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Cyberfriends: The help you're looking for is probably here.
This website collects no information. If you e-mail me, neither your e-mail address nor any other information will ever be passed on to any third party, unless required by law.
This page was last modified July 5, 2010.
I have no sponsors and do not host paid advertisements. All external links are provided freely to sites that I believe my visitors will find helpful.
Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected. No texting or chat messages, please. Ordinary e-mails are welcome.
DoctorGeorge.com is a larger, full-time service.
There is also a fee site at
www.afraidtoask.com.
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I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource.
pathology.org -- my cyberfriends, great for current news and browsing for the general public
EnjoyPath -- a great resource for everyone, from beginning medical students to pathologists with years of experience
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.
Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.
Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.
Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.
If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.
I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!
Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.
This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.
During the fifteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at KCUMB
for making it possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!
I [Allah] am nearer to you than the vein in your neck. --Koran
QUIZBANK:
Hemodynamic #'s 1-30,
Vessels (all)
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
MedEdPORTAL -- American Association of Medical Colleges. Primarily for medical school faculty.
Also:
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta Tumor Photos -- and lots more. Highly recommended.
Bristol Biomedical
Image Archive
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
U. of Virginia Case Studies
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Upstate NY Cases -- works only on some browsers
Society for ultrastructural pathology -- electron microscope cases
PathologyPics -- where pathologists share favorite images. Thanks!
WebPath:
Internet Pathology
Laboratory -- great site
Path Consult -- great photos and text for more advanced learners
Medmark Pathology -- massive listing of pathology sites
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
Atherosclerosis: Hemodynamic 1-30
Tumors / Aneurysms / Vasculitis: Vessels (all)
The term "arteriosclerosis" (literally, "hardening of the arteries") should be avoided by physicians. It includes (1) atherosclerosis; (2) Monckeberg's medial calcific sclerosis; and (3) arteriolar sclerosis (hyaline, hyperplastic, intimal fibrosis). Unqualified, the term usually means "atherosclerosis".
The vascular intima looks simple but isn't. Endothelial cells must maintain their no-stick inner surfaces, help constrict and dilate vessels, and heal damaged vessels. Myointimal cells and macrophages, located between the endothelium and the internal elastic membrane, are the principal actors in atherosclerosis.
Atherosclerosis is a stereotyped response of the inner surfaces of large arteries to a variety of insults. In this disease, the cells between the endothelium and the internal elastic membrane take up cholesterol-rich lipid, which then causes harm. Lesions progress from FATTY STREAKS to FIBROUS PLAQUES to COMPLICATED FIBROUS PLAQUES; they can also regress.
Atherosclerosis may calcify, but the problem in atherosclerosis is not the dystrophic calcification. Monckeberg's medial calcific sclerosis just means dystrophic calcification of the media of an artery, but it is almost never a real problem.
Atherosclerosis is an ancient disease, present in some Egyptian mummies (JAMA 302: 2091, 2009 -- the lesions are real but look quite mild by today's standards).
Atherosclerosis was THE great killer of 20th century North Americans. The epidemic peaked in 1968, and since then the decline has been spectacular, due more than anything else to healthier lifestyles (JAMA 277: 535, 1997; it's been steady since the mid-1980's: NEJM 339: 861, 1998). We are beginning to understand how the common risk factors relate to its pathogenesis. Americans are taking steps to protect themselves, and lifestyle changes can almost certainly reverse much of the damage in all but the most advanced lesions.
Hyaline arteriolar sclerosis results from damage to arterioles usually from increased pressure or increased blood glucose. Hyperplastic arteriolar sclerosis involves hyperplasia of the intimal cells; it results from processes that do severe, acute damage to the endothelium. Fibrosis of the intima results from high blood pressure or "just getting older."
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OBJECTIVES: This is mastery material.
Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:
Give a full account of the vascular changes contributing to, and resulting from, high blood pressure.
Give a full account of each of these clinical syndromes, with anatomic and clinical pathology as applicable:
Describe the range of infections that can affect the blood vessels.
Review the causes of deep vein thrombosis ("thrombophlebitis"), and describe its symptoms, signs, and principal complication.
Give accounts of each of the following, and be able to recognize them clinically:
Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:
Describe the important tumors, hamartomas, and proliferations of blood and lymph vessels, how they behave clinically, and the pitfalls in making the diagnosis.
NORMAL ANATOMY
ARTERIES carry blood from the heart.
ELASTIC ARTERIES ("large arteries") include the aorta and at least the beginnings of its largest branches. These arteries both propel and dampen the pulse wave. These are distinguished by a preponderance of elastic fibers in their media. The subendothelium of their intimal layers thickens over the course of life through the accumulation of collagen fibers and myointimal cells. The elastic tissue proliferates here. You already know that all elastic tissue slowly breaks down as we age. In older adults, the elastic is largely replaced by collagen. This also results in lengthening and thus tortuosity seen in older people. The adventitia and outer media is nourished by vasa vasora. All arteries depend on the blood within their lumens to nourish their intima and inner media.
MUSCULAR ARTERIES ("medium-sized arteries", "distributing arteries") exhibit smooth muscle in their walls, and may expand and contract to regulate the caliber of the lumen and thus the flow of blood. The intima is similar to that of the elastic arteries, and it thickens similarly. Smooth muscle may pass into the intima through fenestrae in the internal elastic membrane. These fenestrae may become wide in old age and be mistaken for damage from previous vasculitis. The media is bounded on either side by an inner and outer elastic membrane.
SMALL ARTERIES are the major site of autonomic regulation of blood flow, and take the worst beating in hypertension. A rule of thumb is that the wall and lumen should have the same thickness. Thickening of the intima occurs here as well. In sites of inflammation or tumor, it may be quite impressive (* "Friedlander's endarteritis obliterans", discovered by the real Dr. Friedlander, 19th century pathologist Carl, 1847-1887). Hyaline arteriolar sclerosis becomes a problem as we age, especially if we get diabetes or hypertension. There's no outer elastic membrane, and the layers become progressively less distinct as the arteries get smaller.
ARTERIOLES continue the anatomy of the small arteries. Two definitions that have been offered: (1) Arterioles have five or fewer layers of smooth muscle; (2) Arterioles have total diameter 100 microns or less.
VEINS and LYMPHATICS have histologic features that you know. In disease, veins do not usually show so much intimal proliferation and fibrosis as do arteries. The muscle in the wall of a vein is thinner, and in the larger veins tends to be less organized. Very large veins have some layers of elastic outside their muscular layer. Lymphatics run very close to arteries (even closer than the veins), and tend to be small and to have thinner walls than the vein that runs with that artery. It's not always possible to tell lymphatics from veins; if the vessel contains red cells, it's most likely a vein.
ENDOTHELIUM is special stuff. It is permeable to water and the small inorganic ions. It transports a
little bit of blood protein by pinocytosis. Electron microscopists recognize it by the
WEIBEL-PALADE BODIES (puh-LAH-dee, made of von Willebrand's factor). It can contract, to regulate capillary
flow. It produces some of the subendothelial connective tissue.
It also makes substances: (1) Prostacyclin (to keep its surface slippery); (2) Von Willebrand's factor;
(3) Endothelin (a vasoconstrictor peptide); (4) Endothelial-derived relaxation factor (nitric oxide,
EDRF; see Nature 368: 62, 1994).
VASCULAR SMOOTH MUSCLE is also special. It has LDL receptors. It can get into the intima through
holes in the internal elastic membrane. Both facts will become important when we study
atherogenesis.
Lymphatic vessels in edema
They are not themselves plugged,
but are dilated from carring away fluid.
BIRTH DEFECTS INVOLVING VESSELS
There are many variations on the normal anatomy of arteries.
Malformations of the coronary arteries may first announce themselves by causing sudden death. More about this soon.
The familiar red "birthmarks" are hemangiomas, and will be covered with "tumors".
The only other birth defects worth mentioning are BERRY ANEURYSMS and ARTERIOVENOUS MALFORMATIONS ("AV malformations", "AV fistulas", "AV aneurysms", etc.)
AV malformations involve a tangle of abnormal medium-sized vessels connecting a large artery and a large vein. The problem is shunting of the blood away from the territory that should be supplied by the artery. The vein will tend to expand ("aneurysm").
Sometimes the AV malformation is a mass of wormy vessels ("cirsoid aneurysm", "racemose aneurysm"; apparently endemic among Klingons). This is most common in the brain, where subarachnoid hemorrhage is the dread complication.
* Future pathologists: It's good to be able to distinguish a baby's AV malformation (which won't go away) from a baby's hemangioma (which probably will go away). An AV malformation does not stain for WT1; a hemangioma that will involute does stain for WT1 (Arch. Derm. 141: 1297, 2005).
ATHEROSCLEROSIS (best recent update J. Am. Coll. Card. 46: 937, 2005; DeBakey
tries to sort out what puts you at risk for what Am. J. Card. 85: 1045, 2000)
{03476} coronary artery atherosclerosis
{06485} coronary artery atherosclerosis, mild
{06491} coronary artery atherosclerosis, severe
{06497} coronary artery atherosclerosis, total
{09446} êtat cribilé from multiple atheroemboli
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Probably still the #1 killer of Americans.
Atherosclerosis causes harm by (1) narrowing / occluding arteries slowly over time (angina, sudden cardiac death without coronary occlusion, ischemic scarring of the myocardium, atherosclerotic dementia, leg claudication, intestinal angina, having one kidney waste away to a hypertension-producing nubbin); (2) occluding arteries suddenly by rupture of plaques (thrombosis, atheroembolization) or hemorrhages into plaques (myocardial infarct, atherosclerotic stroke, gangrene of the bowel); (3) weakening the walls of arteries (atherosclerotic aneurysms, penetrating atherosclerotic ulcers of the aorta).
* The radiologists are now able to see a fresh rupture of a fibrous cap, and correlating it with clinical findings: Circulation 105: 181, 2002; ultrasonography shows that, not surprisingly, the most common site is at the origin of the LAD (J. Am. Coll. Card. 46: 261, 2005).
* Your lecturer was once taken to task severely by opposing counsel's expert for describing "70% occlusion" of a coronary artery. Of course, it's really "70% narrowing", but as I pointed out, the New England Journal of Medicine has used the same language as your lecturer, and you'll see it often.
{06737} atherosclerosis of coronaries
{09443} atherosclerosis of middle cerebral artery
{10889} atheroembolus
You're already familiar with atheroembolization, which is a major cause both of stroke and of lower-extremity ischemia ("blue
toes disease").
Atherosclerosis is a stereotyped response to injury featuring the accumulation of cholesterol-rich fat
in the intima of the large and medium-sized arteries of the body. Typically these are phagocytes
("myointimal cells", visiting macrophages). These masses form PLAQUES, or
ATHEROMAS.
For whatever reason, these cells have a great appetite for LDL cholesterol. When the LDL is
abnormal (Ox-LDL, lipoprotein A; see below), or the LDL is processed down the "bad"
(non-apoprotein B receptor-mediated)
breakdown pathway, these cells accumulate lipid that damages
them and their neighbors. The two pathways: Proc. Nat. Acad. Sci. 91: 4431, 1994.
A good working rule: The pulmonary arteries do not get serious
atherosclerosis. Otherwise, if an artery has its own name, it can be significantly affected by
atherosclerosis. The aortic surfaces of the aortic valve cusps are also prone
to the disease at all stages (Heart 91: 576, 2005 documents what all pathologists already knew).
