
Ectoderm External /outer layer
Surface ectoderm Epidermis; adenohypophysis (from Rathke —
Craniopharyngioma benign Rathke pouch
pouch); lens of eye; epithelial linings of oral tumor with cholesterol crystals, calcifications.
cavity, sensor}- organs of ear, and olfactory
epithelium;final canal below the pectinate line;
parotid , sweat, mammary glands.
Neural tubel Brain ( neurohypophysis, CNS neurons, oligo-
dendrocytes, astrocytes, ependymal cells, pineal
—
Neuroectoderm think CNS.

gland ), retina, spinal cord.

Neural crest .
PNS (dorsal root ganglia , cranial nerves
autonomic ganglia , Schwann cells),
—
Neural crest think PNS and non-neural
structures nearby.
melanocytes, chromaffin cells of adrenal
medulla , parafollicular (C ) cells of thyroid,
pia and arachnoid , bones of the skull ,
odontoblasts, aorticopulmonary septum ,
endocardial cushions, myenteric (Auerbach )
plexuj
Mesoderm Muscle, bone, connective tissue, serous MiddleAneat ” layer.
linings of body cavities (eg, peritoneum ), Mesodermal defects = VACTERL:
spleen (derived from foregut mesentery), Vertebral defects
cardiovascular structures, lymphatics, blood . Anal atresia
wall of gut tube, upper vagina , kidneys, Cardiac defects
adrenal cortex, dermis, testes, ovaries. Tracheo-Esophageal fistula
Notochord induces ectoderm to form Renal defects
neuroectoderm ( neural plate). Its only Limb defects ( bone and muscle)
postnatal derivative is the nucleus pulposus of
the intervertebral disc.
Endoderm Gut tube epithelium ( including anal canal “ Enter nal ” layer.
above the pectinate line), most of urethra and
lower vagina (derived from urogenital sinus),
luminal epithelial derivatives (eg, lungs,
liver, gallbladder, pancreas, eustachian tube,
thymus, parathyroid, thyroid follicular cells).

Types of errors in organ morphogenesis

Agenesis Absent organ due to absent primordial tissue.
Aplasia Absent organ despite presence of primordial tissue.
Hypoplasia Incomplete organ development; primordial tissue present.
Disruption 2° breakdown of previously normal tissue or structure (eg, amniotic band syndrome).
Deformation Extrinsic disruption ; occurs after embryonic period .
Malformation
Sequence
Intrinsic disruption ; occurs during embryonic period (weeks 3-8).
Abnormalities result from a single 1° embryologic event (eg, oligohydramnios
— Potter sequence).
580 SECTION III REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY

Teratogens Most susceptible in 3rd— 8th weeks (embryonic period — organogenesis) of pregnancy. Before week
3, “all-or-none” effects. After week 8, growth and function affected.
TERATOGEN EFFECTS ON FETUS NOTES

Medications
ACE inhibitors Renal damage
Alkylating agents Absence of digits, multiple anomalies
Aminoglycosides Ototoxicity A mean guy hit the baby in the ear.
Antiepileptic drugs Neural tube defects, cardiac defects, cleft High-dose folate supplementation
palate, skeletal abnormalities (eg, phalanx/nail recommended. Most commonly valproate,
hypoplasia, facial dysmorphism) carbamazepine, phenytoin, phenobarbital.
Diethylstilbestrol Vaginal clear cell adenocarcinoma, congenital
Mullerian anomalies
Folate antagonists Neural tube defects Includes trimethoprim, methotrexate,
antiepileptic drugs.
Isotretinoin Multiple severe birth defects Contraception mandatory. IsoTERATinoin.
Lithium Ebstein anomaly (apical displacement of
tricuspid valve)
Methimazole Aplasia cutis congenita
Tetracyclines Discolored teeth, inhibited bone growth “ Teethracyclines.”
Thalidomide Limb defects (phocomelia, micromelia — Limb defects with “ tha-limb-domide.”
“ flipper ” limbs)
Warfarin Bone deformities, fetal hemorrhage, abortion, Do not wage warfare on the baby; keep it heppy
ophthalmologic abnormalities with heparin (does not cross placenta).
Substance abuse
Alcohol Common cause of birth defects and intellectual
disability; fetal alcohol syndrome
Cocaine Low birth weight, preterm birth, IUGR, Cocaine - vasoconstriction.
placental abruption
Smoking Low birth weight (leading cause in developed Nicotine -» vasoconstriction.
(nicotine, CO) countries), preterm labor, placental problems, CO -*• impaired 02 delivery.
IUGR, SIDS
Other
Iodine ( lack or excess) Congenital goiter or hypothyroidism (cretinism)
Maternal diabetes Caudal regression syndrome (anal atresia
to sirenomelia), congenital heart defects,
neural tube defects, macrosomia, neonatal

Methylmercury
hypoglycemia
Neurotoxicity ^ Highest in swordfish, shark, tilefish, king
mackerel.
Vitamin A excess Extremely high risk for spontaneous abortions
and birth defects (cleft palate, cardiac)
X- rays Microcephaly, intellectual disability Minimized by lead shielding.
 REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY SECTION III 581

Fetal alcohol Leading cause of intellectual disability in the US. Newborns of alcohol-consuming mothers
syndrome have t incidence of congenital abnormalities, including pre- and postnatal developmental
retardation, microcephaly, facial abnormalities (eg, smooth philtrum, thin Vermillion border
[upper lip], small palpebral fissures), limb dislocation, heart defects. Heart-lung fistulas and
holoprosencephalv in most severe form. Mechanism is failure of cell migration.

Twinning Dizygotic (“ fraternal ” ) twins arise from 2 eggs that are separately fertilized by 2 different sperm
(always 2 zygotes) and will have 2 separate amniotic sacs and 2 separate placentas (chorions).
Monozygotic (“ identical”) twins arise from 1 fertilized egg ( 1 egg + 1 sperm) that splits in early
pregnancy. The timing of cleavage determines chorionicitv (number of chorions) and amnionicity
(number of amnions).

Note Dizygotic ( fraternal) [- tys) No twinning Monozygotic (identical) [~ tyj]

spelling
change to
Dizygotic O 2 egjs.
G O'
1egg, 1sperm
2 sperm
1
©
2- cell stage <D
2-cell stage 2-cell stage
©
iRevised
I Figure l 0-4 days Cleavage
0>* Dichorionic
diamniotic 125%)

©
2-cell stage Morula Blastocyst
©
Moruta Moi J a

4- 8 days Monochonomc
diamniotic (75%)

3 astocysl

Cleavage Monochonomc
-
8 12 days
IMM DammotK
rare
Chonomc
.Q Amniotic

©- armed
embryonic disc
cavity -

Fort ed
embryonic disc
cavity

Monodvononk
> 13 days
Cleavage or monoammatK
axis duplication [conjoined — rarel
Lhorion
o utei

Ammon \
Endometrium
Dichorionic No twinning if
diamniotic no cleavage
582 SECTION III REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY
Placenta 1° site of nutrient and gas exchange between mother and fetus.
Fetal component
Cytotrophoblast Inner layer of chorionic villi . Cytotrophoblast makes Cells.
Syncytiotrophoblast Outer layer of chorionic villi ; synthesizes and
secretes hormones, eg, hCG (structurally
similar to LH; stimulates corpus luteum to
secrete progesterone during first trimester).
—
Syncytiotrophoblast synthesizes hormones.
Lacks MHC-I expression 1 chance of attack
by maternal immune system.

Maternal component
Decidua basalis Derived from endometrium . Maternal blood in
lacunae.

Branch villus : Endometrial vein

Endometrial artery } Maternal
circulation

Umbilical vein
( rich)
Maternal circulation
02
—
Umbilical arteries ^
(02 poor ) \ 9
«4 Hormones
laG
Drugs
Fetal circulation

H20
Urea, waste products
Hormones Syncytium
Cytotrophoblast

endothelial cell
Amnion

Chorionic plate
Maternal blood Decidua basalis 0
 REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY SECTION III 587

Genital embryology
Female Default development . Mesonephric duct
degenerates and paramesonephric duct
develops. Indifferent gonad

I
Male SRY gene on Y chromosome produces testis¬
determining factor -*• testes development.
Sertoli cells secrete Mullerian inhibitory-
factor ( MIF ) that suppresses development of
—
Paramesonephric duct

Urogenital sinus
— -Gubernaculum

paramesonephric ducts.
Leydig cells secrete androgens that stimulate
development of mesonephric ducts. Testis-devetoping factor

Paramesonephric
( Mullerian ) duct
Develops into female internal structures
fallopian tubes, uterus, upper portion of vagina
— Androgens
MIF

Epididymis
No androgens

( lower portion from urogenital sinus). Male

remnant is appendix testis. ddra ,
;

Mullerian agenesis ( Mayer- Rokitansky-

Kuster- Hauser syndrome) may present —
as 1 ° amenorrhea (due to a lack of uterine JV d id

development ) in females with fully developed Unnary

2° sexual characteristics (functional ovaries). bladder
Degenerated
Mesonephric Develops into male internal structures (except mesonephric

( Wolffian ) duct prostate) — Seminal vesicles, Epididymis, Degenerated

paramesonephric duct
• duel

Ejaculatory duct, Ductus deferens (SEED ). Vas deferens /- - Uterus

In females, remnant of mesonephric duct - Vagina
-* Gartner duct.
EJ

SRYgene

SRI'gene on V chromosome
I
Testis-determining factor
—
O No Sertoli cells or lack of Mullerian inhibitory-
factor develop both male and female

—
internal genitalia and male external genitalia
. Testes
© 5a-reductase deficiency inability to convert—
testosterone into DHT male internal
Sertoli cell Leydig cell genitalia , ambiguous external genitalia until
~t~
°
| Mullerian inhibitory factor | Wolffian duct _
puberty (when t testosterone levels cause
masculinization)
Testosterone (i Male internal genitalia
Sertoli Shuts down female developmental
Degeneration of
paramesonephric ( Mullerian)
duct (female internal
-0 ( except prostate) pathway.
Leydig Leads to male developmental pathway.
genitalia) DHT

Genital tubercle, Male external genitalia,

urogenital sinus prostate
588 SECTION I I I REPRODUCTIVE REPRODUCTIVE — EMBRYOLOGY

Uterine ( Mullerian duct ) anomalies

Septate uterus Common anomaly vs normaluterusJQ. Incomplete resorption of septum Q. 1 fertility. Treat with
septoplasty.
Bicornuate uterus Incomplete fusion of Mullerian ducts Q. t risk of complicated pregnancy.
Uterus didelphys Complete failure of fusion - double uterus, cervix, and vaginalEl. Pregnancy possible.

