BLOOD VESSELS
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com

Cyberfriends: The help you're looking for is probably here.

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.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.


If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Freely have you received, give freely With one of four large boxes of "Pathguy" replies.

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. Someday you may be able to access these pictures directly from this page.

I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:

Also:

KCUMB Pathology Club
Medmark Pathology -- massive listing of pathology sites
Pathology Handout -- Korean student-generated site; I am pleased to permit their use of my cartoons
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures


Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm handling about 200 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:

I've spent time there and they are good. Write "Thanks Ed" on your check.

Help me help others

My home page
More of my notes
My medical students

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 linked below. 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.

This page was last updated February 9, 2008.

During the thirteen 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!

We comply with the HONcode standard for trustworthy health
information:
verify here.

PicoSearch
  Help

More of Ed's Notes:

Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
Inflammation
Fluids
Genes
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Autoimmunity
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
Aging
Infections
Nutrition
Environmental Lung Disease
Violence, Accidents, Poisoning
Heart
Vessels
Respiratory
Red Cells
White Cells
Coagulation
Oral Cavity
GI Tract
Liver
Pancreas (including Diabetes)
Kidney
Bladder
Men
Women
Breast
Pituitary
Thyroid
Adrenal and Thymus
Bones
Joints
Muscles
Skin
Nervous System
Eye
Ear
Autopsy
Lab Profiling
Blood Component Therapy
Serum Proteins
Renal Function Tests
Adrenal Testing
Arthritis Labs
Glucose Testing
Liver Testing
Porphyria
Urinalysis
Spinal Fluid
Lab Problem
Quackery
Alternative Medicine (current)
Alternative Medicine (1983)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB

I [Allah] am nearer to you than the vein in your neck. --Koran

QUIZBANK: Hemodynamic #'s 1-30, Vessels (all)

    Atherosclerosis: Hemodynamic 1-30
    Tumors / Aneurysms / Vasculitis: Vessels (all)

Learn First

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 steaks 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 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."

Cardiovascular
Utah cases for path students
Juliana Szakacs MD

Vascular
Iowa Virtual Microscopy
Have fun

Cardiovascular Diseases
First Section
Chaing Mi, Thailand

Cardiovascular Diseases
Second Section
Chaing Mi, Thailand

Cardiovascular Diseases
Third Section
Chaing Mi, Thailand

Cardiovascular Pathology
Virginia Commonwealth U.
Great pictures

Cardiovascular Diseases
Mark W. Braun, M.D.
Photomicrographs

Cardiovascular System I
Great pathology images
Indiana Med School

Cardiovascular System II
Great pathology images
Indiana Med School

Tulane Pathology Course
Great for this unit
Exact links are always changing

Aorta Exhibit
Virtual Pathology Museum
University of Connecticut

Cardovascular Pathology
Sampurna Roy, MD
Lots of photos and good text

Heart and Vessel Pathology
Photomicrograph collection
In Portuguese

Harvey OBJECTIVES: This is mastery material.

    Give a full account of atherosclerosis, its causes and effects, its full range of anatomic pathology, and its complications. Make sense of its risk factors in terms of what we know about its chemistry and pathophysiology.

    Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:

      atheroembolization
      atherosclerotic aneurysm
      fatty streak
      fibrous plaque
      hemorrhage into an atherosclerotic plaque
      ulcerated atherosclerotic plaque

    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:

      arteriovenous malformation
      Buerger's thromboangiitis obliterans
      Churg-Strauss disease
      Kawasaki mucocutaneous lymph node syndrome
      leukocytoclastic vasculitis
      Takayasu's pulseless disease
      temporal arteritis
      varicose veins
      Wegener's granulomatosis

    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:

      inferior vena cava syndrome
      lymphangitis
      lymphedema
      superior vena cava syndrome

    Recognize each of these anatomic lesions, grossly and/or microscopically as applicable:

      aortic dissection
      berry aneurysm
      cystic medial necrosis
      hyaline arteriolar sclerosis
      intimal fibrosis
      medial calcific sclerosis
      syphilitic aneurysm
      Weibel-Palade body

    Describe the important tumors, hamartomas, and proliferations of blood and lymph vessels, how they behave clinically, and the pitfalls in making the diagnosis.

aortogramNORMAL 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.