Atherosclerosis seems to be the stereotyped way in which most of the large named arteries respond to
a variety of injuries. Don't expect a unified theory of atherogenesis
anytime soon. However,
the manageable risk factors
are, in descending order (1-5 at least) of importance:
1. High levels of LDL cholesterol. This is the over-riding risk factor. Review Lancet 345: 362,
1995.
Your LDL level is a reflection of your heredity, your diet (cholesterol-rich, saturated fatty acid-rich, trans-unsaturated fatty acid-rich
diets raise LDL), and your exercise habits.
Also remember cholestatic jaundice, nephrotic syndrome, hypothyroidism (you need T3
to express LDL receptors on liver cells), amiodarone (* keeps T3 from
letting you make LDL receptors) and (less striking)
Cushingism.
As total cholesterol rises above 160 mg/dL, coronary risk rises roughly linearly.
* The Swedish simvastatin study, which laid to rest concerns about excess mortality from lowering
LDL's: 345: 1274, 1995.
2. Cigaret * "Cigaret" is the preferred spelling. The suffix "-ette" makes the practice sound cute and harmless.
The old story about tobacco "damaging the intima" is giving way to the better-evidenced fact that
tobacco smoke oxidizes LDL, making them into the poorly-digested form that accumulates in the
intima.
This is for me still the most interesting work in atherosclerosis. Oxidized LDL is chemotactic for
macrophages, makes them proliferate, and is cytotoxic once they ingest it, it can make cells produce
cytokines like α-TNF that may be fibrogenic, and it
there can even be autoantibodies.
Now that "atherosclerosis is an inflammatory disease" (ask a clinician),
the tendency is to call the cholesterol-laden cells of plaques "macrophages",
and assume they have their origin from the blood rather than from the myointimal
cells that are normally present.
Smoking oxidizes LDL, HDL protects it from oxidation, vitamin E prevents LDL oxidation (kind
of, antioxidants seem to slow atherosclerosis JAMA 273: 1899, 1995), and so forth and so forth.
* Update on Ox-LDL in atherogenesis: J. Am. Coll. Card. 43:
1731, 2004.
Pathologists: J. Clin. Inv. 92: 471, 1993.
Superoxide plus
NO. generates the noxious ONOO- peroxynitrite radical that oxidizes LDL (Proc. Nat. Acad. Sci.
91: 1044, 1994).
The claim that oxidized LDL is chemotactic for macrophgaes that become
cholesterol-laden, and that it keeps them in the plaque, seems to be robust
(J. Clin. Inv. 119: 136, 2009; NEJM 360: 1144, 2009).
You will probably run into the "pop" claim that "oxidized LDL is the cause of
atherosclerosis and since there is very little oxygen in veins and in the pulmonary artery,
this is why we do not see atherosclerosis here. If this were true, then (1) you'd see atherosclerosis
in the smaller arteries, where oxygen tension is just as high; (2) in pulmonary hypertension, where the
oxygen tension in the pulmonary artery is even less though the pressure is higher, you'd see less rather than
more atherosclerosis; (3) it's not true that there's very little oxygen in venous blood.
* A variety of other modifications of LDL also result in increased phagocytosis by macrophages,
render it toxic to endothelium, smooth muscle, and macrophages, etc., etc.
"Advanced lipoprotein testing" goes beyond LDL and HDL, to include
non-HDL-cholesterol, apoB, LDL particle size, and other deep stuff.
See Endo. Metab. Clin. N.A. 38: 1, 2009. One of many new risk factors is one's lipoprotein-associated phosopholipase A2,
which correlates directly with risk: Lancet 375: 1498, 2010. It's not clear
whether any of these will become "routine labs".
3. High blood pressure "which damages the intima". Review Lancet 345: 362, 1995.
4. Diabetes from any cause.
As a resident, I observed and was taught that when there is bad atherosclerosis
in the smaller arteries (i.e., the ones without names in the anatomy books),
there is usually diabetes. This is finally confirmed: Prog. Cardiovasc. Dis. 50:
112, 2007.
You'll read a tremendous amount about different effects of hyperglycemia,
insulin,
and so forth on
lipoproteins, protein chemistry, and so forth. Some classic
work (Science 258: 651, 1992) focuses on ADVANCED
GLYCOSYLATION END-PRODUCTS
("glycation products"), proteins
that have been non-enzymatically glycosylated (* Schiff-base --> Amadori product --> durable
fluorescent product). Binding of these to endothelium makes it permeable, they inactivate nitric
oxide, there are receptors for these substances which, when they bind, cause
cells to produce fibrous tissue, glycosylated LDL probably can't be
processed normally, etc., etc.
Once advanced glycation products have accumulated on board, runaway atherosclerosis
affects even diabetics who have been restored to euglycemia.
* Another idea: High blood glucose levels cause overexpression of CD36,
the LDL scavenger pathway receptor: Nat. Med. 7: 840, 2001.
The effects of physical exercise are numerous. Possibly "getting in shape" changes lipoprotein
receptor counts, etc., etc. However, contrary to popular mythology, people who are very physically
fit can and do still get serious atherosclerosis.
In the meantime, exercise capacity actually seems to be the best
predictor of not dying of cardiovascular disease: NEJM 346:
793, 2002.
And the famous step-two diet for improving LDL and HDL status actually fails
in men and post-menopausal women if they refuse also to exercise:
NEJM 339: 12, 1998.
Despite some pop claims, the "big four" (cholesterol, smoking, hypertension, diabetes)
still account for the vast majority of heart attacks: JAMA 290: 898, 2003.
6. A variety of biochemical lesions (hereditary, acquired) that promote thrombosis
NEJM 338: 79, 1998, lots more).
Not yet "official", it is probably at least as important a risk factor as diabetes.
7. Other heredity: Important. Currently being sorted out as a risk factor.
You already are familiar with familial hypercholesterolemia, in which there is a defective apoprotein
B-100 receptor (there are many different molecular variants), IDL's are not properly cleared by the
liver and become excess LDL instead, and the "good" receptor-mediated pathway of LDL uptake by
other cells is unavailable.
HDL is composed of A1 AND A2 APOLIPOPROTEINS.
It's been known for over a decade that transgenic mice with lots of A1 get much
less atherosclerosis; those with
lots of A2 paradoxically get more. Science 261: 469, 1993.
A mutated apoA-1 that causes severe atherosclerosis in humans: J. Am. College Card. 44: 1429 2004.
Insurers are now using various "complete" lipid profiles, including a directly-measured LDL plus HDL plus lipoprotein(a),
remnant lipids (IDL and small VLDL), apo-B, "small dense LDL" (a marker for the metabolic syndrome), "LDL pattern B".
In 2008, the much-promoted screen was "VAP", a marketer's eponym.
FAMILIAL COMBINED HYPERLIPIDEMIA, i.e., high VLDL's, high LDL's, low HDL's ("my triglycerides and LDL
both run high"), affects about 1% of folks and is a
major coronary risk (3-10x increase over baseline).
Patients are now considered a subgroup of the "syndrome X" family (more on this below)
since most show central adiposity.
The illness is obviously polygenic. It is expressed only in adults.
A mouse model has mutations at both apoprotein C-III and the LDL receptor (Science 275:
391, 1997). One human gene is apolipoprotein A2
(Nat. Gen. 18:
369, 1998.) Also watch cholesteryl ester transferring protein. * LPR6 (LDL receptor protein 6) is definitely worth watching;
severe mutants have elevated LDL and BP, diabetes, and coronary artery disease,
plus accelerated osteoporosis (Science 315: 1278, 2007).
* "LIPOPROTEIN(A)" (Lp(a))
is LDL with an apoprotein A attached. Levels seem to be
mostly genetic. These notes cited it a likely risk factor
for atherosclerosis during the 1990's,
and seems to have been forgotten for a while. By 2006,
the recommendation was against routine measurement (JAMA 296: 1363, 2006);
however, since it's now easy to measure, insurers are starting to screen ...
and now it does seem to be a real risk factor (JAMA 301: 2331, 2009).
* Common longevity mutation in cholesterol-ester transfer protein, which
produces abnormally large LDL's and HDL's: JAMA 290: 2030, 2003;
update JAMA 2008: 2777, 2008 (many alleles; correlation with vascular health
is real but weak); NEJM 361: 2518, 2009 (two of the alleles are strong risks).
Over the past twenty years, there have been a host of reports of other
putative genes placing one at risk for atherosclerosis. In 2007,
a huge study (in Kansas City!) examined 86 putative genes at 70 loci
and found only one (a fibrinogen variant) that was even nominally statistically
significant (JAMA 297: 1511, 2007).
American Heart Association on "genetics and genomics for prevention and
treatment of cardiovascular disease": Circulation 115, 2878, 2007.
The GOOD news is that these genetic factors (at least whichever ones are real,
as well as the havoc of hypertension) can be
more or less neutralized by lowering LDL levels, by whatever means (Science 272: 629, 1996; Br.
Med. J. 313: 1273, 1996).
8. LOW HDL AND ELEVATED FASTING TRIGLYCERIDES ("THE METABOLIC SYNDROME X").
Perhaps the HDL assay is most useful as a marker for the as-yet-poorly-understood
"metabolic syndrome X" or "insulin resistance syndrome", with hypertension, insulin resistance, low HDL,
high fasting triglycerides, truncal obesity and a serious coronary risk even
with normal LDL / total cholesterol.
This is a hot topic right now. Of course, the mainstay of therapy
is diet and exercise (weight loss is key: Am. J. Card. 87: 827, 2001).
Reviews Am. J. Epidem. 152: 897, 2000,
Am. J. Card. 84(1A): 11J, 1999;
Circulation 100: 123, 1999.
* Some fat in the liver, and elevated liver enzymes, is also typical:
QJM 92: 73, 1999; many have the infamous "non-alcoholic steatohepatitis"
that we'll study later.
* No one understands why, but people with the metabolic syndrome
also have more oxidized LDL: JAMA 299: 2287, 2008.
* Watch for
* There is talk about nicotinic acid being superior to statins for the metabolic syndrome,
but this does not seem to be affecting practice.
Remember that some of the antiretroviral therapies
cause the metabolic syndrome (especialy, redistribution of fat);
we may end up giving these people a growth-hormone releasing factor (NEJM 357: 2359, 2007).
9. Elevated levels of HOMOCYSTEINE.
Homocysteine can be elevated because of (1) an inborn error of metabolism, or (2) low intake of folic
acid, or (3) low intake of vitamin B12. People with the inborn errors get horrendous atherosclerosis early in life.
Most vegetarians have mildly elevated
serum homocysteine levels because of a relative B12 deficiency (Clin. Chim. Acta 326:
47, 2002; Am. J. Clin. Nutr. 78: 131, 2003;
Ann. Nutr. Metab. 46: 73, 2002). The traditional wisdom
is that vegetarians
have less, rather than more, atherosclerotic morbidity and mortality,
though this is not under intensive study recently.
There hasn't been a real paper in a decade.
The most recent review simply points out that people who
become vegetarians along "with comprehensive lifestyle changes"
can have atherosclerotic angina regress (QJM 92: 531, 1999).
Pure vegetarians with good genes
usually have total cholesterol less than 150 unless
they eat a lot of saturated vegetable oil (Am. J. Card. 83: 816, 1999).
Stay tuned.
Homocysteine, in turn...