Normal Septate Bicornuate Didelphys

Male/female genital homologs

Male Undifferentiated Female

Gians penis Genital
Genital groove tubercle

Penile urethra Urogenital

fold Labioscrotal Clitoris
swelling
Urogenital Labia
Opening of
sinus minora
urethra
Scrotum Labia
Opening of majora
Anus vagina

*
Urachus Allantois
X Urachus Uterine

-^
Kidney vesica
Urinary part tube
bladder
Urinary v.
Genital Pehric Urogenital bladder Kidney

^
tubercle part sinus
Testis Clitoris Ovary
Gians "\
Ureter
penis
Spongy
Ductus Rectum
Phallic
part - Uterus
deferens
urethra (f ^ Vagina

Dihydrotestosterone Estrogen
Gians penis Genital tubercle Gians clitoris
Corpus cavernosum Genital tubercle Vestibular bulbs
and spongiosum
Bulbourethral glands Greater vestibular glands
(of Cowper) Urogenital sinus (of Bartholin)

Prostate gland Urethral and paraurethral

Urogenital sinus glands (of Skene)
Ventral shaft of penis
(penile urethra) Urogenital folds Labia minora

Scrotum Labioscrotal swelling Labia majora 0

 REPRODUCTIVE REPRODUCTIVE — ANATOMY SECTION III 591

Male reproductive anatomy

Ureter

Bladder ieir naI vesicle

Vas deferens Apulia

Ejaculatory duct Head of epididymis
Symphysis pubis
Js Prostate Efferent ductule

.e
x
\>r
Bulbourethral Rete testis
Jrethi i
' gland (Cowper )
Corpus cavernosa

Epididymis Sem nlferous Vas deferens

iubules
Prepuce
Tunica
Q ans albuginea
Testis
Scrotum
Tail of epididymis - na

Pathway of sperm during ejaculation —

SEVEN UP:
Seminiferous tubules
Epididymis
Vas deferens
Ejaculatory ducts
(Nothing)
Urethra
Penis

Urethral injury Suspect if blood seen at urethral meatus. Urethral characterization contraindicated
Posterior urethra — membranous urethra prone to injury from pelvic fracture. Injury can cause urine
to leak into retropubic space.
Anterior urethra — bulbar Jarethra at risk of damage due to perineal straddle injury. Can cause urine
to leak beneath deep fascia of Buck. If fascia is torn, urine escapes into superficial perineal space.

Autonomic Erection — Parasympathetic nervous system Point, Squeeze, and Shoot.

innervation of the (pelvic nerve): PDE-5 inhibitors (eg, sildenafil) 1 cGMP
male sexual response
— —
NO -*• t cGMP smooth muscle
relaxation -* vasodilation proerectile.
breakdown.

——
Norepinephrine t [Ca-+]in -* smooth
muscle contraction vasoconstriction
-* antierectile.
Emission — Sympathetic nervous system
( hypogastric nerve).
Ejaculation — visceral and Somatic nerves
(pudendal nerve).
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 601

REPRODUCTIVE — PATHOLOGY

Sex chromosome Aneuploidy most commonly due to meiotic nondisjunction.

disorders
Klinefelter syndrome Testicular atrophy, eunuchoid body shape, Dysgenesis of seminiferous tubules
[male] (47,XXY ) tall, long extremities, gynecomastia, female
hair distribution Q. May present with
- -
1 inhibin B t FSH.

—
Abnormal Leydig cell function 1 testosterone
i 9 developmental delay. Presence of inactivated
X chromosome (Barr body). Common cause of
— —
t LH t estrogen.

hypogonadism seen in infertility work-up.

Turner syndrome Short stature (if untreated), ovarian dysgenesis
[female] (45,XO) (streak ovary), shield chest, bicuspid aortic
l. valve, coarctation (femoral < brachial pulse),
lymphatic defects (result in webbed neck or
cystic hygroma; lymphedema in feet, hands),
M horseshoe kidney Q.
Most common cause of 1° amenorrhea. No Barr
body.
Menopause before inenarche.
1 estrogen leads to t LH, FSH .
—
Sometimes due to mitotic error mosaicism (eg,
45,XO/46,XX).
Pregnancy is possible in some cases (IVF,
_
exogenous estradiol-17P and progesterone).
Can use growth hormone to achieve normal
height .

Double Y males ( XYY ) Phenotypically normal (usually undiagnosed),

very tall. Normal fertility. May be associated
with severe acne, learning disability, autism
spectrum disorders.
Ovotesticular disorder 46,XX > 46,XY.
of sex development Both ovarian and testicular tissue present
(ovotestis); ambiguous genitalia. Previously
called true hermaphroditism.
602 SECTION III REPRODUCTIVE REPRODUCTIVE — PATHOLOGY

Diagnosing disorders Testosterone LH Diagnosis

of sex hormones t t Defective androgen receptor
t i Testosterone-secreting tumor, exogenous
steroids
i t Hvperqonadotrophic hypogonadism (1°)l

i 1 Hypogonadotropic hypogonadism (2°)

Other disorders of sex Disagreement between the phenotypic (external genitalia) and gonadal (testes vs ovaries) sex.
development Include terms pseudohermaphrodite, hermaphrodite, and intersex.
46,XX DSD Ovaries present, but external genitalia are virilized or ambiguous. Due to excessive and
inappropriate exposure to androgenic steroids during early gestation (eg, congenital adrenal
hyperplasia or exogenous administration of androgens during pregnancy).
46,XY DSD Testes present, but external genitalia are female or ambiguous. Most common form is androgen
insensitivity syndrome ( testicular feminization).

Placental aromatase Inability to synthesize estrogens from androgens. Masculinization of female (46,XX ) infants
deficiency (ambiguous genitalia), t serum testosterone and androstenedione. Can present with maternal
virilization during pregnancy (fetal androgens cross the placenta).

Androgen insensitivity Defect in androgen receptor resulting in normal-appearing female; female external genitalia with
syndrome (46,XY ) scant sexual hair, rudimentary vagina; uterus and fallopian tubes absent. Patients develop normal
functioning testes (often found in labia majora; surgically removed to prevent malignancy),
t testosterone, estrogen, LH (vs sex chromosome disorders).

5a- reductase Autosomal recessive; sex limited to genetic males (46,XY ). Inability to convert testosterone to DHT.
deficiency Ambiguous genitalia until puberty, when t testosterone causes masculinization/t growth of
external genitalia. Testosterone/estrogen levels are normal; LII is normal or t . Internal genitalia
are normal.

Kallmann syndrome Failure to complete puberty; a form of hypogonadotropic hypogonadism. Defective migration of
GnRH cells and formation of olfactory bulb; i synthesis of GnRH in the hypothalamus; anosmia;
1 GnRH, FSH, LH, testosterone. Infertility (low sperm count in males; amenorrhea in females).
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 605

Pregnancy complications (continued )

Vasa previa Fetal vessels run over, or in close proximity
to, cervical os. May result in vessel rupture,
exsanguination, fetal death. Presents with
triad of membrane rupture, painless vaginal
bleeding, fetal bradycardia (< 110 beats/min).
Placenta
Emergency C-section usually indicated. Placenta . I succenturiate
lobe) *
Frequently associated with velamentous
umbilical cord insertion (cord inserts in
chorioamniotic membrane rather than
—
placenta fetal vessels travel to placenta
unprotected by Wharton jelly).
Postpartum Due to 4 T’s: Tone (uterine atony; most
hemorrhage common), Trauma (lacerations, incisions,
.
uterine rupture) Thrombin (coagulopathy),
Tissue (retained products of conception).
Ectopic pregnancy Most often in ampulla of fallopian tube Pain +/— bleeding.
A
( shows 10-mm embryo in oviduct at 7 Risk factors:
weeks of gestation). Suspect with history of • Prior ectopic pregnancy
amenorrhea, lower-than-expected rise in hCG History of infertility

C
based on dates, and sudden lower abdominal Salpingitis ( PID)
pain; confirm with ultrasound. Often Ruptured appendix
5

clinically mistaken for appendicitis. • Prior tubal surgery

Asherman syndrome Condition characterized by adhesions and/or fibrosis of the endometrium, often associated with
I New I dilation and curettage of the intrauterine cavity.
I Fact 1
Amniotic fluid abnormalities
Polyhydramnios Too much amniotic fluid; associated with fetal malformations (eg, esophageal /duodenal atresia,
anencephaly; both result in inability to swallow amniotic fluid), maternal diabetes, fetal anemia,
multiple gestations.
Oligohydramnios Too little amniotic fluid; associated with placental insufficiency, bilateral renal agenesis, posterior
urethral valves (in males) and resultant inability to excrete urine. Any profound oligohydramnios
can cause Potter sequence.
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 607

Vaginal tumors
Squamous cell Usually 2° to cervical SCC; 1° vaginal carcinoma rare.
carcinoma !
Clear cell Affects women who had exposure to DES in utero.
adenocarcinoma
Sarcoma botryoides| Embryonal rhabdomyosarcoma variant.
Affects girls < 4 years old; spindle-shaped cells; desmin ©.
Presents with clear, grape-like, polypoid mass emerging from vagina.

Cervical pathology
Dysplasia and Disordered epithelial growth; begins at basal layer of squamocolumnar junction (transformation
carcinoma in situ zone) and extends outward. Classified as CIN 1, CIN 2, or CIN 3 (severe dysplasia or carcinoma
in situ), depending on extent of dysplasia. Associated with HPV 16 and HPV 18, which
produce both the E6 gene product (inhibits pS 3 suppressor gene) and E7 gene product (inhibits
RB suppressor gene). May progress slowly to invasive carcinoma if left untreated. Typically
asymptomatic (detected with Pap smear) or presents as abnormal vaginal bleeding (often
0
postcoital).
' Risk factors: multiple sexual partners (#1), smoking, starting sexual intercourse at young age, HIV
infection.
V
Invasive carcinoma Often squamous cell carcinoma. Pap smear can detect!cervical dysplasia (koilocytes Q) before it
progresses to invasive carcinoma. Diagnose via colposcopy and biopsy. Lateral invasion can block
ureters -*• renal failure.