    Lymphatic vessels in edema
    They are not themselves plugged,
    but are dilated from carring away fluid.

    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.

Pete Maravich 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
{09440} atherosclerosis of vertebral and basilar arteries
{09446} êtat cribilé from multiple atheroemboli

Aortic Atherosclerosis, longstanding
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Occlusive Atherosclerosis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Mild, moderate & severe atherosclerosis
WebPath Photo

Cholesterol emboli

KU Collection

Atherosclerosis
Photo and mini-review
Brown U.

Occluded common iliac
Spectacular x-ray
Brazilian Medical Students

    Probably still the #1 killer of Americans.

    Atherosclerosis causes harm by (1) occluding arteries slowly over time (angina, 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).

      Claudication is the least subtle of these. Patients will have calf pain after walking a certain distance (usually about the same each time); the stenosis will of course be way proximal from the pain. Review Lancet 358: 1257, 2001.

      * 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).

{06737} atherosclerosis has caused ischemic fibrosis of the heart
{09443} atherosclerosis of middle cerebral artery
{10889} atheroembolus

Kidney
ERF/KCUMB

Severe atherosclerosis of a coronary artery
WebPath Photo

Atheroembolus
WebPath Photo

    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.

      * 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.

      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 smoking, "which damages the intima".

        * "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).

          * 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.

      3. High blood pressure "which damages the intima". Review Lancet 345: 362, 1995.

        Angiotensin II itself is now one of the "usual suspects" in discussions of molecules that mediate atherogenesis: Am. J. Med. Sci. 323: 17, 2002.

      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.

          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.

          * Another idea: High blood glucose levels cause overexpression of CD36, the LDL scavenger pathway receptor: Nat. Med. 7: 840, 2001.

      5. Lack of exercise (made "official" in 1992), independent of the above (NEJM 330: 1565, 1992).

        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.

          * 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).

          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.

          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.

          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.

        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 biochemical lesion is overproduction of apo B in the lipoproteins (review J. Clin. Endo. Metab. 89: 2601, 2004).

          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.)

        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).

        * 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. It was examined as a risk factor for atherosclerosis during the 1990's, but is now mostly discussed by the "complementary and alternative medicine" people. Very high levels may be a risk factor, but no one seems to recommend routine measurement (JAMA 296: 1363, 2006).

        * Common longevity mutation in cholesterol-ester transfer protein, which produces abnormally large LDL's and HDL's: JAMA 290: 2030, 2003.

        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 & elevated fasting triglycerides.

        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 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.

        * Watch for

        • a problem with some hormone (perhaps resistin or adiponectin) as etiologic
        • inclusion of Stein-Leventhal, hirsutism-obesity in older women, non-alcoholic steatohepatitis, and endometrial cancer in the constellation
        • more on the rat model, induced by feeding a greasy American-type diet (Hypertension 37: 1323, 2001)
        • everybody soon treating it primarily with diet and exercise
        • new categories of medications to treat the defect at the cellular level (* Including the altered nuclear membrane receptors: NEJM 353: 604, 2005)

      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.

          * Even a common, mild mutation in methylenetetrahydrofolate reductase is a serious risk factor for atherosclerosis: Circulation 99: 2361, 1999.

          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). Of course vegetarians overall have less, rather than more, atherosclerotic morbidity and mortality, though this is not under intensive study recently; 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...

        • is a mitogen for vascular smooth muscle;
        • damages endothelium (possible mechanism Circulation 105: 1037, 2002);
        • makes blood hypercoagulable.

        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. Soon everybody may be taking betaine supplements.

      10. Chronic kidney disease. Hard to sort out from the others, but probably real (Am. J. Kid. Dis. 49: 8, 2007.)

      11. Being on a protease inhibitor for HIV infection ("dyslipidemia": NEJM 356: 1723, 2007).

      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.