There's now pretty good evidence that elevated blood homocysteine (as in folks who are deficient in
folic acid, which is still probably true for many Americans) is a major independent risk factor for atherosclerosis
(NEJM 332: 234, 1995; JAMA 281: 1817, 1999;
lancet 355: 523, 2000;).
and
a
prospective series (JAMA 275: 1929, 1996). Review for everybody: Am.
Fam. Phys. 56: 1607, 1997.
Among the homocysteine-challenged.... Making early atherosclerosis shrivel with B6 and folic acid
works: Lancet 355: 511, 2000.
Supplementing all post-MI patients with vitamin B12 and folate
reduces homocysteine and doesn't seem to hurt, but doesn't improve
vascular outcomes (JAMA 303: 2486, 2010 -- darn).
11. Being on a protease inhibitor for HIV infection ("dyslipidemia": NEJM 356:
1723, 2007).
* 12. Adult-onset growth-hormone deficiency. Now a robust finding.
Still poorly-understood and
hard-to-recognize, but supplementing seems to reverse the risk (J. Clin. Endo. Metab. 93:
3416, 2008).
NOTE: Despite all of the above, women are relatively protected from atherosclerosis until
menopause. Afterwards, their risk increases rapidly to equal men's. Post-menopausal estrogen is
protective (other bad press notwithstanding:
Ann. Int. Med. 135: 939, 2001), and the addition of progesterone does not remove this protection: NEJM 335: 453, 1996.
NOTE: People of Japanese ancestry, living in Japan,
have historically had relatively low risk for atherosclerosis. This has changed
dramatically over the past two decades (Arch. Int. Med. 160: 2297, 2000).
When they move to America and become Americanized, their risk approaches that of the rest of us.
NOTE: Finland and Scotland have slightly higher rates of atherosclerosis (reflected in rates of death
from ischemic heart disease). The United States probably ranks next, followed by the rest of the
"Western World", and far more than Japan or the poor nations.
When a third-world country develops rapidly, so does atherosclerosis (Atherosclerosis 153:
9, 2000).
NOTE: The French, with a very high-saturated-fat diet (that's part of why French cooking is so
good), have a relatively low rate of atherosclerosis. This is probably due to their tremendous alcohol
consumption; there was talk in the 1990's about
tannins in red wine inhibiting oxidation of LDL's
in the French. There could perhaps be something to this;
watch resveratrol (an anti-oxidant from grapes) as an anti-atherosclerosis compond.
NOTE: * Watch the impact of carotenoids and their close kin
in preventing atherosclerosis. Works for mice.... Circulation 103: 2922, 2001.
NOTE: The Inuit ("Eskimos"), who eat a lot of fat, are supposedly protected by omega-three fatty
acids.
NOTE: "No-cholesterol" dietary items are still LDL-raisers and supposedly
atherogenic if rich in saturated fat.
NOTE: After 1991, the coronary artery mortality in Poland plummeted.
Probably it's from a better diet, with more fresh fruits and vegetables
and vegetable fats
and less lard (BMJ 316: 1047, 1998).
NOTE: You can go nuts trying to keep track of which factors and their remediation affect, correlate
with, and "are associated with" which other factors, listed or rumored to be important in
atherogenesis. I am unpersuaded that "stress", independent of these other variables, is a significant
risk factor for atherosclerosis. (For a review of the claim that
the hormones produced by psychological stress slowly promote atherosclerosis,
see Lancet 370: 1089, 2007). However, higher serum epinephrine levels probably would increase a
person's risk of sudden cardiac death in a potentially rhythm-disturbing situation, all other things
being equal.
NOTE: I am still not aware of any reason to
believe that obesity is a major risk factor for atherosclerosis except insofar as it is related
to the above (i.e., high cholesterol from bad diet, smoking, hypertension, diabetes, lack of exercise, metabolic syndrome X).
Obesity (especially "central obesity" / "syndrome X type",
i.e., the dude's butt-crack shows over his beltline when he squats) produces
the hormone resistin, which renders muscle and liver resistant to the effects of insulin
and maybe does other things. Watch this one.
NOTE: Don't ask me to sort out the "trans-fatty acids are evil" prevailing wisdom.
The original synthetic trans-fatty acid was Crisco; however, there are a few
natural trans-unsaturated fatty acids as well.
The huge review in NEJM 354: 1601, 2006 is filled with multivariate
stuff on people and effects on molecules, but strangely there is only a single animal experiment,
only marginally relevant, cited.
And I could not find a single animal study focused on trans-fats in their diet -- ever!
The business is political. New York City banned
trans-fats from restaurant food (Ann. Int. Med. 151: 129, 2009 -- a
diner wouldn't be able to tell any difference.) The authors' claim that
trans-fatty acids cause 30,000 premature deaths in the USA each year
seems to come from thin air, as it does NOT appear in the NEJM article to which
it is referenced but is extrapolated from the assumption that because somebody's group of
Crisco-eaters had 30% high C-reactive protein.... well, you can understand
how difficult it is to sort everything out.
The much-discussed ongoing Nurses' Health Study could find an impressive
correlation between red-cell trans-fatty acid concentration and
atherosclerosis only in the upper quartile and didn't control for such obvious
things as obesity and lack of exercise; to be fair, there was a positive correlation
between total LDL cholesterol and trans-fatty acid levels (Circulation 115: 1858, 2007).
The recent big French study
couldn't find any clear effect of either synthetic or natural trans-fats
on lipid profiles or cardiovascular mortality in ordinary, non-hyperlipidemic folks
(Am. J. Clin. Nutr. 87: 558, 2008.)
Am. J. Clin. Nutr. 90: 88, 2009 refuted the claim that
trans-fats impair insulin sensitivity in overweight ladies.
Underclass kids have "reduced dietary quality" including eating a lot of
trans-unsaturated fats (surprise! J. Am. Diet. Assoc. 109: 1612, 2009)
and overall fats as well. Go figure. Given that gorging on Crisco-cooked
french-fries may run with other unhealthy habits, sorting everything out is
impossibile -- thankfully, nobody will miss trans fats except Crisco stockholders.
NOTE: I have never been impressed with isolated
fasting triglyceride levels as an independent risk factor (neither was the
NIH consensus panel JAMA 269: 505, 1993). Iron overload may also
be a risk factor maybe by oxidizing LDL
(yes! Circulation 96: 3300, 1997;
no! NEJM 330: 1119, 1994), the no's seem to have won.
Claims about coffee has repeatedly flopped;
in the most recent study, drinking either the real stuff or decaf
actually seems to protect (Am. J. Med. 148: 904, 2008).
The "baldness is an independent risk factor" article (JAMA 269:
998, 1993; even a bright kid could point out methodologic howlers) was sponsored
by the hair-restorer folks anticipating some
lawyer finding "a higher rate of MI's in people using hair-restorer".
NOTE: Consensus panel on lipid profiling (JAMA 269: 505, 1993) recommends screening
HDL-C along with routine cholesterol screens, but can't find much reason to check triglycerides or
consider them an independent risk factor.
CONTROVERSY: "Atherosclerosis as an infectious / inflammatory disease."
From time to time, people find what seem to be bits of microbes in atherosclerotic plaques and suggest the bugs are
etiologic. DNA sequences from various bugs get reported fairly often
in plaque debris. Immunofluorescence identifies antigens from these
bugs in the debris as well. Since many different "microbes"
have been identified in this way (including the very unlikely Helicobacter
pylori), and since the bacteria themselves are never convincingly
visualized, the obvious explanation is that the plaque grunge itself
soaks up whatever microbial debris may be in the bloodstream.
The CMV Correlating the presence of a microbe and severity of atherosclerosis
makes for an extremely easy "scientific study."
And these studies are driven by the hope that atherosclerosis might respond
to an antibiotic-based regimen as has worked so well for stomach ulcers.
A key difference is that everybody can see the bacteria in stomach ulcers, and
nobody can actually see them in atherosclerosis.
And a conspicuous lack of controls distinguishes
most of the "positive" studies I've seen.
For example, a handful of studies finding that people with helicobacter in their stomachs
get worse coronary atherosclerosis fail to control for tobacco smoking
and dietary habits. (We'll let you find this stuff on your own.)
Most recently the talk is about "infectious burden", i.e., the more different usual suspects that you're
making antibodies against, the greater your risk of dying of a heart attack
(Circulation 105: 15, 2002). The fact that the "usual suspects" now
include genital herpes
C-REACTIVE PROTEIN is still the subject of much
excitement, since serum levels in the absence of the acute phase reaction
seem to correlate with the extent of atherosclerosis in both humans and
animal models of atherosclerosis.
There's much talk about the "proinflammatory phenotype" (J. Clin. Endo. Metab. 90:
4549, 2005), i.e., the person who's likely to have high C-reactive protein levels in the
absence of obvious inflammation. Surprise! These people are older and
fatter, have higher triglyceride levels, higher insulin levels (i.e., insulin resistance), and
higher leptin levels -- all obviously involved with atherosclerosis. For some reason,
other acute-phase-reaction markers (fibrinogen, stimulated interleukin beta,
some more obscure proteins)
also average higher. People with a mutation that elevates C-reactive protein are not at extra
risk for atherosclerosis (told you so.... NEJM 359: 1897, 2008).
All this says to me is that there is some link between the C-reactive protein
system and lipid metabolism. The conclusion that people with atherosclerosis
harbor more smoldering infections hardly seems warranted.
Update on the molecules that are supposedly involved in "inflammation as a cause
of atherosclerosis": Circulation 109(S2):II-2, 2004.
I'm anything but impressed by the "lymphocytic infiltrates" that supposedly
abound in plaques, especially as they get worse. Somebody else will tell you
that "inflammation is usually what causes the plaques to rupture", which is hard to believe
given their strong propensity to rupture at times of hard physical or emotional
exertion -- a mechanical explanation would seem easier to believe.
Supporting your lecturer's skepticism is a single study that addressed the
obvious question. Mice with a genetic predisposition to atherosclerosis
get exactly the same lesions whether they are germ-and-virus free or have
the usual microflora (J. Exp. Med. 191: 1437, 2000.) No one has
repeated this work, and this fact alone tells me something about the whole
field.
NOTE: There are several situations in which development of atherosclerosis is
ACCELERATED. These
include
In these situations, "endothelial damage" and
"thrombosis" appear to be critical. Still helpful: Mayo Clin. Proc. 66: 818, 1991.
Okay, atherosclerosis is actually a pattern of injury.
{03473} atherosclerosis, in a vein graft
The innocent precursors: (anatomy: Am. J. Path. 143: 1444, 1993)
{11057} fatty streak
Don't worry about FATTY DOTS, lone macrophages with cholesterol.
Every toddler in the world probably has FATTY STREAKS, masses of lipid-rich foam cells (mostly
macrophages as this stage) in the intima. These impart a pretty two-tone appearance to the intima of
most everyone's aorta, without causing other problems. Most researchers now consider these
precursor lesions to common-type serious atherosclerosis.
Not yet explained: (1) Their distribution differs from serious plaques; (2) Their presence seems
unrelated to diet, etc., (3) They seem to regress later in life as fibrous plaques grow more severe.
We've got plenty still to learn about the pathogenesis of the fatty streak, but parts of the picture have
recently become clear.
Fatty streaks result from macrophages taking up LDL cholesterol, but the LDL (we think) must first be altered
to OXIDIZED LDL ("Ox-LDL", i.e., with its cholesterol and/or unsaturated fat peroxidated) taken up
by an exotic "Ox-LDL receptor" (cloned Nature 385: 73, 1997) on the macrophage surface, and
processed via the "scavenger pathway". The alteration can be brought about by endothelium or
smooth muscle.