Premature ovarian Premature atresia of ovarian follicles in women i estrogen, t LH, t FSH.
failure of reproductive age. Patients present with signs
of menopause after puberty but before age 40.

Most common causes Pregnancy, polycystic ovarian syndrome, obesity, HPO axis abnormalities, premature ovarian
of anovulation failure, hyperprolactinemia, thyroid disorders, eating disorders, competitive athletics, Cushing
syndrome, adrenal insufficiency.

Polycystic ovarian Hvperinsulinemia and/or insulin resistance hypothesized to alter hypothalamic hormonal feedback
syndrome ( Stein-
Leventhal syndrome )
——
response t LH:FSH, t androgens (eg, testosterone) from theca interna cells, 1 rate of follicular
maturation unruptured follicles (cysts) + anovulation. Common cause of subfertility in women.
Enlarged, bilateral cystic ovaries Q; presents with amenorrhea /oligomenorrhea, hirsutism, acne,
i fertility. Associated with obesity, t risk of endometrial cancer 2° to unopposed estrogen from
repeated anovulatory cycles.
Treatment: cycle control — weight reduction ( 1 peripheral estrone formation), OCPs ( prevent
endometrial hyperplasia due to unopposed estrogen); infertility — cloniiphene, metformin (induce
ovulation); hirsutism — spironolactone ( androgen receptor inhibitor ), OCPs, ketoconazolej
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 609

Ovarian neoplasms ( continued )

Malignant ovarian neoplasms
Granulosa cell tumor Most common malignant stromal tumor. Predominantly women in their 50s. Often produces
estrogen and/or progesterone and presents with postmenopausal bleeding, sexual precocity
( in pre-adolescents), breast tenderness. Histology shows Call-Exner bodies 0 ( granulosa cells
arranged haphazardly around collections of eosinophilic fluid , resembling primordial follicles).
Serous Most common malignant ovarian neoplasm , frequently bilateral. Psammoma bodies,
cystadenocarcinoma
Mucinous Pseudomyxoma peritonei-intraperitoneal accumulation of mucinous material from ovarian or
cystadenocarcinoma appendiceal tumor.
Immature teratoma Aggressive, contains fetal tissue, neuroectoderm . Commonly diagnosed before age 2Qt Typically-
represented by immature/embryonic-like neural tissue.
Dysgerminoma Most common in adolescents. Equivalent to male seminoma but rarer. 1% of all ovarian tumors;
30% of germ cell tumors. Sheets of uniform “ fried egg” cells Q. hCG, LDH = tumor markers.
Yolk sac (endodermal Aggressive, in ovaries or tested and sacrococcygeal area in young children . Most common tumor in
sinus) tumor -
male infants. Yellow, friable ( hemorrhagic), solid mass. 50% have Schiller Duval bodies ( resemble
glomeruli ) Q. AFP = tumor marker.
Krukenberg tumor GI malignancy that metastasizes to ovaries -* mucin-secreting signet cell adenocarcinoma.

m
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610 SECTION III REPRODUCTIVE REPRODUCTIVE — PATHOLOGY
Endometrial conditions
Polyp Well-circumscribed collection of endometrial tissue within uterine wall. May contain smooth
muscle cells. Can extend into endometrial cavity in the form of a polyp. May be asymptomatic or
present with painless abnormal uterine bleeding.
Adenomyosis Extension of endometrial tissue ( glandular) into uterine myometrium . Caused by hyperplasia of
basal layer of endometrium . Presents with dysmenorrhea , menorrhagia , uniformly enlarged , soft,
globular uterus.
Treatment: GnRH agonists, hysterectomy.
Leiomyoma (fibroid ) Most common tumor in females. Often presents with multiple discrete tumors Q. t incidence in
African Americans. Benign smooth muscle tumor; malignant transformation to leiomyosarcoma is
—
rare. Estrogen sensitive tumor size t with pregnancy and i with menopause. Peak occurrence at
20-40 years old . May be asymptomatic, cause abnormal uterine bleeding, or result in miscarriage.
Severe bleeding may lead to iron deficiency anemia. Whorled pattern of smooth muscle bundles
with well-demarcated borders Q.
Endometrial Abnormal endometrial gland proliferation Q usually caused by excess estrogen stimulation t risk for
,

hyperplasia endometrial carcinoma ; nuclear atypia is greater risk factor than complex (vs simple) architecture.
Presents as postmenopausal vaginal bleeding. Risk factors include anovulatory cycles, hormone
replacement therapy, polycystic ovarian syndrome, granulosa cell tumor.
Endometrial Most common gynecologic malignancy Q. Peak occurrence at 55-65 years old. Presents with
carcinoma vaginal bleeding. Typically preceded by endometrial hyperplasia. Risk factors include prolonged
use of estrogen without progestins, obesity, diabetes, hypertension , nulliparity, late menopause,
early menarchej Lynch syndrome.
Endometritis Inflammation of endometrium Q associated with retained products of conception following
delivery, miscarriage, abortion, or with foreign body (eg, IUD). Retained material in uterus
promotes infection by bacterial flora from vagina or intestinal tract.
Treatment: gentamicin + clindamycin +/— ampicillin.
Endometriosis Non-neoplastic endometrial glands/stroma outside endometrial cavity Q- Can be found anywhere;
most common sites are ovary (frequently bilateral ), pelvis, peritoneum . In ovary, appears as
endometrioma ( blood-filled “ chocolate cyst ” ). May be due to retrograde flow, metaplastic
transformation of multipotent cells, transportation of endometrial tissue via lymphatic system .
Characterized by cyclic pelvic pain , bleeding, dysmenorrhea , dyspareunia, dyschezia ( pain with
defecation ), infertility; normal-sized uterus.
Treatment: NSAIDs, OCPs, progestins, GnRH agonists, danazol , laparoscopic removal .

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612 SECTION III REPRODUCTIVE REPRODUCTIVE — PATHOLOGY
Malignant breast Commonly postmenopausal . Usually arise from Risk factors: t estrogen exposure, t total number
tumors terminal duct lobular unit. Overexpression of menstrual cycles, older age at 1st live birth,
of estrogen / progesterone receptors or c-erbB2 obesity ( t estrogen exposure as adipose tissue
( HER-2 , an EGF receptor) is common; triple converts androstenedione to estrone), BRCA1
negative ( ER 0, PR ©, and Her2/ Neu ©) more oi[ BRCA2 gene mutations, African American
aggressive; type affects therapy and prognosis. ethnicity ( t risk for triple © breast cancer).
Axillary lymph node involvement indicating
metastasis is the most important prognostic
factor in early-stage disease. Most often located
in upper-outer quadrant of breast.
TYPE CHARACTERISTICS NOTES
Noninvasive
Ductal carcinoma in Fills ductal lumen ( black arrow in Q indicates Early malignancy without basement membrane
situ neoplastic cells in duct ; blue arrow shows penetration .
engorged blood vessel ). Arises from ductal
atvpia. Often seen early as microcalcifications
on mammography.
Comedocarcinoma Ductal , central necrosis (arrow in Q). Subtype
ofDCIS.
Paget disease Results from underlying DCIS or invasive breast
cancer. Eczematous patches on nipple Q.
Paget cells = intraepithelial adenocarcinoma
cells.
Invasive
Invasive ductal Firm , fibrous, “ rock-hard ” mass with sharp Most common (~ 75% of all breast cancers).
carcinoma margins and small , glandular, duct-like
cells 0. Can have dimpling of breast due to
deformation of suspensory ligaments by tumor.
Grossly see classic “ stellate” infiltration .
Invasive lobular
carcinoma
Orderly row of cells (“ single!file”
i E-cadherin expression .
0), due to
location._
Often bilateral with multiple lesions in the same

Lines of cells = Lobular.

Medullary carcinoma Fleshy, cellular, lymphocytic infiltrate.
Inflammatory breast Dermal lymphatic invasion by breast
cancer carcinoma. Peau d orange ( breast skin
resembles orange peel Q); neoplastic cells
block lymphatic drainage.
Good prognosis.
Poor prognosis ( 50% survival at 5 years).
Often mistaken for mastitis or Paget disease.
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 613

Malignant breast tumors (continued )

m m*
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.
S';
%

urn
m
mm . &T
*
Penile pathology
Peyronie disease Abnormal curvature of penis due to fibrous plaque within tunica albuginea. Associated with
erectile dysfunction. Can cause pain, anxiety. Consider surgical repair once curvature stabilizes.
Distinct from penile fracture (rupture of corpora cavernosa due to forced bending).
Ischemic priapism Painful sustained erection lasting > 4 hours. Associated with sickle cell disease (sickled RBCs
block venous drainage of corpus cavernosum vascular channel! ? ), medications (eg, sildenafil,

trazodone). Treat immediately with corporal aspiration, intracavernosal phenylephrine, or surgical

decompression to prevent ischemia.
Squamous cell More common in Asia, Africa, South America. Precursor in situ lesions: Bowen disease (in
carcinoma penile shaft, presents as leukoplakia), erythroplasia of Quevrat (cancer of glans, presents as
erythroplakia), Bowenoid papulosis (carcinoma in situ of unclear malignant potential, presenting
as reddish papules). Associated with HPV and lack of circumcision.

Cryptorchidism Undescended testis (one or both); impaired spermatogenesis (since sperm develop best at
temperatures < 37°C ); can have normal testosterone levels (Leydig cells are mostly unaffected
by temperature); associated with t risk of germ cell tumors. Prematurity t risk of cryptorchidism.
1 inhibin B, t FSH, t LH; testosterone 1 in bilateral cryptorchidism, normal in unilateral.

Testicular torsion Rotation of testicle around spermatic cord and vascular pedicle.
Commonly presents 12-18 years of age. Characterized by acute, severe pain, high riding testis, and
absent cremasteric reflex .
New Treatment: surgical correction (orchiopexy) within 6 hours, manual detorsion if surgical option
Fact
unavailable in timeframe. If testis is not viable, orchiectomy. Bilateral orchiopexy must always be
performed, contralateral testis at risk for subsequent torsion.
614 SECTION III REPRODUCTIVE REPRODUCTIVE — PATHOLOGY

Varicocele Dilated veins in pampiniform plexus due to t venous pressure; most common cause of scrotal
enlargement in adult males; most often on left side because of t resistance to flow from left
gonadal vein drainage into left renal vein; can cause infertility because of t temperature;
diagnosed by standing clinical exam (distension on inspection and “ bag of worms” on palpation)
or ultrasound with Doppler Q; does not transilluminate.
Treatment: varicocelectomy, embolization.