        * 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.

      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, but nothing much lately.

      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: 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. 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."

        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.

        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-causes-atherosclerosis flap of the 1980's came to nothing. Now it's 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.

        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 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.

        C-reactive protein is presently 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.

          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.

          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 have much 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.

          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

      • previous radiation to an artery (infamous: Cancer 106: 718, 2006);
      • arteries in transplanted hearts (inflammation, of course: Circulation 106: 1536, 2002)
      • vein grafts in coronary bypass surgery
      • coronary arteries after angioplasty
      • situations in which the walls of arteries are burdened with immune complexes.

      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
{06581} atherosclerosis after radiation

    The innocent precursors: (anatomy: Am. J. Path. 143: 1444, 1993)

{11057} fatty streak
{25024} fatty streak
{41533} foam cells

Fatty streaks
WebPath Photo

Fatty streaks
WebPath Photo

    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 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 calcification, 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.)

      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.

      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.

Fatty streaks
WebPath Photo

Severe atherosclerosis
WebPath Photo

Atherosclerotic plaque with needles and clot
WebPath Photo

Needles & foam cells
WebPath Photo

Coronary graft vascular disease
Pittsburgh Pathology Cases

      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
{14216} the nasty stuff
{25461} the nasty stuff
{53265} the nasty stuff

Atherosclerosis
Prosthesis in place
Urbana Atlas of Pathology

    As a person continues to be at risk for atherosclerosis, the plaques become complicated. Any of the following unpleasant things can happen:


    • The surface of the plaque becomes damaged, resulting in thrombus formation.
      • 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).

        • Plaque rupture: The cap ruptures, exposing the necrotic core beneath. Classically, the common-sense idea that the core itself must contain something that clots blood is now being supplanted by the idea that white cells reacting to the exposed plaque cause the thrombus. Stay tuned.
        • Plaque erosion: The thrombus overlies an area of proteoglycans and smooth muscle cells "with minimal inflammation" but without endothelium.
        • Calcified nodule: Metaplastic bone or heavy-duty dystrophic calcification, without endothelial cells.

        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.

          A bleed into a plaque can also organize and make it grow. Proof by an imaging study: Circulation 111: 2768, 2005.

        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 (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.

    • The fibrous cap cracks, discharging grumous debris into the lumen. This can result in embolization if the artery is large (heart attack, renal shutdown, King Herod's disease), or thrombosis.
    • One of the weak little arteries that develops in the plaque ("neovascularization") bursts, ballooning the roof of the plaque against the opposite wall of a small artery.
      • 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

Hemorrhage into a plaque
Caused death
ERF/KCUMB


    • The plaque deprives the inner media of its nutrients, causing it to weaken and balloon out ("aneurysm").
      • 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).

    The good news: It's reversible

      Although the idea is little-known, there is abundant evidence from animal work (and some from humans) 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.

      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")

        * 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.)

    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

Medial Calcification
From Chile
In Spanish

    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, or make "radial artery blood-gas sticks" difficult and hazardous.

    On the "plus" side, it makes for some great x-rays.

    * 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.

Monckeberg's
UHS Case
Photo by Ed

Monckeberg's
WebPath Photo

ARTERIOLAR SCLEROSIS ("arteriolosclerosis")

Arterial Sclerosis I
From Chile
In Spanish

Arterial Sclerosis II
From Chile
In Spanish

    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", 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.

    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.

      Extremely common. The causes are

      • prolonged high blood pressure from any cause;
      • prolonged hyperglycemia from any cause.
      • radiation injury (typically iatrogenic, an expected result of radiation therapy)
      • * focal-segmental glomerulosclerosis / hyperfiltration lesion in the failing kidney (more about this soon)

      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 "triple-P" (pretty poor protoplasm). "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
{40267} hyaline arteriolar sclerosis
{40347} hyaline arteriolar sclerosis

Hyalinized intramyocardial artery (diabetes)
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office

Hyaline arteriolar sclerosis
Photo and mini-review
Brown U.