The risk factors have little to do with fatty streaking, which is universal. Boys have more than girls,
blacks more than whites, it takes over maybe 30% of the surface by the teens.
The time bombs: Fibrous plaques
{11054} fibrous plaques Later in life (and it all depends on risk factors), a person develops
FIBROUS PLAQUES. These are masses
of cholesterol-rich cells
with an overlying FIBROUS CAP. There may be dystrophic CALCIFICATIONS,
extensive fibrosis and/or smooth muscle hyperplasia in the plaque, and some calcification.
Cholesterol-laden cells appear as FOAM CELLS; these are usually both of smooth
muscle and macrophage origin. When they die, there will be CHOLESTEROL
NEEDLES
(remember these?) and GRUMOUS DEBRIS. ("Grumous" is a charming near-synonym for "grunge", i.e.,
granular, semi-solid material.)
In acute coronary occlusion, angioplasty fails to establish re-flow
in up to 30% of cases. We now know that many of these people actually
have the grunge ("plaque gruel") released from the plaques by the
procedure, and this itself plugs the artery (Circulation 106: 1672, 2002).
* Watch "pregnancy-associated protein A", present in vulnerable
plaque, as a serum marker for having just ruptured one.
I predict this will prove to be of limited specificity for
coronary disease, since people with
generalized atherosclerosis often have a bare plaque somewhere
other than the coronaries. But see NEJM 345: 1057, 2001.
While we are talking about calcium...
"Chelation therapy" is an old "alternative treatment" for atherosclerosis.
The patient is given a calcium chelator, usually EDTA, by vein, and told that
this removes the plaques, which are supposedly
made primarily from calcium. This causes tingling
of the fingers (transient hypocalcemia) which the practitioner tell the patient is due
to improved circulation to the fingers. No need to belabor why this is nonsense,
and of course the empirical work has shown no effect on plaques. "Chelation therapists"
promote healthy lifestyles and perhaps they serve a useful function for this reason.
I believe that anyone practicing "chelation therapy" nowadays is knowingly deceiving the public.
In at least many cases, atherosclerotic lesions are monoclonal, suggesting that
Nowell's law / natural
selection operates in their pathogenesis. This isn't surprising, especially since (1) we now know that
oxidized-LDL is mitogenic for macrophages, and (2) the smooth muscle of
the aorta itself is made of large groups of clonal cells
(Am. J. Path. 152: 913, 1998). However, the old claim that each plaque arises from a
single cell has now been amply refuted.
Much work now indicates that progression from the fatty streak to the fibrous plaque is at least in
part the result of incorporation and organization of thrombi (* "the Rokitansky theory"). Most
fibrous plaques are rich in material that immunostains as fibrin (though this is absent from normal
artery or fatty streaks).
The distribution of the fibrous plaques is fairly predictable. Probably
because of increasing turbulence (farther downstream, and running up
against the iliac bifurcation), they increase
centrifugally in the aorta. They are especially common at bifurcations "where turbulence damages
the endothelium". Unfortunately, the carotid bifurcation and origin of the left anterior descending
coronary artery are favorite sites. Renal artery ostia are vulnerable, though the rest of the renal
artery is spared. Iliac arteries get it much worse than brachial arteries. The low-pressure pulmonary
arteries are almost never seriously affected; finding any plaques at all strongly suggests pulmonary
hypertension. The killers: Complicated plaques
{11060} the nasty stuff
As a person continues to be at risk for atherosclerosis, the plaques become
COMPLICATED. Any of the
following unpleasant things can happen:
Platelets, fibrin, or both accumulate wherever the endothelial cells are damaged or lost. Platelets
produce such factors as platelet-derived growth factor, transforming growth-factor beta, and others.
Fibrin makes endothelial cells migrate (rendering the surface permeable), causes vascular smooth
muscle to proliferate, presents a surface on which LDL may accumulate, binds the LDL variant
Lp(a) (i.e., LDL with a bound apoprotein A molecule) that accumulates in the plaque with the
fibrin, etc., etc. Fibrin degradation products also enhance vascular permeability.
There are three different lesions that can be seen beneath a coronary artery thrombus (J. Am. Coll. Card. 47: C13, 2006).
The thrombus can embolize if the artery is large, or plug the lumen if the artery is small (i.e., a
coronary or cerebral artery). This is probably the cause of a majority of myocardial infarcts and
cases of unstable angina pectoris.
If the "Rokitansky theory" is correct, the thrombus is even more likely to become incorporated into
the plaque, making it grow. For an update on thrombus formation on top of plaques, see Ann. Int. Med. 134:
224, 2001.
ENDOTHELIAL DAMAGE ALONE might result from "high LDL" (see above), a virus (seems doubtful), or shear
forces of flowing blood (plausible, since atherosclerosis is worse at bifurcations). As noted, the body
responds by accumulating lipids and monocytes with cell-derived growth factors causing smooth
muscle cells to proliferate. This probably begins the spontaneous atherosclerosis process.
CRACKING-FISSURING OF THE FIBROUS CAP (old review: Circulation 82(S II): II-47, 1990) leads to deposition
of at least a platelet layer, and often a real thrombus. There are often cracks in coronary arteries and
little thrombi even in patients dying of something other than MI.
If the injury reaches the MEDIA, the clotting cascade will surely be activated, smooth muscle cells
will migrate in, and fibrosis will occur. And thrombin appears to be mitogenic for smooth muscles cells
(either directly or indirectly).
Since atherosclerosis is a patchy process, it would seem reasonable to think that plaques exacerbate
local conditions that contribute to their own growth. Two such mechanisms could be thrombosis
and turbulent blood flow.
This is probably the second most common mechanism by which a coronary artery becomes
occluded.
{06524} lethal hemorrhage into a plaque in a coronary artery
The good news: It's reversible
In the regressed lesion, the intracellular lipid vanishes, the extracellular lipid where the cells have
died diminishes, the fibrous cap remodels and flattens, and the endothelial damage overlying the
fibrous cap heals. See Am. J. Card. 65: 33F, March. 20, 1990.
Not surprisingly, the reallly hard, calcified lesions are least likely to
regress (J. Am. Coll. Card. 49: 263, 2007).
For an update on plaque regression using statins, see J. Am. Coll. Card. 46: 106, 2005.
A similar, huge study: Am. J. Med. 118(S-12A): 22, 2005.
If you believe the "inflammation" model of atherosclerosis,
they you'll accept that "statins are the most effective
agents available today for the reduction of vascular inflammation (Circulation 109(S2):II-2, 2004 --
they do rapidly lower C-reactive protein levels independent of LDL levels, but
of course, they're not front-line for other inflammatory diseases);
whatever you decide, the statins do stop macrophages from making their own cholesterol.
This is now mainstream;
I predicted this in 1994.
* The "Pathobiological Determinants of Atherosclerosis in Youth Study"
(JAMA 281: 727, 1999) looked at people aged 15-34 and under who
died of unrelated causes, and found fatty streaks to be ubiquitous and
little fibrous plaques fairly common. Any pathologist could have showed you without
your having to spend any money, Uncle Sam. Accepting the study's conclusion
that "primary prevention of atherosclerosis must begin in childhood
or adolescence" requires us to make the dubious assumption that
today's harmless streak or bump
must be tomorrow's killer plaque, and that today's clean
coronary is far more likely to be clean in 30 years. Given the
suddenness with which severe atherosclerotic lesions appear (consider
the effect of female menopause) and regress (see below), that's
asking us to assume a lot. THINK! In the space below, review how each risk factor or intervention might work at the
molecular and chemical levels:
High LDL is bad
Cigaret smoking is bad
High blood pressure is bad
Diabetes is bad
An aspirin a day is good (HINT: Thrombi and platelets,
maybe "reduced inflammation") NOTE: Don't confuse atherosclerosis with the notable non-disease, MONCKEBERG'S
MEDIAL CALCIFIC SCLEROSIS (see below).
NOTE: Together, atherosclerosis, Monckeberg's, and the two kinds of arteriolar sclerosis listed
below are ARTERIOSCLEROSIS. In other words, avoid using that word altogether.
* NOTE: When diet and exercise fail....
Cholestyramine / colestipol: Binds cholesterol in the gut
Niacin: Decreased LDL and VLDL synthesis
Gemfibrozil: Enhances VLDL clearance
Statin family: Blocks cholesterol synthesis * Torcetrapib, a new would-be wonder drug that inhibits
cholesterol ester transfer protein, decreased LDL and increased HDL
marvellously, but had no effect whatsoever on atherosclerosis.
Puzzle that out. See NEJM 356: 1302, 2007.
MONCKEBERG'S MEDIAL CALCIFIC SCLEROSIS
Dystrophic calcification (sometimes even ossification) of the media of arteries, typically in older
adults.
This is a common, banal, pretty much harmless process. At worst, it can widen one's pulse pressure
due to decreased aortic compliance,
or make "radial artery blood-gas sticks" difficult and hazardous. It may be visible
on x-ray.
Despite the term "medial", the internal elastic membrane is always calcified
(settled Arch. Path. Lab. Med. 132: 47, 2008).
* Evidently the smooth muscle cells produce at least four proteins that indicate
they want to make bone. You can read about it in Circ. 100: 2168, 1999.
ARTERIOLAR SCLEROSIS ("arteriolosclerosis")
Three processes that narrow the lumens of the small arteries and arterioles in some or all of the
body
INTIMAL FIBROSIS or (better) "fibroelastic hyperplasia" (and some call it "intimal sclerosis"),
is the slow buildup of fibrous tissue (usually with some layers of elastic)
in the intima of a small artery. It's a part of aging, and is exacerbated
by high blood pressure. It involves smaller arteries (rather than
the larger ones, as in
atherosclerosis) and doesn't feature the lipid buildup. It also spares
the arterioles. The most familiar form is the damage
to the small arteries of the kidney seen in longstanding high blood pressure.
HYALINE ARTERIOLAR SCLEROSIS: slow buildup of basement-membrane type material, eventually
obliterating the cellular structure of the wall and narrowing the lumen.
Mostly the arterioles are involved.
The most common place where
we see this is in the arterioles of the kidney in high blood
pressure and diabetes.
However, it turns up often, and can appear anywhere. The most familiar causes are
No one really knows why any of these causes "hyaline arteriolosclerosis", but the
anatomic pathology is impressive.
Hypertension is the least potent. The effects on tissue perfusion, and probably on the sympathetic
regulation of blood pressure, are not salutary.
Future pathologists: Look in the fat just outside the adrenal capsules to get a good idea about the
extent of systemic hyaline arteriolosclerosis. Lots of hyaline change of the small arteries here is a
great marker for longstanding hypertension. "Binswanger's encephalopathy" is a dread,
Alzheimer-like dementia caused by hyaline arteriolosclerosis of the brain.
If you like, you can consider amyloidosis of small arteries, which hyalinizes
but is less likely to cause much stenosis,
to be a form of it. No one will argue or care.
{11777} hyaline arteriolar sclerosis
HYPERPLASTIC ARTERIOLAR SCLEROSIS: Concentric, often rapid proliferation of the intimal (or sometimes smooth muscle) cells
of an arteriole.
"Onion-skin
arteriole".