Extragonadal germ cell Arise in midline locations. In adults, most commonly in retroperitoneum, mediastinum, pineal, and
tumors suprasellar regions. In infants and young children, sacrococcygeal teratomas are most common.

Scrotal masses Benign scrotal lesions present as testicular masses that can be transilluminated (vs solid testicular
tumors) .
Congenital hydrocele Common cause of scrotal swelling in infants, Transilluminating swelling,
due to incomplete obliteration of processus
vaginalis. Most spontaneously resolve by 1 year
of a gej
Acquired hydrocele Scrotal fluid collection usually 2° to infection,

Spermatocele
trauma, tumor. If bloody
— hematocele.
Cyst due to dilated epididymal duct or rete Paratesticular fluctuant nodule,
testis.

Testicular germ cell ~ 95% of all testicular tumors. Most often occur in young men. Risk factors: cryptorchidism,
tumors Klinefelter syndrome. Can present as a mixed germ cell tumor. Testicular mass that does not
transilluminate.
Seminoma Malignant; painless, homogenous testicular enlargement; most common testicular tumor. Does
not occur in infancy. Large cells in lobules with watery cytoplasm and “ fried egg” appearance ,

t placental ALP. Radiosensitive. Late metastasis, excellent prognosis.

Yolk sac (endodermal Yellow, mucinous. Aggressive malignancy of testes, analogous to ovarian yolk sac tumor. Schiller-
sinus) tumor Duval bodies resemble primitive glomeruli t AFP is highly characteristic. Most common
,

testicular tumor in boys < 3 years old.

Choriocarcinoma Malignant, t hCG. Disordered syncytiotrophoblastic and cytotrophoblastic elements.
Hematogenous metastases to lungs and brain. May produce gynecomastia, symptoms of
hyperthyroidism (hCG is structurally similar to LH, FSII, TSH).
Teratoma Unlike in females, mature teratoma in adult males may be malignant. Benign in children .
Embryonal carcinoma Malignant, hemorrhagic mass with necrosis; painful; worse prognosis than seminoma. Often
glandular /papillary morphology. “ Pure" embryonal carcinoma is rare; most commonly mixed
with other tumor types. May be associated with t hCG and normal AFP levels when pure ( t AFP
when mixed).
 REPRODUCTIVE REPRODUCTIVE — PATHOLOGY SECTION III 615

-
Testicular non germ 5% of all testicular tumors. Mostly benign .
cell tumors
Leydig cell Golden brown color; contains Reinke crystals (eosinophilic cytoplasmic inclusions). Produce
androgens or estrogens -*• gynecomastia in men, precocious puberty in boys. ^
Sertoli cell Androblastoma from sex cord stroma .
Testicular lymphoma Most common testicular cancer in older men. Not a 1° cancer; arises from metastatic lymphoma to
testes. Aggressive.

Benign prostatic Common in men > 50 years old . Characterized Benign

Anterior lobe
hyperplasia by smooth, elastic, firm nodular enlargement prostatic
hyperplasia
( hyperplasia not hypertrophy) of periurethral Urethra
( lateral and middle) lobes, which compress the
urethra into a vertical slit. Not premalignant . Lateral lobe % K\
Often presents with t frequency of urination , I

— ____
nocturia , difficulty starting and stopping urine Middle lobe
stream, dvsuria. May lead to distention and
m m » »

hypertrophy of bladder, hydronephrosis, UTIs. Posterior

ior lobe Prostate
Pf ostai cancer
t free prostate-specific antigen ( PSA).
Treatment: (Xj-antagonists ( terazosin ,
tamsulosin ), which cause relaxation of
smooth muscle; 5a-reductase inhibitors (eg,
finasteride); PDE-5 inhibitors (eg, tadalafil j

Prostatitis Dvsuria , frequency, urgency, low back pain . Warm , tender, enlarged prostate. Acute bacterial-
most common cause is E coli in older men , young males consider C trachomatis, N gonorr /ioec/e;
chronic bacterial or abacterial

Prostatic Common in men > 50 years old . Arises most often from posterior lobe ( peripheral zone) of prostate
adenocarcinoma gland and is most frequently diagnosed by t PSA and subsequent needle core biopsies. Prostatic
acid phosphatase ( PAP) and PSA are useful tumor markers ( t total PSA, with i fraction of free
PSA) . Osteoblastic metastases in bone may develop in late stages, as indicated by lower back pain
and t serum ALP and PSA.
 REPRODUCTIVE REPRODUCTIVE — PHARMACOLOGY SECTION III 619

Testosterone, methyltestosterone
MECHANISM Agonists at androgen receptors.
CLINICAL USE Treat hypogonadism and promote development of 2° sex characteristics; stimulate anabolism to
promote recovery after burn or injur)'.
Mbsculinization in females; 1 intratesticular testosterone in males by inhibiting release of LH (via
—
ADVERSE EFFECTS
negative feedback) gonadal atrophy. Premature closure of epiphyseal plates, t LDL, 1 HDL.

Antiandrogens l
Finasteride Sex-reductase inhibitor (i conversion of Testosterone ^-reductase f)HT (more potent).
testosterone to DHT). Used for BPH and male-
pattern baldness.
Flutamide Nonsteroidal competitive inhibitor at androgen
receptors. Used for prostate carcinoma.
Ketoconazole Inhibits steroid synthesis (inhibits 17,20
desmolase/17a-hvdroxylasd). Used for polycystic ovarian syndrome to reduce
androgenic symptoms. Both have side effects of
Spironolactone Inhibits steroid binding, 17,20 desmolase / 17a-
gynecomastia and amenorrhea.
hydroxylase
^
Tamsulosin OC ]-antagonist used to treat BPH by inhibiting smooth muscle contraction. Selective for <XjA D
receptors (found on prostate) vs vascular ajB receptors.

Phosphodiesterase Sildenafil, vardenafil, tadalafil.

type 5 inhibitors
MECHANISM Inhibit PDE- 5 -* t cGMP -* prolonged Sildenafil, vardenafil, and tadalafil fill the
smooth muscle relaxation in response to NO penis.
-*• t blood flow in corpus cavernosum of penis,
1 pulmonary vascular resistance.
CLINICAL USE Erectile dysfunction, pulmonary hypertension,
BPH (tadalafil only).
ADVERSE EFFECTS Headache, flushing, dyspepsia, cyanopia “ Hot and sweaty ” but then Headache,
( blue-tinted vision). Risk of life-threatening Heartburn, Hypotension.
hypotension in patients taking nitrates.

Minoxidil
MECHANISM Direct arteriolar vasodilator.
CLINICAL USE Androgenetic alopecia; severe refractory hypertension.
HIGH - YI E LD SYSTEMS

Respiratory

“ There’s so much pollution in the air now that if it weren’t for our lungs, Embryology 622
there 'd he no place to put it all.”
— Robert Orben Anatomy 624

“ Mars is essentially in the same orbit. Somewhat the same distance from Physiology 626
the Sun , which is very important. We have seen pictures where there are
canals, we believe, and water. If there is water, that means there is oxygen. Pathology 632
If there is oxygen, that means we can breathe.”
— Former Vice President Dan Quayle Pharmacology 643

“ Whenever I feel blue , I start breathing again.”

— L. Frank Baum
“ Life is not the amount of breaths you take; it’s the moments that take
your breath away."
— Hitch

621
622 SECTION III RESPIRATORY RESPIRATORY — EMBRYOLOGY
RESPIRATORY — EMBRYOLOGY
Lung development Occurs in five periods. Initial development includes development of lung bud from distal end of
respiratory diverticulum during week 4| .
STAGE

Embryonic
( weeks 4-7 )
IMPORTANT TERMS

— ——
Lung bud -* trachea bronchial buds!
mainstem bronchi secondary ( lobar)
NOTES

Errors at this stage can lead to TE fistula.

Pseudoglandular
( weeks 5-1
Canalicular
( weeks 16-2
——
bronchi -*• tertiary (segmental ) bronchi .
Endodermal tubules terminal bronchioles.
Surrounded by modest capillary network .
Terminal bronchioles respiratory bronchioles
-* alveolar ducts. Surrounded by prominent
Respiration impossible, incompatible with life.

Airways increase in diameter.

Respiration capable at 25 weeks.
^
Saccular
( weel
Alveolar
( weel
426-birth)
436j-8 years)
capillary network .

——
Alveolar ducts terminal sacs. Terminal sacs
separated by 1° septae. Pneumocytes develop.
Terminal sacs adult alveoli (due to 2°
septation ).
At birth: 20-70 million alveoli.
By 8 years: 300-400 million alveoli .
In utero, “ breathing” occurs via aspiration
and expulsion of amniotic fluid -*• t vascular
resistance through gestation.
At birth , fluid gets replaced with air — A in
pulmonary vascular resistance.

Embyronic Fetal Postnatal

Alveolar
Saccular
Canalicular BIRTH
Pseudoglandular
Embryonic Surfactant

”
2 4 6 8 10 12 14 16 18 20 22 24 26 28 50 52 54 56 58 40 2 4 6 8
< — Weeks Years *—
<D
a
X 0

Congenital lung malformations

Pulmonary hypoplasia Poorly developed bronchial tree with abnormal histology. Associated with congenital diaphragmatic
hernia ( usually left-sided ), bilateral renal agenesis ( Potter sequence [syndrome!1
Bronchogenic cysts Caused by abnormal budding of the foregut and dilation of terminal or large bronchi . Discrete,
round , sharply defined and fluid-filled densities on CXR ( air-filled if infected!Generally
asymptomatic but can drain poorly causing airway compression and /or recurrent respiratory
infection
^
 RESPIRATORY RESPIRATORY — EMBRYOLOGY SECTION III 623

Pneumocytes
Type I cells 97% of alveolar surfaces. Line the alveoli. „ ,,
Collapsing pressure ( r ) =
2 (surface tension)
Squamous; thin for optimal gas diffusion. radius
Type II cells
—
Secrete pulmonary surfactant I alveolar
surface tension, prevents alveolar collapse,
Alveoli have t tendency to collapse on expiration
as radius 1 (law of Laplace).
Pulmonary surfactant is a complex mix of
Type II pneumocyte 1 lung recoil, and t compliance. Cuboidal and

u*%* clustered Q. Also serve as precursors to type lecithins, the most important of which is
I cells and other type II cells. Type II cells dipahnitoylphosphatidvicholine ( DPPCj
proliferate during lung damage. Surfactant synthesis begins around week 26 of
gestation, but mature levels are not achieved
! until around week 35.
Club cells Nonciliated; low-colunmar /cuboidal with
secretory granules. Secrete component of
surfactant; degrade toxins; act as reserve cells.