Fortunately uncommon. The causes are
{39559} hyperplastic arteriolar sclerosis in pulmonary hypertension
Note that all these are processes that specifically damage the intima of vessels, which
presumably
undergo hyperplasia in response. This is a much more aggressive process. (You could think of it as
a callus of the endothelium.)
Note that any of these processes can be severe enough to cause some necrosis of the vessel.
Malignant hypertension is usually this severe.
Don't confuse either of these processes with the inexorable FIBROUS
THICKENING OF THE INTIMA OF SMALL ARTERIES in mild hypertension and normal aging. This is so common and so important that
IT DOESN'T HAVE A NAME BEYOND "INTIMAL FIBROSIS".
TRANSPLANT VASCULOPATHY is a concentric fibrous thickening, mostly confined to the intima, in
allografts (heart, kidney, liver, others) that have survived for a long time; the process develops rather abruptly, and while
immunity must be a factor, it cannot be the only explanation. See Am. Heart. J. 129: 791, 1995.
THE VASCULITIS FAMILY (update Am. J. Clin. Path. 124(S): S-84, 2005)
POLYARTERITIS NODOSA
Due to hepatitis B infection (antigen-antibody complexes), anti-myeloperoxidase disease ("anti-neutrophil cytoplasmic
antibody disease", now distinguished from "true polyarteritis nodosa"), or "idiopathic".
The principal discussion of polyarteritis nodosa,
Wegener's, and their family comes under immunopathology.
Remember
classic polyarteritis nodosa as an important cause of infarcts
anywhere in the body except lung.
LEUKOCYTOCLASTIC VASCULITIS
Generally type III immune injury of the venules, often diagnosed on skin biopsy (the patient has
"palpable purpura"). Common, but infarcts and serious damage are fortunately rare.
"Leukocytoclastic" refers to the dead neutrophils lying about, visible as nuclear dust.
{14284} leukocytoclastic vasculitis
Mostly this results from taking medicines. Less common causes are cryoglobulinemia (how?), lupus
and its kindred, and the antigenemia of HBV and malignancy.
WEGENER'S GRANULOMATOSIS
You know anti-proteinase 3 disease. Lung cavities, segmental necrotizing glomerulonephritis with crescents,
and/or vanishing nose, all most likely with granulomas.
CHURG-STRAUSS DISEASE {38497} old burned-out Wegener's, without good granulomas
TEMPORAL ARTERITIS ("cranial giant cell arteritis",
when elsewhere "giant cell arteritis")
A disease of older folks, mostly over 60 (nobody's immune), still of unknown etiology, in which the macrophages seem to
become
angry with the internal elastic membrane of the arteries of the external carotid system.
"Jaw claudication" (tired jaw on chewing) is a picturesque syndrome, but sudden blindness (the
dread complication) is a catastrophe. Despite the conventional wisdom
that the vertebrobasilar and internal carotid systems are not involved
much, one group found that around 3% of biopsy-proven "temporal arteritis"
patients had a stoke between the onset of symptoms and the initiation
of glucocorticoid treatment (Medicine 88: 227, 2009).
Many of these patients also suffer from pain and weakness in the muscles, the distinctive
POLYMYALGIA RHEUMATICA. Future clinicians: The diagnosis is supported by finding everything
normal on physical exam except perhaps for tender temporal arteries, plus normal labs except for a
high "sed rate".
Only recently has it become clear that there is systemic overproduction of
interleukins 1 and 6 for some reason, and activation of macrophages in the vascular intima.
There is still a great deal that' s unknown (Ann. Int. Med. 139: 505, 2003).
Prove your diagnosis with a temporal artery biopsy, which may or may not show granulomas on the
inner elastic membrane. There is also a striking non-granulomatous fibrous
proliferation of the intima.
When in doubt, treat with prednisone or some similar glucocorticoid. * A variant involves the female genital tract (South. Med. J. 98:
469, 2005).
Polymyalgia rheumatica can occur in young people and/or in
the absence of elevated sed rate (Arch. Int. Med. 157S:
317, 1997). When in doubt, treat.
* Future pathologists: Biopsies remain positive even after several weeks of glucocorticoid
therapy (Br. J. Ophth. 86: 530, 2002).
{22095} temporal arteritis
TAKAYASU'S PULSELESS DISEASE ("aortic arch disease", etc.)
A fortunately-rare, idiopathic disease of younger adults (almost always) in which the aortic arch and
its great branches thicken and their ostia become stenotic, strangling off blood flow to the upper part
of the body.
No one knows the cause, and the histology is nonspecific, with granulomas, lymphocytes, plasma
cells, and so forth, in addition to the fibrosis and contraction.
* The molecular biology of temporal arteritis and Takayasu's
is evidently similar. What's known: NEJM 349: 160, 2003.
More on Takayasu's and temporal arteritis as a continuum: Medicine 88: 183 & 221, 2009.
Watch
for aspirin to be added to the glucocorticoid regimens, to prevent
platelet-related intimal fibrosis in both diseases.
Whatever the real cause, surgical repair of the involved arch and branches
is now giving excellent results (Ann. Thor. Surg. 81: 178, 2006).
On medical therapy, or when surgery is not possible, the long-term prognosis
is generally not good (Arth. Rheum. 56: 1000, 2007).
{48983} Takayasu's
COGAN'S DISEASE is another thankfully-rare
disease usually affecting young adults. It features abrupt onset of nerve deafness,
interstitial keratitis (you'll see it only on a slit lamp exam), and/or a systemic vasculitis often with aortic aneurysm
formation. It's evidently caused by an autoantibody against inner ear and endothelium
(Lancet 360: 915, 2002).
KAWASAKI'S DISEASE ("mucocutaneous lymph node syndrome";
Ped. Clin. N.A. 46: 313, 1999; Am. Fam. Phys. 59:
3093, 1999; Lancet 364: 533, 2004; Heart 95: 787, 2009)
A febrile disease that resembles adult polyarteritis nodosa histologically but occurs in babies and
toddlers, mostly of Japanese ancestry (no matter what country).
The fact that almost all patients are around 2-5 years, the fact that occasionally
an older child or adult gets the disease, the fact that there are outbreaks,
and the fact that babies don't get it
as long as they have maternal antibody all tell me the cause is an unidentified, ubiquitous virus.
You'll want to see five of these six signs:
Most patients are of Japanese of Korean ancestry, regardless of where they live,
but no HLA links are found.
The most serious concern is coronary vasculitis, which causes myocardial infarcts. Healing can
produce coronary aneurysms, etc. See Arch. Dis. Child. 87: 145, 2002.
* By electron microscopy, the endothelial cells are separated and perforated,
rendering them hyperpermeable; again, no one knows why
(Circulation 105: 766, 2002).
We treat Kawasaki's with aspirin and intravenous immunoglobulin. The
outcome is good unless coronary disease becomes apparent.
A disease of
smokers, usually young men,
in which the small neurovascular bundles in the extremities
become inflamed and undergo thrombosis.
No one has a clue as to the real etiology, beyond the link to
tobacco
smoking. It's also an ultra-rare complication of marijuana
smoking (Br. J. Derm. 152: 166, 2005). The typical patient,
after losing all his fingers, holds his cigaret between his last two toes. Not a pretty sight.
The prognosis is hopeless unless the patient stops smoking.
The anatomic pathology remains poorly worked-out. Neutrophils touching
giant cells within thrombi is supposed to be characteristic.
The most recent study
(Virchows Archiv 436: 59, 2000) found instead that an intact
internal elastic membrane, fibrosis much worse in the adventitia than
anywhere else, endothelial swelling in the vasa vasora, and onionskinning
of recanalization vessels were most helpful.
INFLAMMATORY AORTIC ANEURYSM (JAMA 297: 395, 2007)
The overwhelming majority of patients are smokers. Otherwise, the etiology
is unknown. I predict that the molecular cause of Buerger's and
inflammatory aneurysm will be found at the same time.
Unlike classic atherosclerotic aneurysms, the outer surface is shiny-white with
prominent little vessels,
and usually there are fibrous adhesions to the nearby structures.
The histopathology is intense inflammation and fibrosis of the adventitia.
INFECTIOUS ARTERITIS
Rickettsial disease, syphilis Worth mentioning here: A MYCOTIC ANEURYSM is a spot at a branch-point of an artery where a septic
embolus (usually) has lodged and set up an infection, weakening the wall. ("Mycotic" is an
unfortunate misnomer, since fungi aren't usually the culprits.)
RAYNAUD"S DISEASE / PHENOMENON
Spasm and occlusion of the arteries supplying the fingers, which turn white ("pallor"), then red ("suffusion"),
then blue ("cyanosis").
Triggered by cold weather, it's most often idiopathic; known causes range from vasculitis syndromes
to operating jack-hammers.
Scleroderma patients and some others have this process greatly exacerbated by hyperplastic
arteriolar sclerosis in the digital arteries.
If it's a bother, get out the calcium-channel blockers, and/or a nice warm pair of gloves.
{24503} Raynaud's
Long-mysterious, it's now pretty clear that it's a small-fiber
neuropathy (Arch. Derm. 139: 1337, 2003; Brain 126: 567, 2003;
update Anes. Anal. 104: 438, 2007).
The red color of affected body parts probably results from
opening of arteriovenous channels and closure of precapillary
sphincters.
Lack of nutritive blood flow contributes to the pain,
while the excess non-nutrative blood flow causes a burning
sensation.
There's a hereditary form with mutated neuronal sodium channels (Neurology 67: 1538, 2006),
and it is possible that the adult acquired form results from
autoantibodies against this channel (Am. J. Med. Sci. 335: 320, 2008).
These patients present a major pain-management problem -- Mayo's has a series
(Arch. Derm. 144: 1578, 2009).
ATHEROSCLEROTIC AORTIC ANEURYSMS
ATHEROSCLEROSIS often causes aneurysms,
usually distally in the aorta, above the level of the iliacs.
When the abdominal aortic diameter exceeds 3.0 cm, it's an aneurysm.
Exceed 5 cm or so and it's likely to burst (retroperitoneally, intra-peritoneally, intra-duodenal), with
(usually) lethal consequences. Patients may complain first of back pain, etc. Aneurysms are always
lined by thrombus (why?), which sometimes embolizes. Iliac aneurysms are also common; basilar
artery aneurysms seldom rupture but may compress important things.
Occasionally these get infected; the usual bug is salmonella (Am. J.
For. Med. Path. 23: 382, 2002).
* Albert Einstein's physicians knew he had an aneurysm, but when it burst, they got focused on his
gallbladder instead. He died as a result.
{03665} atherosclerotic aortic aneurysm
SYPHILIS It's hard to follow the argument that a proximal aneurysm is always luetic.
Nowadays, syphilis is very rare, and atherosclerosis is common. I wouldn't assume an
ascending
aortic aneurysm is luetic unless the arch is free of significant atherosclerosis.
* "Tree-barking" is just stretch-marks of the aorta. The only reason this is supposed to be
"more typical of syphilis than atherosclerosis" is that, in atherosclerosis, the intima is already
distorted by the atherosclerotic plaques. I know this, because in my several cases of Marfan-style
dilatation of the aortic root, there's always been tree-barking.
{10224} syphilitic aneurysm
AORTIC DISSECTION
DISSECTING HEMATOMA, often miscalled "dissecting aneurysm", is blood
that has entered the wall of
the aorta and is following a weak plane ("cystic medial necrosis",
actually there are no cysts and no
necrosis, just diminished elastic and maybe a little extra mucoid goo).
This catastrophe results in progressive compromise of arteries, backwards rupture damaging the
aortic valve and/or coronary ostia, or further backwards rupture into the pericardial sac or pleural
space.
Patients experience a "ripping", agonizing chest pain as the false lumen expands. Michael
DeBakey's claim to fame is having classified and devised the surgical treatment for these people.
Otherwise, the patient's only hope is to have the blood re-enter the lumen, establishing a "double-barrel aorta", with the false
lumen eventually becoming covered with normal endothelium.
Marfan types are more prone to this lesion, but nobody's immune. An epidemic of dissecting
aneurysms occurred among turkeys who acquired lathyrism after eating beta-NH2-propionitrile in
sweet peas.
* The most spectacular multiple aneurysms in medicine are perhaps seen in the
Marfan-like Loeys-Dietz syndrome, caused by a mutation in one or the other receptor
for transforming growth factor beta (Nat. Genet. 37: 275, 2005).
Minor variants, with limited extension of a bleed into the aortic wall or down
around the root, also exist. These may or may not turn into the fully-expressed, deadly disease.
Trauma to the aorta (for example, a car wreck) or another major artery
(infamously, the vertebral arteries in a very bad neck manipulation)
can cause dissection of blood down a torn media.
"Spontaneous"
dissection of arteries in the neck can cause stroke in young people (NEJM 330: 393, 1994).
Non-surgical management using a stent-graft: NEJM 340: 1585, 1999 (wow!).
{17467} dissecting aneurysm
CORONARY ARTERY DISSECTION is thankfully rare. For some reason,
it most commonly occurs after childbirth.
VEINS
VARICOSE VEINS
A self-perpetuating process caused by loss of competency in the leg vein valves and support
structures.
We lose our elastic fibers as a result of aging, or blow out valves (by getting fat, having babies,
straining at stool, standing up doing surgery). The tendency to get varcose
veins is hereditary.
The weight of the column of blood doesn't make life easier for the next valve or the support of the
next few cm of vein. Get elastic leg wraps and hope for the best. If it gets too hard to pump blood
back to the heart by way of the veins, or the weight of the column of blood causes continuous micro-hemorrhages, you will see
the familiar hemosiderin STASIS PIGMENTATION and/or ischemic
STASIS ULCERS.
Stasis ulcers themselves are a very common, very hard-to-treat problem
of older folks. Older explanations ("the poor circulation produces hypoxia")
are being supplemented by new work (the weight of blood causes capillaries to
rupture, with red cells and plasma proteins being extravasated, with
local cytokine activation; Surg. Clin. N.A. 83: 671, 2003.) This fits with there usually being pigmentation
here, and with the accompanying local fibrosis (lipofibrosclerosis).
Fortunately, thrombi that may form in varicose veins very seldom embolize.
THROMBOPHLEBITIS ("trombone fleabites", better "phlebothrombosis";
reviews Lancet 353: 479 & 1167, 1999)
Thrombosis of a deep vein, most often in the leg. You're already familiar with the causes, and the
dread complication (pulmonary embolus). Usually, pain and swelling result, hence "-itis".
Vicious variants include MILK LEG ("phlegmasia alba / cerulea dolens", thrombosis of the iliac vein,
around the time of parturition), BUDD-CHIARI SYNDROME (thrombosis of the hepatic veins) and
DURAL SINUS THROMBOSIS.
TROUSSEAU'S MIGRATORY THROMBOPHLEBITIS affects first one vein, then another. The cause is usually
cancer of the pancreas, less often another adenocarcinoma.
SUPERIOR VENA CAVA SYNDROME
From occlusion, usually from extrinsic compression by lung cancer.
Patients have dusky skin in the head, upper extremities, and upper chest.
"SVC syndrome" can cause a bad
headache just from the markedly increased venous pressure.
INFERIOR VENA CAVA SYNDROME
From occlusion, usually by cancer in para-aortic lymph nodes.
Patients have dusky lower bodies and unusual patterns of collateral circulation.
LYMPHATICS
LYMPHANGITIS Inflammation of lymphatics, usually by a bacterium that's good at invading them (i.e.,
streptococcus LYMPHEDEMA
Compromise of lymphatic draining of the extremities and/or genitalia. The most important causes
are cancer of the cervix, filariasis, iatrogenic (i.e., after the overly-zealous old mastectomies),
autosomal dominant ("Milroy's disease", the lymphatics don't form properly), or "idiopathic" (again,
sometimes the lymphatics don't form properly). Turner's girls often have lymphedema of the hands
and feet.
If there's hyperplasia of the overlying epidermis, it's ELEPHANTIASIS.
"Massive localized lymphedema" looks clinically and microscopically
like a sarcoma, but results from lymphatics obstructed by masive obesity
(J. Clin. Path. 62: 808, 2009).
TUMORS OF BLOOD VESSELS
The cell of origin is the endothelial cell.
When the vascular origin of a tumor isn't obvious,
we confirm the diagnosis using immunostains (von Willebrand's factor, CD31, CD34);
old-timers found Weibel-Palade bodies in the
endothelium on electron microscopy.
HEMANGIOMAS
Mostly hamartomas. You'll see a variety of these clinically.
* Future pathologists: There are some rare, exotic tumors of blood
vessel origin. Don't worry about them.
CAPILLARY HEMANGIOMAS (little vessels) and CAVERNOUS HEMANGIOMAS (big vessels "resembling erectile
tissue") are common on the skin. STORK BITES (backs of the neck and/or forehead of a baby)
usually involute (i.e., thrombose and organize) after a
few years, while CHERRY ANGIOMAS of the skin start popping up after age 20 or so.
{05888} hemangioma
PORT-WINE STAIN (one form of "nevus flammeus"), fashionable in the Gorbachev era, can be treated by
laser if the patient wishes. A hemangioma in the meninges (bad, shunts blood away),
generally with an overlying port-wine stain in the V1 area (or check the eyelids; Pediatrics 87: 323,
1991), is STURGE-WEBER syndrome.
{53705} Sturge-Weber
PYOGENIC GRANULOMA (noted misnomer; neither pyogenic nor a granuloma) pops up the gums of
pregnant ladies, or the skin of anybody. Grossly, it looks like a rotten cherry and bleeds
very easily. Microscopically, it
looks like granulation tissue.
{13141} "pyogenic granuloma"
* EPITHELIOID HEMANGIOMAS are curious bumps of small
vessels surrounding a single large one; the connective tissue between
the vessels is packed with eosinophils.
* PAPILLARY ENDOTHELIAL HYPERPLASIA is just an unusual way
way for a thrombus to organize. Endothelial cells make little papillae.
The lack of anaplasia distinguishes it from an angiosarcoma.
Large hemangiomas can consume a person's platelets, the serious
KASABACH-MERRITT SYNDROME (Am.
J. Clin. Path. 99: 628, 1993; a kid received 6622 units of platelets over 19 months, a new record;
Am. J. Med. Sci. 333: 293, 2007 disseminated angiosarcoma).
{12237} Kasabach-Merritt giant hemangioma
KLIPPEL-TRENAUNAY SYNDROME is a huge capillary hemangioma plus
enlargement-deformity, always from a somatic mutation (* gene VG5Q: Nature 427:
640, 2004). A single extremity (or perhaps more than one) is involved.
Mayo Clin. Proc. 73: 28, 1998. VON HIPPEL-LINDAU anti-oncogene deletion syndrome results from mutated VHL. It features the most
troublesome hemangiomas in all of medicine, as well as renal cell carcinoma.
GLOMANGIOMAS (glomus tumors)
Painful tumors of the smooth muscle of the vestigial human GLOMUS organs, little thermoregulatory
left-overs from mammalian evolution and found in the fingertips, toes, and coccyx (the rat's tail is
the most familiar glomus).
{09017} glomus tumor
TELANGIECTASIS
"Dilatations of the ends of little vessels".
OSLER-WEBER-RENDU TELANGIECTASIAS ("hereditary hemorrhage telangiectasia") result from any of several autosomal dominant genes (* some,
but not all, patients lack a binder for transforming growth factor beta). Patients have little vascular
malformations connecting little arteries and little veins along their whole GI tract (often easiest to see on
the lips, of course), and often lots of other places. These are prone to bleed. Reviews NEJM 333:
918, 1995; NEJM 345: 325, 2001 (* many of these patients also have
"idiopathic pulmonary hypertension", also from faulty vascular development; depends on the allele).
The familiar "liver spider" is a centrally dilated artery supplying several little arterioles
that
blanch when the "spider's body" is pressed.
CANCERS OF THE BLOOD VESSELS
HEMANGIOENDOTHELIOMAS are low-grade cancers of endothelium. They makes little vessels. Leave
the diagnosis to the pathologists.
(HEM)ANGIOSARCOMAS (Arch. Path. Lab. Med. 133: 1804, 2009): A host of aggressive cancers. Best-known is epidemic hepatic angiosarcoma,
caused by exposure to vinyl chloride or "Thorotrast" contrast medium.
Hopefully that's rare today, but occcasionally sun-exposed
skin develops angiosarcomas. At other sites, they often
follow therapeutic radiation. Update Arch. Path. Lab. Med. 133: 1804, 2009.
Angiosarcomas are treacherous, especially to pathologists, and often look
deceptively benign. There may
be little or no anaplasia. Any "hemangioma"
that isn't nicely circumscribed should raise the suspicion of angiosarcoma.
* Don't worry about the hated "atypical vascular lesion", the super-low-grade
angiosarcoma that arises in the papillary dermis.
{10863} hemangiosarcoma
HEMANGIOPERICYTOMAS: Low-grade cancer of the pericytes. As you'd expect, the tumor cells interlace
with vessels, beautifully demonstrated in reticulin-stained preparations. Again, leave the diagnosis
to the pathologists.
{09484}* hemangiopericytoma. This is subtle.
KAPOSI'S "SARCOMA: The business cell is endothelium, and it can spread and choke off the viscera.
The cause, of course, is herpes virus 8 Classic American Kaposi's of the pre-AIDS era mostly involved the legs of older men, and seldom
caused major problems.
Epidemic non-AIDS related Kaposi's is a disease mostly affecting young men in
central Africa. It's
more aggressive than classic Kaposi's, but not so much as in AIDS-related Kaposi's.
Renal transplant patients are prone to yet another Kaposi's variant.
LYMPHANGIOMAS: Hamartomas. The best-known is "cystic hygroma" of the necks of babies.
{23443} lymphangioma
LYMPHANGIOSARCOMAS: Cancers of the lymphatics, generally arising in lymphedema (i.e., after
mastectomy, called * "Stewart-Treves syndrome") or after exposure to radiation.
HIGH TECHNOLOGY
ANGIOPLASTY is surely familiar to you.
What has helped most in preventing these problems is the
placing of metal stents.
* After thirty years of "study" in the U.S., evidence that acupuncture
actually works for ANY disease of the cardiovascular system remains
conspicuous by its absence. The best available is that some hypertensives'
blood pressure drops some while they are actually in the mellow, comforting
acupuncturist's
office, only to return to their usual levels when the treatments are
over (Circulation 103: 2038, 2001). A major recent study at and near Harvard
(SHARP -- Stop Hypertension with the Acupuncture Research Program) has
been undertaken, using sham acupuncture for controls (Cont. Clin. Tri. 25:
76, 2004); I predicted in 2004 that it would not publish positive results,
and judging on the data (Hypertension 48: 838, 2006) it was a total failure
in every category. It's to the great credit of the New England School of
Acupuncture, which did a lot of the work, that they were up-front about the
whole thing.