Neonatal respiratory
distress syndrome
— —
Surfactant deficiency t surface tension
alveolar collapse (“ground-glass” appearance
Screening tests for fetal lung maturity: lecithin-
sphingomyelin ( L /S ) ratio in amniotic fluid
of lung fields) Q. j (> 2 is healthy; < 1.5 predictive of NRDS ), foam
Risk factors: prematurity, maternal diabetes ( due stability index test, surfactant-albumin ratio.
to t fetal insulin), C-section delivery ( 4 release
of fetal glucocorticoids; less stressful than
Persistently low Q-, tension
—
risk of PDA.

vaginal delivery!
r-
'

Mature
Complications: fDA, necrotizing enterocolitis. £ 15-
Treatment: maternal steroids before birth;
:o 10 - Transitional
exogenoujsurfactant for infant.
-1
Therapeutic supplemental 0-> can result in us *22
Retinopathy of prematurity, Intraventricular 3 Immature

hemorrhage, Bronchopulmonary dysplasia i

26 30
i i
35 40
(RIB). Gestational age (wk )
 HEMATOLOGY AND ONCOLOGY HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY SECTION III 387

Plasma cell Produces large amounts of antibody specific to Multiple myeloma is a plasma cell cancer,
a particular antigen. “ Clock-face” chromatin
I distribution and eccentric nucleus, abundant
RER, and well-developed Golgi apparatus

!<
' (yellow arrows in Q). Found in bone marrow
• and normally do not circulate in peripheral
blood.

HEMATOLOGY AND ONCOLOGY — PHYSIOLOGY

Fetal erythropoiesis Fetal erythropoiesis occurs in: Young Liver Synthesizes Blood.
Yolk sac ( 3-8 weeks)
Liver ( 6 weeks-birth)
Spleen ( 10-28 weeks)
Bone marrow ( 18 weeks to adult)
Hemoglobin Embryonic globins: £ and e.
development Fetal hemoglobin (HbF) = CX2Y2 - From fetal to adult hemoglobin:
Adult hemoglobin (HbAj) = a2P2. Alpha Always; Gamma Goes, Becomes Beta.
HbF has higher affinity for O? due to less avid
binding of 2,3-BPG, allow ing HbF to extract
02 from maternal hemoglobin (HbAj and
HbA2) across the placenta. HbA -? ( ObS? ) is a
minor form of adult hemoglobin present in
small amounts.
BIRTH

Site of Yolk -
L vc 1 Bone marrow
erythropoiesis sac crn

0.1
'

40 0
Fetal (HbF )
If
Adult (HbAj)
% of total 30
globin synthesis
20
tmbryomc globins
10

Weeks: 6 12 18 24 50 6 12 18 24 40 40 L
FETUS (weeks) POSTNATAL (months) ADULT »
0
 RESPIRATORY RESPIRATORY — ANATOMY SECTION III 625

Lung relations Right lung has 3 lobes; Left has Less Lobes (2) Instead of a middle lobe, the left lung has a
and Lingula ( homolog of right middle lobe). space occupied by the heart.
Right lung is more common site for inhaled The relation of the pulmonary artery to the
foreign body because the right main stem bronchus at each lung hilum is described by
bronchus is wider and more vertical than —
RALS Right Anterior; Left Superior.
the left.
If you aspirate a peanut:
—
While upright enters inferior segment of
right lowed lobe.
—
While supine enters posterior segments of
right upper lobe or superior segment of right
lower lobcj

Trachea Upper lobe

HON:: r t •
1

fissure
Oblique
Assure
Middle lobe Lingula Revised
Oblique fissure Figure

Right Left
Inferior lobe 3
* R L
Lowei

i
Lower
lobe

bronchus bronchus Anterior view Posterior view

Diaphragm structures Structures perforating diaphragm : Number of letters = T level :

At T8: IVC , right phrenic nervel T8: vena cava
Central tendon
At T10: esophagus, vagus (CN 10; 2 trunks) T10: “ oesophagus”
Inferior vena cava (T8)
* At T12: aorta ( red ), thoracic duct (white ), T12: aortic hiatus
Esophagus (T10)
azygos vein ( blue) (“ At T-l-2 it's the red , I ( IVC ) ate (8) ten ( 10) eggs (esophagus) at
white, and blue ” ) (aorta ) twelve ( 12 ).
Diaphragm is innervated by C3, 4, and 5
C 3, 4, 5 keeps the diaphragm alive.
( phrenic nerve). Pain from diaphragm
Other bifurcations:
irritation (eg, air, blood , or pus in peritoneal
/ The common carotid bifourcates at C 4.
< 10 Aorta CT12 ) cavity) can be referred to shoulder (C 5 ) and
° The trachea bifourcates at T4.
'
Vertebrae trapezius ridge (C3, 4).
Inferior view The abdominal aorta bifourcates at L4.
626 SECTION III RESPIRATORY RESPIRATORY — PHYSIOLOGY
RESPIRATORY — PHYSIOLOGY
Lung volumes
Inspiratory reserve Air that can still be breathed in after normal Lung volumes (LITER ):
volume 6.0
inspiration
Tidal volume Air that moves into lung with each quiet
IRV Volume
inspiration, typically 500 mL (L) 1C VC TLC
Expiratory reserve Air that can still be breathed out after normal
2.7
volume
Residual volume
expiration
Air in lung after maximal expiration ; any lung
TV
AAA) 2.2
ERV
volume or capacity that includes RV cannot be
1.2 FRC
measured by spirometnj
RV RV
Inspiratory capacity IRV + TV
Functional residual RV + ERV
0 l
A capacity is a sum of > 2 physiologic volumes.
capacity Volume of gas in lungs after normal expiration ;
includes RV, cannot be measured bv
spirometry!
Vital capacity TV + 1RV + ERV
Maximum volume of gas that can be expired
after a maximal inspiration
Total lung capacity IRV + TV + ERV + RV
Volume of gas present in lungs after a maximal
inspiration; includes RV, cannot be measured
by spirometry

Determination of ,, . Paco2 - Pi .co: Taco, Paco, PECO, Paco (refers to order of

physiologic dead V d ~ V t *.
w
variables in equation )
space VD = physiologic dead space = anatomic dead —
Physiologic dead space approximately
space of conducting airways plus alveolar equivalent to anatomic dead space in normal
dead space; apex of healthy lung is largest lungs. May be greater than anatomic dead
contributor of alveolar dead space. Volume space in lung diseases with V/Q defects.
of inspired air that does not take part in gas —
Pathologic dead space when part of the
exchange. respiratory zone becomes unable to perform
V j = tidal volume . gas exchange. Ventilated but not perfused .
Paco2 = arterial Pco? .
PECO? = expired air Pco?.

^ VEJLVD
Ventilation V
Minute ventilation Total volume of gas entering lungs per minute Normal values:
< VE) VE = VT x RR Respiratory rate ( RR) = 12-20 breaths/min
Alveolar ventilation Volume of gas per unit time that reaches alveoli VT = 500 mL/breath
(VA > VA = ( VT - VD) x RR VQ = 150 mL/breath
 RESPIRATORY RESPIRATORY — PHYSIOLOGY SECTION III 627

Lung and chest wall Elastic recoil — tendency for lungs to collapse Chest wall
'

inward and chest wall to spring outward. - LC

At FRC, inward pull of lung is balanced by

Lung -chest
outward pull of chest wall, and system pressure wall system
is atmospheric. 3 -

Elastic properties of both chest wall and lungs 7

S vT
determine their combined volume. FRC
At FRC, airway and alveolar pressures are 0,
and intrapleural pressure is negative (prevents Lung
atelectasij). PVR is at minimum.
Compliance — change in lung volume for a -20 -10 0 10 20 30 40
change in pressure; expressed as AV/AP and is Transorgan static pressure (cmH20)
inversely proportional to wall stiffness. High
compliance = lung easier to fill (emphysema, Compliant lungs comply (cooperate) and fill
normal aging!lower compliance = lung easily with air.
harder to fill ( pulmonary fibrosis, pneumonia,
NRDS, pulmonary edema!(Surfactant
increases compliance.
Hysteresis — lung inflation curve follows a
different curve than the lung deflation curve
due to need to overcome surface tension forces
in inflation.