* "How many miles of blood vessels are there in a pound of fat?" People
write me about this every once in a while. Let's figure it out. Assume an
adipocyte is 50 microns across; it'll vary from 10-100 depending on how fat
the person is. The fatter you are, the less vascular is your fat, which is one
more reason that this whole inquiry is silly.
In a section of body fat, which I examine often enough under the microscope,
the capillary (there has to be at least one) that supplies each fat cell is not
usually visible, so I'll assume one per adipocyte, and all going in the same
direction.
Put a single capillary between each pair of fat cells and
that's about 20 capillaries per millimeter, or about 500 capillaries per inch,
or 250,000 capillaries per square inch.
Assume a pound of fat is a cube 4" on a side, which is good enough
for junk science, or 16 square inches, and that is 4,000,000 capillaries
running through the cube, 16,000,000 inches. There are 12 inches in a foot
and 5280 feet in a mile, so if you get 500 miles you did the arithmetic
the same way that I did.
If you prefer 100 miles as in other estimates, simply assume
that there's a capillary between every other pair of adipocytes, rather
than every pair.
That this question is fundamentally wrong-headed can be understood
by anyone who considers whether moving a certain total number of cars through Kansas City would be easier
with more highways or fewer highways. Further, the vast majority of these capillaries
are completely closed at any moment during your life, and not carrying
any blood. At autopsy, blood usually dribbles from other organs but not from fat.
At surgery, other organs bleed plenty but fat barely bleeds.
The real question isn't, "How many extra miles of blood vessels?",
but "How much rougher is it on my heart to be fat?" Think about walking around
carrying 100 lb of weights everywhere you go. The truth is that "education"
and moral exhortation do not cause people to lose weight; overeating is
programmed just like scratching when you itch.
{03184} tricuspid valve, normal
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about
heart pathology
to consult these standard textbooks.
In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!
Ed says, "This world would be a sorry place if
people like me who call ourselves Christians
didn't try to act as good as
other
good people
."
Prayer Request
Teaching Pathology
Kidney
ERF/KCUMB
* Philologists: "Atheros" means "gruel", "porridge", or "grits".
Think about blobs of 7-day-old dried buttery
Malt-o-Meal lining a dirty sink, and you have a pretty good
image of atherosclerosis.
smoking, "which damages the intima".
Angiotensin II itself is now one of the "usual suspects"
in discussions of molecules that mediate atherogenesis: Am. J. Med. Sci. 323:
17, 2002.
It's been reported that giving the soluble form of the glycation product
receptor removes the products and suppresses accelerated atherosclerosis.
See Nat. Med. 4: 1025, 1998. Stay tuned.
5.
Lack of exercise (made "official" in 1992), independent of the above (NEJM
330: 1565, 1992).
* Couch potatoes wishing to increase the numbers of LDL-receptors
without exercising may benefit from a new class of drugs that
bind to the sterol regulatory element-binding
protein cleavage-activating protein (Nature Med. 7: 1332, 2001).

Apo-A1 seems to have the most to do with removal of cholesterol from membranes.
This is by now quite well-established (Am. J. Card. 91 12E, 2003.
There's even been talk of using A1 instead of HDL as your measure of "good"
cholesterol (Arch. Path. Lab. Med. 121: 678, 1997), but so far it remains
a research topic (Circulation 97: 1784, 1998) Thie may change.
The biochemical lesion is overproduction of apo B in the lipoproteins
(review J. Clin. Endo. Metab. 89: 2601, 2004).
TANGIER DISEASE is an autosomal recessive disease
in which patients have near-zero HDL levels, low LDL levels,
and extensive deposition of cholesterol esters in the tissues.
Patients have orange
tonsils, a neuropathy, and precocious atherosclerosis. Even heterozygotes
have many foam cells, low HDL's, and perhaps increased coronary risk.
Gene (ABCA1) and syndrome:
Nat. Genet. 22: 352, 1999; the missing protein is responsible
for taking cholesterol to the surface of cells to be carried off
by apo-A-I. There is also a dominant low-LDL syndrome
at this locus
("familial hypoalphalipoproteinemia, possibly also an atherosclerosis risk:
Lancet 354 134, 1999). Update on the many alleles here that influence
health even in heterozygotes: JAMA 299: 2524, 2008.
* Rimonabant, the diet pill that blocks the cannabinoid type I receptor
(the one that gives stoners the munchies) for the metabolic syndrome ("and it
raises HDL-C and lowers glycosylated hemoglobin too!"):
JAMA 299: 1547, 2008.
* My prediction's coming true... using adiponectin and its oligomers
to determine whether metabolic syndrome is present seems to work
(Am. J. Clin. Path. 129: 815, 2008; ongoing questions J. Allerg. 121:
326, 2008). This won't replace the
physical exam and labs, but supports the idea that this hormone is key.
10. Chronic kidney disease. Hard to sort out from the others,
but probably real (Am. J. Kid. Dis. 49: 8, 2007.)
* Even a common, mild mutation in methylenetetrahydrofolate reductase
is a serious risk factor for atherosclerosis: Circulation 99: 2361, 1999.
* The mechanism by which estrogens protect remains obscure.
One idea is that estradiol greatly up-regulates FasL expression on endothelium,
which keeps out the inflammatory cells: Circulation 104: 2576, 2001.
You will be told that that micro-organisms
cause atherosclerosis, both by acting at the sites of the lesion or
and by "increasing the total body burden of inflammation."
Your lecturer does not believe this is true. You can decide for yourself, of
course, but here are the facts.
-causes-atherosclerosis flap of the 1980's came to nothing.
In the 1990's it was
chlamydia-in-your-plaques (J. Inf. Dis. 175: 883, 1997;
negative study Br. Med. J. 318: 1035, 1999, J. Am. Coll. Card. 41: 1482, 2003;
two more Br. Med. J. 321: 204 & 208, 2000).
Even the proponents admit the case is hardly made: JAMA 288: 2724, 2002. The inflammation
in plaques hardly resembles what you see in
trachoma
,
psittacosis
,
lymphogranuloma venereum
or other known chlamydial illnesses -- these display spectacular proliferation
of lymphoid germinal centers and abundant plasma cells, and/or suppurating
granulomas.
Chlamydia are easy to see in the illnesses they obviously cause,
but in atherosclerosis the actual organisms (rather than just their DNA
or antigens) remain incredibly elusive.
The most recent sighting is Acta. Biol. Hung. 86:
233, 2005 and the "chlamydia" were calcified and of varying sizes ... just as
in classic dystrophic calcification without any organisms.
Draw your own conclusions.
and stomach helicobacter invites the idea that
old folks who are sicker are more likely to have polyclonal B-cell activation, which is simply
common sense.
In animals, C-reactive protein is found in the plaques between the cells in all stages
of their development (co-localizing with apolipoprotein B), and seems to be soaked up from the plasma
(Am. J. Path. 167: 923, 2005). In turn, I wonder whether it's perhaps being produced
in the plaques, explaining the elevated levels. Stay tuned.
{06581} atherosclerosis after radiation
{25024} fatty streak
{41533} foam cells
Despite all the current excitement about "inflammation as the cause of atherosclerosis",
the inflammatory cells (T-lymphocytes)
are usually found only as a few insignificant-looking, inactive-looking
little clusters at the edges of the plaque.
Marvels of technology: Today's intraluminal ultrasounds and MRI's have reminded
clinicians of the existence of soft, mushy cores of plaques. These are now
called VULNERABLE PLAQUE or HIGH-RISK PLAQUE or THIN CAP FIBROATHEROMA, i.e., where you're likely
to have a rupture
or bleed, as opposed to fibrous stuff which isn't
going to rupture or bleed. MRI's: Am. J. Card. 88(2A): 42E, 2001;
J. Am. Coll. Card. 47(S8): C13-8, 2006.
Coronary graft vascular disease
Pittsburgh Pathology Cases
* I've always taught that laminar flow is atheroprotective,
and now the molecular biology seems to be emerging (lots and lots of molecules
involved, of course: Circulation 117: 1082, 2008).
{14216} the nasty stuff
{25461} the nasty stuff
{53265} the nasty stuff
Atherosclerosis
Prosthesis in place
Urbana Atlas of Pathology
A bleed into a plaque can also organize and make it grow. Proof by an imaging
study: Circulation 111: 2768, 2005.
Hemorrhage into a plaque
Caused death
ERF/KCUMB
This is most common in the big arteries (why?)
(* Future pathologists: Sometimes a plaque itself may thin the wall of the
aorta so much that it bursts outward, with fatal results:
AJFMP 17: 38, 1996 -- penetrating ulcer).
Although the idea is little-known, there is abundant evidence from animal work (and
plenty from
humans -- especially autopsy) that ATHEROSCLEROTIC LESIONS CAN AND DO REGRESS, if the risk factors are corrected.
How the cholesterol leaves the plaques when the LDL situation
improves: Circulation 99: 1959, 1999.
* The British anti-platelet study: Br.
Med. J. 308: 81 & 159, 1994; aspirin sounds good for those at high risk for myocardial infarction,
but for those at low risk, the hazard of hemorrhagic stroke may outweigh the benefits). Aspirin
review: Am. Heart J. 137: S-9, 1999. Despite claims that
"aspirin works by suppressing systemic inflammation", going on aspirin
seems to have no effect on C-reactive protein levels (Circulation 109(S2):II-2, 2004.)
{40267} hyaline arteriolar sclerosis
{40347} hyaline arteriolar sclerosis

* What's probably happening is failure of endothelial cells to undergo
apoptosis when they should: Nat. Med. 4: 222, 1998. Look for
novel treatments based on this!
{24854} hyperplastic arteriolar sclerosis, scleroderma kidney
In contrast to atherosclerosis, transplant vasculopathy of the coronaries
is concentric (atherosclerotic lesions are usually eccentric),
does not calcify, and often involves the intramyocardial arteries quite extensively.
* Future pathologists: The Chapel Hill Consensus Conference (1994)
set the standards
for separating these troublesome entities (Arth. Rheum. 37: 187, 1994).

{14286} leukocytoclastic vasculitis
{14287} leukocytoclastic vasculitis
{14289} leukocytoclastic vasculitis
{14290} leukocytoclastic vasculitis
{14292} leukocytoclastic vasculitis
{14293} leukocytoclastic vasculitis
{14294} leukocytoclastic vasculitis
{14295} leukocytoclastic vasculitis
{14296} leukocytoclastic vasculitis
{14298} leukocytoclastic vasculitis
This is an eosinophilic vasculitis accompanied by asthma, usually of new onset.
We cover this under "immuno", it is a great mimic (Chest 128:
1047, 2005). The response to glucocorticoids is usually better than
in other vasculitis syndromes.
* Methotrexate to supplement the prednisone for a more-effective,
more-tolerable treatment: Arth. Rheum. 56: 2789, 2007.
How long to treat: Arch. Int. Med. 159: 577, 1999.
{22096} temporal arteritis
{22098} temporal arteritis
{24777} temporal arteritis
{28019} temporal arteritis
* A few years ago, coronavirus NL63 was a suspect
but was exonerated: J. Inf. Dis. 194: 1697, 2006).
* For some reason, glucocorticoids are contraindicated
because they actually increase the risk of the most serious complication,
coronary aneurysms.