Hemoglobin Hemoglobin ( Hb) is composed of 4 polypeptide
subunits ( 2 a and 2 (3) and exists in 2 forms:
T (taut; deoxvgenated) form has low affinity
for 02, thus promoting release /unloading of
Fetal Hb ( 2a and 2y subunits) has a higher
affinity for 07 than adult Hb, driving diffusion
of oxygen across the placenta from mother to
fetus t 07 affinity results from i affinity of
,

07. HbF for 2,3-BPG.

R (relaxed; oxygenated) form has high Taut in Tissues.
Heme
affinity for 07 ( 300x). Hb exhibits positive Relaxed in Respiratory area.
cooperativitv and negative allostery
,

t Cl-, 11+, C07, 2,3 -BPG, and temperature favor

taut form over relaxed form (shifts dissociation Hemoglobin acts as buffer for H+ ions.
curve right
— t 07 unloading).
628 SECTION III RESPIRATORY RESPIRATORY — PHYSIOLOGY

Hemoglobin Lead to tissue hypoxia from 1 07 saturation and i 07 content.

modifications
Methemoglobin
,
Oxidized form of Hb (ferric, Fe +) that does Methemoglobinemia can be treated with
not bind 07 as readily, but has t affinity for methylene blue and vitamin C.
cyanide. Nitrites (eg, from dietary intake or polluted/high
Iron in Hb is normally in a reduced state altitude water source j) and benzocaine cause
(ferrous, Fe2+). poisoning by oxidizing Fe2+ to Fe’+.
Methemoglobinemia may present with cyanosis Fe2+ binds 07.
and chocolate-colored blood.
Induced methemoglobinemia (using nitrites,
followed by thiosulfate) may be used to treat
cyanide poisoning.
Carboxyhemoglobin Form of Hb bound to CO in place of 07.
Causes l oxygen-binding capacity with left - -' ’
'’
''' Nor nal|100% Ibl

shift in oxygen-hemoglobin dissociation curve.

i 07 unloading in tissues. -
CO binds competitively to Hb and with 200x
greater affinity than 07. _ 50% COHb
‘

Presents with headaches, dizziness, and cherry ^ 50% Hb anemia)

red skin. May be caused by fires, car exhaust, -
/i
^ \
\

4
N
or gas heaters.
Treat with 100% 07 and hyperbaric 07.
0 20 40 60 80 100
Po ? (mm Hg)

Oxygen-hemoglobin dissociation curve

Sigmoidal shape due to positive cooperativitv Right shift— ACE BATs right handed:
(ie, tetrameric Hb molecule can bind 4 07 Acid
molecules and has higher affinity for each co7
subsequent 07 molecule bound). Myoglobin Exercise
is monomeric and thus does not show 2,3-BPG
positive cooperativitv; curve lacks sigmoidal Altitude
appearance. Temperature
When curve shifts to the right, 1 affinity of Hb
Myoglobin
for 07 (facilitates unloading of 07 to tissue).
An t in all factors (including H+) causes a shift Oxygenated blood
leaving the lungs
of the curve to the right. Hemoglobin
A I in all factors (including H+) causes a left

— —
shift 1 07 unloading -*• renal hypoxia
—
t EPO synthesis compensatory
erythrocytosis. Lower = Left. 25
Fetal Hb has higher affinity for O-, than adult
Hb (due to low affinity for 23-BPG j so its
C
dissociation curve is shifted left. 25 50 75 100
Po2 (mm Hg)
 RESPIRATORY RESPIRATORY — PHYSIOLOGY SECTION III 629

Oxygen content of O, content = (134 x Hb x Sao7) + (0.003 x Pao?)

blood Hb = hemoglobin level
Sao7 = arterial 07 saturation
Pao7 = partial pressure of Q,- in arterial blood
Normally 1 g Hb can bind 134 mL O,- ; normal Hb amount in blood is 15 g/dL.
07 binding capacity * 20.1 mL 07 /dL blood.
With 1 Hb there is 1 O-, content of arterial blood, but no change in 07 saturation and Pao7 .
07 deliver}' to tissues = cardiac output x O, content of blood.

Dissolved 02
Hb concentration % 02 sat of Hb (Pao2) Total 02 content
CO poisoning Normal 1 (CO competes Normal »
with 07)
Anemia i Normal Normal i
Polycythemia t Normal Normal t

Pulmonary circulation Normally a low-resistance, high-compliance A consequence of pulmonary hypertension is cor

system. Po7 and Pco, exert opposite effects pulmonale and subsequent right ventricular
on pulmonary and systemic circulation. A failure ( jugular venous distention, edema,
i in PAO7 causes a hypoxic vasoconstriction hepatomegaly).
that shifts blood away from poorly ventilated
Diffusion: Vgas = A x Dk x hzh where
regions of lung to well-ventilated regions of T
lung. A = area, T = alveolar wall thickness,
Perfusion limited— Oz (normal health), CO,- , Dj.(Pj — P7) = difference in partial pressures:
N70. Gas equilibrates early along the length of A 1 in emphysema.
the capillary. Diffusion can be t only if blood 5
T t in pulmonary fibrosis.
flow t. ,
D rn is the extent to which CO, a surrogate
Diffusion limited — 07 (emphysema, fibrosis), tor oxygen, passes from air sacs of lungs into
CO. Gas does not equilibrate by the time blood!
blood reaches the end of the capillary.
.
Diffusion limited (eg CO)

.
Perfusion limited (eg, C02, N20) Oxygen

I Equilibration
p .
p

*
Normal

Exercise
^ *
Partial pressure
difference between *
x
----
Fibrosis
p. alveolar air and
pulmonary capillary
blood
p. -

Length along pulmonary capillary Length along pulmonary capillary Length along pulmonary capillary

Pa = partial pressure of gas in pulmonary capillary blood

PA = partial pressure of gas in alveolar air
632 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY
RESPIRATORY — PATHOLOGY
Rhinosinusitis

*
—
Obstruction of sinus drainage into nasal cavity inflammation and pain over affected area
( typically maxillary sinuses , which drain into the middle meatus, in adults).
Most common acute cause is viral URI; may cause superimposed bacterial infection, most
commonly S pneumoniae, H influenzae, M catarrhalis.

-
Epistaxis Nose bleed. Most commonly occurs in anterior segment of nostril ( Kiesselbach plexus). Life-
threatening hemorrhages occur in posterior segment (sphenopalatine artery, a branch of maxillary

^
artery ). Common causes include foreign body, trauma , allergic rhinitis, and nasal angiofibroma

Head and neck cancer

—
Mostly squamous cell carcinoma . Risk factors include tobacco, alcohol , HPV-16 (oropharyngeal ),
EBV ( nasopharyngeal ). Field cancerization : carcinogen damages wide mucosal area multiple
tumors that develop independently after exposure
^
Deep venous
thrombosis
Virchow triad (SHE ):
—
Blood clot within a deep vein swelling,
redness Q, warmth , pain. Predisposed by

Stasis (eg, post-op, long drive /flight )

Most pulmonary emboli arise from proximal
deep veins of lower extremity.

pain .
—
Homan sign forced dorsiflexionjof foot -*• calf

Hypercoagulability (eg, defect in Use unfractionated heparin or low-molecular-

coagulation cascade proteins, such as
factor V Leiden )
Endothelial damage (exposed collagen
triggers clotting cascade)
D-dimer lab test used clinically to rule out DVT
( high sensitivity, low specificity).
weight heparins (eg, enoxaparin) for
prophylaxis and acute management .
Use oral anticoagulants (eg, warfarin,
rivaroxaban ) for treatment ( long-term
prevention ).
Imaging test of choice is compression ultrasound
with Doppleij
 RESPIRATORY RESPIRATORY — PATHOLOGY SECTION III 633

Pulmonary emboli V/Q mismatch -*• hypoxemia -*• respiratory CT pulmonary angiography is imaging test of
alkalosis. Sudden-onset dyspnea, pleuritic choice for PE ( look for filling defects) Q.
chesjl pain, tachypnea, tachycardia. Large
emboli or saddle embolus Q may cause
sudden death.
Lines of Zahn are interdigitating areas of pink
( platelets, fibrin) and red ( RBCs) found only in
thrombi formed before death; help distinguish
pre- and postmortem thrombi Q.
Types: Fat, Air, Thrombus, Bacteria, Amniotic An embolus moves like a FAT BAT.
fluid, Tumor.
Fat emboli— associated with long bone fractures
and liposuction; classic triad of hypoxemia,
neurologic abnormalities, petechial rash.
Amniotic fluid emboli— can lead to D1C,
especially postpartum.
Air emboli — nitrogen bubbles precipitate
in ascending divers (caisson disease,
decompression sickness); treat with hyperbaric
O-,; or, can be iatrogenic 2° to invasive
procedures (eg, central line placement).

•SXZE Nr
1
634 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY

LONG PAGE — Please edit to lose lines.

Obstructive lung Obstruction of air flow resulting in air trapping in lungs. Airways close prematurely at high lung
diseases - -
volumes t RV and T FRC, t TLC. PFTs: U FEVj, 1 FVC iFEV /FVC ratio ( hallmark), ,
V/Q mismatch. Chronic, hypoxic pulmonary vasoconstriction can lead to cor pulmonale. Digital
clubbing can be caused by bronchiectasis, but not COPD or asthmai
TYPE PATHOLOGY OTHER
Chronic bronchitis Hypertrophy and hvperplasiajof mucus- Productive cough for > 3 months in a yea jfor
("blue bloater " ) secreting glands in bronchi - Reid index consecutive years.
(thickness of mucosal gland layer to thickness Findings: wheezing, crackles, cyanosis (early-
of w all between epithelium and cartilage) onset hypoxemia due to shunting), late-onset
>po%. dyspnea, CO-, retention 2° polycythemia.
^
Chronic complications: pulmonary
hypertension, cor pulmonale.
Emphysema ("pink Enlargement of air spaces, 1 recoil, t elastase activity -* loss of elastic fibers
puffer ") t compliance, 1 JQiresulting from -*• t lung compliance.
destruction of alveolar walls (arrow in Q). Tw o Exhalation through pursed lips to t airway
types:
e
Centriacinar — associated with
pressure and prevent airway collapse
Barrel-shaped chest 0. X-ray shows t AP^
smoking Q Q. Frequently in upper lobes. diameter, flattened diaphragm, t lung field
Panacinar — associated w ith oq-antitrypsin lucency.
deficiency. Frequently in lower lobes.
Asthma Bronchial hyperresponsiveness causes reversible Can be triggered by viral URIs, allergens, stress.
bronchoconstriction. Smooth muscle hyper Aspirin-induced asthma: COX inhibition

— —
¬

trophy, Curschmann spirals Q (shed epithelium leukotrienc overproduction airway

forms whorled mucus plugs), and Charcot-
Leyden crystals (eosinophilic, hexagonal,
double-pointed, needle-like crystals formed
from breakdown of eosinophils in sputum).
Bronchiectasis Chronic necrotizing infection of bronchi
permanently dilated airways, purulent
-*•
sputum, recurrent infections, hemoptysis,
digital clubbing.
constriction. Associated with nasal polvpsj
Clinical diagnosis can be supported by
spirometry and methacholine challenge.
Findings: cough, wheezing, tachypnea,
dyspnea, hypoxemia, l inspiratory/expiratory
ratio, pulsus paradoxus, mucus plugging Q.
Peribronchial cuffing on CXR .
Associated with bronchial obstruction, poor
ciliary motility (eg, smoking, Kartagener
syndrome), cystic fibrosis 0, allergic
bronchopulmonary aspergillosis.