BUERGER'S DISEASE ("thromboangiitis obliterans": review
Angiology 47: 419, 1996; update Am. J. Med. Sci. 337: 285, 2009)
A little-known disease, accounting for perhaps 5% of abdominal aortic
aneurysms, as well as an unknown percentage of thoracic aneurysms.
They are more likely to hurt ("I have low back pain")
and less likely to rupture than their better-known atherosclerotic counterparts.
,
septic emboli (look for "Roth's spots!"), walls of abscesses, and a host of
others.
{25459} Raynaud's
{39657} Raynaud's
{39654} Kawasaki's?
{39655} Kawasaki's?
{48983} Takayasu's
* ERYTHROMELALGIA
This is a thankfully-rare
pain syndrome in which there is a burning sensation
in the distal extremities, sometimes triggered
by exercise or environmental heat. Patients
are easy to recognize because they put the involved
hands / feet into ice water to get relief.
Hard-to-treat, one group reports success in children using
sodium nitroprusside (Arch. Dis. Child. 87: 229, 2002).
{11042} atherosclerotic aortic aneurysm
{11048} atherosclerotic aortic aneurysm, repaired
{11642} atherosclerotic aortic aneurysm
{11645} atherosclerotic aortic aneurysm
{18717} atherosclerotic aortic aneurysm
{20305} atherosclerotic aortic aneurysm
{24780} atherosclerotic aortic aneurysm
{25742} atherosclerotic aortic aneurysm
{04589} atherosclerotic basilar artery aneurysm
{24836} atherosclerotic aneurysm, brain
Thoracic aortic aneurysm
Atherosclerotic
Ed Lulo's Pathology Gallery
Coronary Artery Aneurysm
Classic drawing
Adami & McCrae, 1914
causes ischemic damage (by narrowing / occluding vasa vasora) to the walls of the arteries, and is
famous for causing proximal aneurysms that rupture impressively. Before rupture occurs, look
for the infamous "tree bark" grooves on the intima, as well as occlusion of the coronary and other
ostia and compromise of the aortic valve ring.
{18716} syphilitic aneurysm
Syphilitic aneurysm
Classic patient photo
Adami & McCrae, 1914
Think of the blood acting as a chisel under the strokes of the heart.
Aortic dissection
Classic drawing
Adami & McCrae, 1914
Aortic dissection
Dr. Heuser
Wikimedia Commons
"Cystic medial necrosis"
WebPath Photo
Lathyrism occurs in the poor nations after severe droughts, as a result
of eating drought-tolerant sweet peas. There were outbreaks in Ethiopia
and Bangladesh in the 1990's (Lancet 354: 306, 1999; Lancet 362: 1808, 2003).
{18718} dissecting aneurysm
{20222} dissecting aneurysm
{25747} dissecting aneurysm
Hemopericardium
This was secondary to aortic dissection
WebPath Photo
A PSEUDOANEURYSM, or pulsating hematoma, is a place where
an artery has bled non-fatally, and where the organizing hematoma communicates
with the lumen. Of course, the wall of the "aneurysm" (and it may look
very much like an aneurysm)
will lack the normal elastic layers of an artery.
Looks similar: POST-THROMBOPHLEBITIS SYNDROME, with stasis changes
due to damage to the valves after an episode of deep-vein thrombosis.
You already know from physiology about ESOPHAGEAL VARICES and
HEMORRHOIDS as evidence of portal
hypertension.
group A.) You'll see red streaks running along an extremity, etc.
Lymphedema
Patient education site
By a cyberfriend
* The endothelial cells are of course clonal and show some enhanced responses
to some growth factors
(J. Clin. Inv. 107: 745, 2001).
{12235} hemangioma
{13041} hemangioma
{13042} hemangioma
{13044} hemangioma
{13045} hemangioma
{13047} hemangioma
{13048} hemangioma
{13050} hemangioma
{13051} hemangioma
{13141} hemangioma
{17507} hemangioma in liver
{21832} hemangioma
{21834} hemangioma
{21835} hemangioma
{22116} hemangioma
{22118} hemangioma
{22119} hemangioma
Cavernous Hemangioma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Lasering them off, with dye-pulses: NEJM 338 1028, 1998.
{12786} "pyogenic granuloma"
{12789} "pyogenic granuloma"
{12225} pyogenic granuloma
![]()
* Golfer Casey Martin is the best-known Klippel-Trenaunay patient. In 2001,
the US Supreme Court ruled (PGA tours vs. Martin) he could ride in a cart despite the PGA's complaining
it would give in an unfair advantage.
* Treatment with thalidomide, which causes the vessels to mature: Nat. Med. 16: 420, 2010.
Epithelioid angiosarcomas (epithelioid hemangioendotheliomas)
are common, and look like carcinomas.
Bizarre new variant: Arch. Pat. Lab. Med. 121: 980, 1997.
{21065} angiosarcoma, breast
{40635} angiosarcoma
{09486}* hemangiopericytoma
{09489} hemangiopericytoma, reticulin stain
{09490} hemangiopericytoma, reticulin stain
BACILLARY ANGIOMATOSIS is a curious proliferation of small
vessels with cells packed with Bartonella bacteria (cat scratch and trench fevers).
It first got recognized in AIDS patients, and is cured with antibiotics.
.
{13392} cystic hygroma
* Lymphangioma circumscripta is a small, localized hamartoma of lymphatics.
The dilated lymphatic vessels, with their valves,
will be obvious. Look for hyperkeratosis and an epidermal collarette.
Lymphangioma circumscripta
Great example of this
uncommon, benign lesion
Lymphangioma circumscripta
Great example of this
uncommon, benign lesion
Lifestyle changes have done wonders in reducing morbidity from atherosclerosis.
In addition, we can be thankful for interventions that have saved lives and
relieved symptoms when atherosclerosis does occur.
When a plaque is re-opened
forcefully, there are three possible adverse effects.
ARTIFICIAL ARTERIES are often made of gore-tex, like the thermal
running suits. They usually re-endothelialize (form a "neointima")
for only a cm or two
from where they are attached to the natural arteries. The remaining lumen is
lined by a mix of clot and scar ("pseudointima"). It is surprising that thrombosis is not
a more common problem.
Further, the lesion will heal by proliferation of the local
cells, and it's about an even chance that in six months, the artery
will be just as narrow.
* SLICE OF LIFE REVIEW: VESSELS AND HEART
{03187} tricuspid valve, normal
{03329} atrium, normal
{03344} hypertrophy & normal, (l) vent.
{03347} hypertrophy & normal, (l) vent.
{03401} comparison of atria, normal ra & la free walls
{03467} heart, normal histology
{03575} ventricular slice method of dissection normal heart
{03581} cardiac base method of dissection, normal heart
{03599} short axis dissection, normal heart
{03605} four chamber dissection, normal heart
{03611} long axis dissection, normal heart
{03629} cardiomyopathy, dilated; normal
{03683} pericardium intact opened, normal
{03686} pericardium opened removed, normal
{03689} pericardial sac, normal with and without heart removed
{03692} pericardium, normal with anterior portion removed
{03698} heart anterior, normal
{03716} heart, normal (r) (l) ant. oblique
{03719} heart anterior, normal
{03734} heart, normal (r)
{03749} heart, normal
{03758} tricuspid valve, normal
{03764} tricuspid valve (r) ventricle view, normal
{03767} mitral valve opened, normal
{03776} mitral chordae, normal
{03779} mitral valve, normal viewed from LA and LV aspects
{03785} aortic-mitral valvular continuity, normal
{03788} tricuspid mitral valves, normal comparison of shapes
{03791} tricuspid mitral valves, normal
{03794} heart, normal
{03797} heart, normal right ventricle
{03800} heart, normal left ventricle
{03803} heart, normal compare ventricle thick.
{03806} heart, normal
{03809} heart, normal
{03812} heart, normal
{03815} heart, normal: how to cut
{03818} heart, normal: how to cut
{03821} heart, normal: how to cut
{03851} myocardial cell, normal left ventricle
{03854} membranous septum (l) ventricle, normal
{03857} membranous septum (r) ventricle, normal
{03863} pulmonary valve, normal
{03866} aortic valve, normal
{03869} aortic valve closed opened, normal
{03872} aortic valve cusp in elderly, normal
{03881} aortic valve from above, normal
{03884} cardiac valves (all four), normal
{03899} coronary ostia, normal
{03902} aortic valve coronary ostia, normal
{03905} aortic valve coronary ostia, normal
{03908} coronary arteries, normal
{03911} coronary arteries sup. inf., normal
{03914} coronary artery dominance, normal
{03920} septum perforators of (l) ant. desc., normal
{03923} septum coronary arteries, normal
{03926} coronary arteries, normal
{03929} coronary arteries, normal
{04472} hear, normal
{04475} aorta, normal
{06218} superior vena cava aorta pulm. artery, normal
{06224} aortic arch, normal longitudinal section
{06233} vein, normal
{06539} coronary angiogram, normal
{09464} artery, normal
{09828} artery, normal
{11036} artery, normal
{11402} vertebral basilar artery, normal
{11405} vertebral basilar artery, normal
{11408} vertebral basilar artery, normal
{11738} heart, normal ventricle myocardium
{11799} heart, normal
{11800} heart, normal
{11809} aorta, intimal surface
{12889} venogram, normal
{12892} venogram, abnormal
{12894} venogram, abnormal
{14627} Purkinje fibers cross section
{14628} Purkinje fibers long.
{14687} capillary, normal
{14689} arteriole-venule, normal
{14692} artery, muscular
{14693} artery, muscular; shows internal elastic membrane
{14694} artery, small muscular
{14695} artery, small muscular
{14696} artery, muscular
{14697} artery, muscular; b=media, c=external elastic, d=adventitia, e=nerve
{14698} artery, vein
{14699} artery, vein
{14700} aorta, normal
{14701} aorta, normal (elastic stain)
{15047} adrenal medulla (central vein), normal
{15180} stomach, cardia
{15181} stomach, cardia
{15209} Purkinje fibers, heart
{15210} epicardium, #17
{15211} endocardium, #17
{15212} epicardium, #17
{15213} endocardium, #17
{15214} atrium, endocardium
{15215} atrium, endocardium
{15217} artery and vein, elastic stain
{15218} artery, #29
{15219} vein, #29
{15220} aorta, #22, elastic stain
{17466} artery, normal
{20234} ecg, normal
{20255} chest, normal x-ray
{20567} insufficiency, aortic with normal on r
{20798} vein
{20816} Purkinje fiber, heart
{20817} myocardium in cross section
{20818} epicardium with fat and blood vessel
{20819} myocardium with epicardium too
{20820} endocardium
{20821} atrium of heart, endocardial surface
{20822} atrium of heart, endocardial surface
{20823} atrium of heart, epicardial surface
{20824} artery and vein, longitudinal section
{20825} artery and vein, cross section
{20826} artery, elastic
{20839} artery
{31412} internal carotid artery, normal
{31442} straight sinus nerve vein of Galen, normal venous anatomy
{37643} heart, normal
{38015} artery, normal
Abbott's Atlas of Congenital Cardiovascular Disease
Hurst's The Heart
Robbins and Cotran Pathologic Basis of Disease
Rosai and Ackerman's Surgical Pathology
Rubin's Pathology: Clinicopathologic Foundations of Medicine
Silver's Cardiovascular Pathology
Silverberg's Surgical Pathology
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