U
\
&
A
->
1

•«
(
k
7

*
 RESPIRATORY RESPIRATORY — PATHOLOGY SECTION III 635

Restrictive lung Restricted lung expansion causes i lung volumes (I FVC and TLC). PFTs: FEVj /FVC ratio > 80%.
diseases Patient presents with short, shallow breaths.
Types:
Poor breathing mechanics (extrapuhnonarv, peripheral hypoventilation, normal A-a gradient):
Poor muscular effort — polio, myasthenia gravis, Guillain-Barre syndrome
H

° Poor structural apparatus — scoliosis, morbid obesity

4 Interstitial lung diseases ( pulmonary 1 diffusing capacity, t A-a gradient):
W * Acute respiratory distress syndrome ( ARDS)
T Neonatal respiratorv distress syndrome (NRDS; hyaline membrane disease)
Pneumoconioses (eg, coal workers’ pneumoconiosis silicosis, asbestosis)
Sarcoidosis: bilateral hilar lymphadenopathy, noncaseating granuloma; t ACE and Ca-+
Idiopathic pulmonary fibrosis Q (repeated cycles of lung injury and wound healing with
t collagen deposition, “ honeycomb ” lung appearance and digital clubbing)
pranulomatosis with polyangiitis ( Wegener)
Pulmonary Langerhans cell histiocytosis (eosinophilic granuloma)
Hypersensitivity pneumonitis
Drug toxicity (bleomycin, busulfan, amiodarone, methotrexate)_
Hypersensitivity pneumonitis — mixed type III/IV hypersensitivity reaction to environmental
antigen. Causes dyspnea, cough, chest tightness, headache. Often seen in farmers and those
exposed to birds.

Flow volume loops Obstructive lung volumes > normal ( t TLC, t FRC, t RV ); restrictive lung volumes < normal. In
obstructive, FEV| is more dramatically reduced compared with FVC
ratio. In restrictive, FVC is more reduced or close to same compared with FEV )
—
decreased FEVj /FVC
increased or
—
normal FEVi /FVC raticj
OBSTRUCTIVE NORMAL RESTRICTIVE
Loop shifts to the left Loop shifts to the right
8 8
!
4
\ J
1
1 A
V « /
-
i; o 8 6 4 2 / 0 -
Volume (L)

4
vV >
!
4 - \v_y7w 4

8
I
- 8.
TLC-
636 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY
Pneumoconioses

—
Coal workers’ pneumoconiosis, silicosis, and
asbestosis t risk of cor pulmonale, cancer,
and Caplan syndrome ( rheumatoid arthritis
and pneumoconioses with intrapulmonary
nodules!)
Asbestos is from the roof (was common in
insulation ), but affects the base ( lower lobes ).
Silica and coal are from the base ( earth ), but
affect the roof ( upper lobes ).

Asbestosis Associated with shipbuilding, roofing, Affects lower lobes.

plumbing. “ Ivory white,” calcified ,
supradiaphragmatic!El and pleural Q
plaques arej pathognomonic of asbestosis.
Risk of bronchogenic carcinoma > risk of
mesothelioma.
Berylliosis Associated with exposure to beryllium in
aerospace and manufacturing industries.
Granulomatous on histology and therefore
Asbestos (ferruginous) bodies are golden-brown
fusiform rods resembling dumbbells 0,
found in alveolar sputum sample!visualized
using Prussian blue stain , often obtained by
bronchoalveolar lavage,
t risk of pleural effusions.
Affects upper lobes.

Coal workers'
pneumoconiosis —
occasionally responsive to steroids.
Prolonged coal dust exposure macrophages
laden with carbon -*• inflammation and
fibrosis.
Also known as black lung disease.
Affects upper lobes.
Anthracosis — asymptomatic condition found in
many urban dwellers exposed to sooty air.

Silicosis Associated with foundries, sandblasting, Affects upper lobes.

mines. Macrophages respond to silica Chest x-rav shows “ eggshell ” calcification of
and release fibrogenic factors, leading to hilar lymph nodeil
fibrosis. It is thought that silica may disrupt
phagolysosomes and impair macrophages,
increasing susceptibility to I B .
'P,
r <
:: • i f
*

-
r? A
 RESPIRATORY RESPIRATORY — PATHOLOGY SECTION III 637

Acute respiratory Diagnosis of exclusion characterized by

distress syndrome respiratory failure w ithin 1 week of alveolar f
insult, bilateral lung opacities, I PaCVFIO-,
( hypoxemia due to t intrapulmonary shunfmg
"

and diffusion abnormalities ), no evidence

•
»
m ?
•
>

WL
of HF/fluid overload . Caused by sepsis, .•
pancreatitis, pneumonia , aspiration , trauma ,
or shock . Endothelialdamage -* t alveolar
-
rr r: ~
—
*
capillar}- permeability -* protein-rich leakage
into alveoli diffuse alveolar damage and '

noncardiogenic pulmonary edema ( normal

PCWP) Q- Results in formation of intra-
alveolar hyaline membranes Q. Initial damage
due to release of neutrophilic substances
toxic to alveolar wall and pulmonary capillary
endothelial cells, activation offcoagulation
cascade, and oxygen-derived free radicals.
Management: mechanical ventilation with low
tidal volumes, address underlying cause.

Sleep apnea

— —
somnolence. Normal Pao? during the day. —
Repeated cessation of breathing > 10 seconds during sleep disrupted sleep -* daytime

Nocturnal hypoxia systemic/pulmonary hypertension , arrhythmias (atrial fibrillation /flutter),

sudden death .
Hypoxia t EPO release t erythropoiesis.
Obstructive sleep Respiratory effort against airway obstruction . Associated with obesity, loud snoring. Caused by
apnea excess parapharyngeal tissue in adults, adenotonsillar hypertrophy in children . Treatment: weight
loss, CPAP, surgery.
Central sleep apnea No respiratory effort due to CNS injurv/toxicitv, HF, opioids. May be associated with Cheyne-
Stokes respiration . Treat with bilevel positive airway pressure (cm H -,Oi

Obesity
hypoventilation
syndrome
and t PaCOo during sleep] —
> 30 kg /m ~ ) hypoventilation t PaCO-, during waking hours ( retention ); 1 PaOi
Obesity ( BMI
638 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY

Pulmonary Normal mean pulmonary artery pressure = 10-14 mm Hg; pulmonary hypertension > 25 mm I Ig at
hypertension rest. Results in arteriosclerosis, medial hypertrophy, intimal fibrosis of pulmonary arteries. Course:

ETIOLOGIES
—
severe respiratory distress • cyanosis and RVH
— death from decompensated cor pulmonale.

Pulmonary arterial Idiopathic PAH.

hypertension Heritable PAH — often due to an inactivating mutation in BMPR2 gene (normally inhibits vascular
smooth muscle proliferation); poor prognosis.
Other causes include drugs (eg, amphetamines, cocaine), connective tissue disease, HIV infection,
portal hypertension, congenital heart disease, schistosomiasis.
Left heart disease Causes include systolic /diastolic dysfunction and valvular disease (eg, mitral lung).
Lung diseases or Destruction of lung parenchyma (eg, COPD), lung inflammation/fibrosis ( eg, interstitial lung
hypoxia diseases), hypoxemic!vasoconstriction (eg, obstructive sleep apnea, living in high altitude).
Chronic Recurrent microthrombi -* 1 cross-sectional area of pulmonary vascular bed.
thromboembolic
Multifactorial Causes include hematologic, systemic, and metabolic disorders.

Lung — physical findings

ABNORMALITY BREATH SOUNDS PERCUSSION FREMITUS TRACHEAL DEVIATION
Pleural effusion i Dull i — or away from side of
lesion (if large)
Atelectasis ( bronchial i Dull i Toward side of lesion
obstruction)
Simple pneumothorax i Hyperresonant i —
Tension i Hyperresonant i Away from side of lesion
pneumothorax
Consolidation Bronchial breath Dull t
( lobar pneumonia, sounds; late inspiratory
pulmonary edema ) crackles, egophonv,
bronchophonv,
whispered pectoriloqu\|
 RESPIRATORY RESPIRATORY — PATHOLOGY SECTION III 639

Pleural effusions Excess accumulation of fluid between pleural layers Q -*• restricted lung expansion during
inspiration. Can be treated with thoracentesis to remove fluid Q.
Transudate 1 protein content. Due to t hydrostatic pressure (eg, CHFj) or 1 oncotic pressure (eg, nephrotic
syndrome, cirrhosis).
Exudate t protein content, cloudy. Due to malignancy, pneumonia, collagen vascular disease, trauma
(occurs in states of t vascular permeability). Must be drained due to risk of infection.
Lymphatic Also known as chylothorax. Due to thoracic duct injury from trauma or malignancy. Milky-
appearing fluid; t triglycerides.

V
Gf) Pretreatment
n
Pneumothorax Accumulation of air in pleural space Q. Dyspnea, uneven chest expansion. Chest pain, 1 tactile
fremitus, hvperesonace, and diminished breath sounds, all on the affected sidej
Primary spontaneous Due to rupture of apical subpleural bleb or cysts. Occurs most frequently in tall, thin, young males.
pneumothorax
Secondary Due to diseased lung (eg, bullae in emphysema, infections), mechanical ventilation with use of
spontaneous
pneumothorax
—
high pressures barotrauma.

Traumatic Caused by blunt (eg, rib fracture) or penetrating (eg, gunshot) trauma.
pneumothorax
Tension
pneumothorax
Can be any of the above. Air enters pleural space but cannot exit. Increasing trapped air
pneumothorax. Trachea deviates away from affected lung Q. Needs immediate needle
— tension

decompression and chest tube placement.

r
r''
.
m.
•y
4
640 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY
Pneumonia
TYPE
Lobar

Bronchopneumonia
TYPICAL ORGANISMS
S pneumoniae most frequently, also
Klebsiella
S pneumoniae, S aureus, H influenzae,
Klebsiella
Legionella,
CHARACTERISTICS
Intra-alveolar exudate
— consolidation Q; may
involve entire lobe Q or lung.
Acute inflammatory infiltrates H from
bronchioles into adjacent alveoli; patchy
distribution involving > 1 lobe 0.
Interstitial (atypical ) Mycoplasma , Chlamydophila pneumoniae . Diffuse patchy inflammation localized to
pneumonia Chlamydia psittaci Legionella , viruses ( RSV, interstitial areas at alveolar walls; diffuse
CMV, influenza , adenovirus) distribution involving > 1 lobe Q. Generally
follows a more indolent course (“ walking”
pneumonia ).
Bronchiolitis Noninfectious pneumonia characterized bv
obliterans organizing inflammation of bronchioles and surrounding
pneumonia structures. Caused bv chronic inflammatory
diseases (eg, rheumatoid arthritis ) or medication
side effects ( eg, amiodarone ). Negative sputum
and blood cultures, no response to antibiotics.

V
- -

Lung abscess Localized collection of pus within Air-fluid levels Q often seen on CXR. Fluid
parenchyma Q. Caused by aspiration of levels common in cavities; presence suggests
oropharyngeal contents (especially in patients cavitation . Due to anaerobes (eg, Bacteroides ,
• predisposed to loss of consciousness [eg, Fusobacterium, Peptostreptococcus ) or S aureus.
1 alcoholics, epileptics] ) or bronchial obstruction Lung abscess 2 ° to aspiration is most often found
*
s
——
(eg, cancer). in right lung. Location depends on patient's

m Treatment: clindamycin . position during aspiration :

5
^
Upright inferio segments of right lower
lobe
Supine posterior segments of right upper
lobe or superior segment of right lower lobe
 RESPIRATORY RESPIRATORY — PATHOLOGY SECTION III 641

Mesothelioma Malignancy of the pleura associated with Psammoma bodies seen on histology.
asbestosis. May result in hemorrhagic pleural Cytokeratin and calretinin © in almost all
effusion (exudative), pleural thickening. mesotheliomas, © in most carcinomas.
Smoking not a risk factor.

Pancoast tumor Carcinoma that occurs in the apex of lung Q may cause Pancoast syndrome by invading cervical
( superior sulcus sympathetic chain.
tumor ) Compression of locoregional structures may cause array of findings:
n —
Recurrent laryngeal nerve hoarseness
Stellate ganglion!-» Horner syndrome (ipsilateral ptosis, miosis, anhidrosis)
Superior vena cava -*• SVC syndrome_
—
s

Brachiocephalic vein • brachiocephalic syndrome (unilateral symptoms)

Brachial plexus -» sensorimotor deficit!

Superior vena cava An obstruction of the SVC that impairs blood

syndrome drainage from the head (“ facial plethora”;
note blanching after fingertip pressure in Q),
neck ( jugular venous distention), and upper
extremities (edema). Commonly caused by MfU
malignancy ( eg, mediastinal mass, Pancoast LV
tumod) and thrombosis from indwelling
catheters Q. Medical emergency. Can raise
intracranial pressure (if obstruction is severe)
— headaches, dizziness, t risk of aneurysm/
rupture of intracranial arteries.
642 SECTION III RESPIRATORY RESPIRATORY — PATHOLOGY

Lung cancer Leading cause of cancer death. SPHERE of complications:

Presentation: cough, hemoptysis, bronchial Superior vena cava syndrome
obstruction, wheezing, pneumonic “coin” Pancoast tumor
lesion on CXR or noncalcified nodule on CT. Horner syndrome
Sites of metastases from lung cancer: Endocrine (paraneoplastic)
adrenals, brain, bone (pathologic fracture), Recurrent laryngeal nerve compression
liver ( jaundice, hepatomegaly). (hoarseness)
In the lung, metastases (usually multiple Effusions ( pleural or pericardial)
lesions) are more common than 1° Risk factors include smoking, secondhand smoke,
neoplasms. Most often from breast, colon, radon, asbestos, family history.
prostate, and bladder cancer. Squamous and Small cell carcinomas are Sentral
(central) and often caused by Smoking.
TYPE LOCATION CHARACTERISTICS HISTOLOGY
Small cell
Small cell (oat cell )
carcinoma
Central
—
Undifferentiated very aggressive.
May produce ACTH (Cushing syndrome), SI ADII, or
Neoplasm of
neuroendocrine
Antibodies against presynaptic Ca 2+ channels (Lambert- Kulchitsky cells - small
Eaton myasthenic syndrome) or neurons (paraneoplastic dark blue cells CJ.
myelitis, encephalitis, subacute cerebellar degeneration). Chromogranin A ©,
Amplification of myc oncogenes common. Managed neuron-specific
with chemotherapy +/- radiation. enolase ©.
Non- small cell
Adenocarcinoma Peripheral Most common lung cancer in nonsmokers and overall Glandular pattern on
(except for metastases). Activating mutations include histology, often stains
KRAS , EGFR , and ALK . Associated with hypertrophic mucin © Q.
osteoarthropathy (clubbing). Bronchioloalveolar subtype:
Bronchioloalveolar subtype ( adenocarcinoma in situ): grows along alveolar septa
CXR often shows hazy infiltrates similar to pneumonia;
better prognosis.
— apparent “ thickening”
of alveolar walls. Tall,
Bronchial carcinoid and bronchioloalveolar cell columnar cells containing
carcinoma have lesser association with smoking. mucus.
Squamous cell Central Hilar mass arising from bronchus Q; Cavitation; Keratin pearls 0 and
carcinoma Cigarettes; hyperCalcemia (produces PTHrP). intercellular bridges.
Large cell Peripheral Highly anaplastic undifferentiated tumor; poor prognosis. Pleomorphic giant
carcinoma Less responsive to chemotherapy; removed surgically. cells Ql
Strong association with smoking

Bronchial carcinoid Excellent prognosis; metastasis rare. Nests of neuroendocrine

tumor Symptoms due to mass effect or carcinoid syndrome cells; chromogranin A ©.
(flushing, diarrhea, wheezing).

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 RESPIRATORY RESPIRATORY — PHARMACOLOGY SECTION III 643

RESPIRATORY — PHARMACOLOGY

Antihistamines Reversible inhibitors of Hj histamine receptors.

First generation Diphenhydramine, dimenhydrinate, Names contain “-en /-ine” or “-en/-ate.”
chlorpheniramine.
CLINICAL USES Allergy, motion sickness, sleep aid.
ADVERSE EFFECTS Sedation, antimuscarinic, anti-a-adrenergic.
Second generation Loratadine, fexofenadine, desloratadine, Names usually end in “-adine.”
cetirizine.
CLINICAL USES Allergy.
ADVERSE EFFECTS Far less sedating than 1st generation because of
i entry into CNS.

Guaifenesin Expectorant — thins respiratory secretions; does not suppress cough reflex.

!V-acetylcysteine Mucolytic — liquifies mucous in chronic bronchopulmonary diseases (eg, COPD, CF) by disrupting
disulfide bonds. Also used as an antidote for acetaminophen overdose.

Dextromethorphan Antitussive (antagonizes NMDA glutamate receptors). Synthetic codeine analog. Has mild opioid
effect when used in excess. Naloxone can be given for overdose. Mild abuse potential. May cause
serotonin syndrome if combined with other serotonergic agents.

Pseudoephedrine, phenylephrine
MECHANISM -adrenergic agonists, used as nasal decongestants.
(X

CLINICAL USE Reduce hyperemia, edema, nasal congestion; open obstructed eustachian tubes. Pseudoephedrine
also illicitly used to make methamphetamine.
ADVERSE EFFECTS Hypertension. Can also cause CNS stimulation/anxiety ( pseudoephedrine).

Pulmonary hypertension drugs

DRUG MECHANISM CLINICAL NOTES

BosENtan Competitively antagonizes ENdothelin-1 Hepatotoxic (monitor LFTs).

Sildenafil
—
receptors 1 pulmonary vascular resistance.
Inhibits PDE-5 which t cGMP, thereby Also used to treat erectile dysfunction
,

prolonging vasodilatorv effect of nitric oxidej

Epoprostenol, iloprost PGI? (prostacyclin) with direct vasodilator)' Side effects: flushing, jaw pain,
effects on pulmonary and systemic arterial
vascular beds. Inhibits platelet aggregation.
644 SECTION III RESPIRATORY RESPIRATORY — PHARMACOLOGY

Asthma drugs Bronchoconstriction is mediated by (1) inflammatory processes and ( 2) parasympathetic tone;
therapy is directed at these 2 pathways.
Albuterol — relaxes bronchial smooth muscle (short acting ( -agonist) Used during acute .
^
- agonists
exacerbation. ^
Salmeterol, formoterol — long-acting agents for prophylaxis. Adverse effects are tremor and
arrhythmia.
Inhaled Fluticasone, budesonide — inhibit the synthesis of virtually all cytokines. Inactivate NF-KB, the
corticosteroids transcription factor that induces production of TNF-a and other inflammatory agents, lst-line
therapy for chronic asthma. May cause oral thrusht
Muscarinic Tiotropium, ipratropiumj— competitively blocks muscarinic receptors, preventing
antagonists bronchoconstriction. Also used for COPD. Tiotropium is long acting.
Antileukotrienes Montelukast, zafirlukast — block leukotriene Exposure to antigen
receptors (CvsLTl ). Especially good for (dust, pollen, etc)
aspirin-induced and exercise-induced asthmqj
Zileuton — 5 -lipoxygenase pathway inhibitor. —
I (3) — Avoidance
Blocks conversion of arachidonic acid to
.
leukotrienes Hepatotoxic.
Anti- lgE monoclonal Omalizumab — binds mostly unbound serum —
Antigen and IgE [-{3) Omalizumab
on mast cells
therapy IgE and blocks binding to FceRI. Used in
allergic asthma with t IgE levels resistant to
I— (3}— Steroids
inhaled steroids and long-acting [ -agonists.
^
Methylxanthines Theophylline — likely causes bronchodilation
by inhibiting phosphodiesterase t cAMP
levels due to i cAMP hydrolysis. Usage is
— Mediators
(leukotrienes, histamine, etc)

limited because of narrow therapeutic index p -agonists

(cardiotoxicity, neurotoxicity); metabolized Theophylline Steroids
by cytochrome P- 450. Blocks actions of Muscarinic -GH H5>- Antileukotrienes
antagonists
adenosine.
ATP

Bronchodilation AC | < — ( )—
+ 0-agonists Early response: Late response:
bronchoconstriction inflammation
—
) cAMP

Q Bronchial tone
^ I PDEji O—
AMP
Theophylline

Symptoms
Bronchial
hyperreactivity
ACh • — — Adenosine
* *

Muscarinic Theophylline
antagonists
Bronchoconstriction

Methacholine Muscarinic receptor (MJ agonist. Used in bronchial challenge test to help diagnose asthma.