Hyaline arteriolar sclerosis
Tom Demark's Site

Hyaline arteriolar sclerosis
Tom Demark's Site

Hyalinized arteriole
WebPath Photo

Arteriolar sclerosis
Thick intima, hyaline media

    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

      • malignant hypertension (i.e., very bad high blood pressure that damages the vessels)
      • bad pulmonary hypertension
      • scleroderma (fingers, kidneys, other)
      • hemolytic-uremic syndrome (E. coli burger disease, kidneys especially)
      • * Degos's disease (a curious skin disease)
      * 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!

{39559} hyperplastic arteriolar sclerosis in pulmonary hypertension
{24854} hyperplastic arteriolar sclerosis, scleroderma kidney

Hyperplastic arteriolar sclerosis
WebPath Photo

Hyperplastic arteriolar sclerosis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

      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.

    Transplant vasculopathy
    WebPath Photo

THE VASCULITIS FAMILY (update Am. J. Clin. Path. 124(S): S-84, 2005)

Angiitis I
From Chile
In Spanish

Angiitis II
From Chile
In Spanish

    * Future pathologists: The Chapel Hill Consensus Conference (1994) set the standards for separating these troublesome entities (Arth. Rheum. 37: 187, 1994).

    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".

      We've already studied this (these?) dread, protean disease(s). 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
{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

      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

      This is an eosinophilic vasculitis accompanied by asthma, usually of new onset. We've already covered this disease, which is a great mimic (Chest 128: 1047, 2005). The response to glucocorticoids is usually better than in other vasculitis syndromes.

{38497} old burned-out Wegener's, without good granulomas

    Temporal arteritis ("cranial giant cell arteritis")

      A disease of older (>60) adults (> 2:1), 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.

      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.

        How long to treat: Arch. Int. Med. 159: 577, 1999.

        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
{22096} temporal arteritis
{22098} temporal arteritis
{24777} temporal arteritis
{28019} temporal arteritis

Temporal arteritis
WebPath Case of the Week

Temporal arteritis
WebPath Photo

Temporal arteritis
WebPath Photo

    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. 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).

{48983} Takayasu's

    Cogan's disease is another thankfully-rare disease usually affecting young adults. It features abrupt onset of nerve deafness, interstitial keratitis, and/or a systemic vasculitis often with aortic aneurysm formation. It's apparently 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)

      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:

      • fever (will last more than five days)

      • non-purulent conjunctivitis in both eyes

      • rash

      • red cracked lips and/or strawberry tongue and/or red oral mucosa

      • red palms and soles; later they desquamate

      • a big (1.5 cm or more) node in the neck

      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.

      There are a host of immune abnormalities, and presently folks are talking mostly about sensitization to a bacterial superantigen (i.e., something that makes large numbers of lymphocytes go crazy). Toxic shock syndrome, caused by a superantigen, is a similar illness. Yet the substance causing Kawasaki's remains unidentified. See J. Clin. Imm. 15(6S): 11-S, 1995; Ped. Inf. Dis. 19: 91, 2000.

      * By electron microscopy, the endothelial cells are separated and perforated, rendering them hyperpermeable; the molecular explanation remains elusive (Circulation 105: 766, 2002).

      We treat Kawasaki's with aspirin and intravenous immunoglobulin. The outcome is good unless coronary disease becomes apparent.

        * 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)

      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 cigaret smoking. 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)

      A little-known disease, accounting for perhaps 5% of abdominal aortic aneurysms. They are more likely to hurt ("I have low back pain") and less likely to rupture than their better-known atherosclerotic counterparts.

      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.

      Fixing an inflammatory aneurysm
      Nice, From the Italian
      surgeons' photo gallery

    Infectious arteritis

      Rickettsial disease, syphilis, septic emboli (look for "Roth's spots!"), walls of abscesses, and a host of others.

      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, then red, then blue. 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
{25459} Raynaud's
{39657} Raynaud's
{39654} Kawasaki's?
{39655} Kawasaki's?
{48983} Takayasu's

    Erythromelalgia

      This thankfully-rare pain syndrome probably results from opening of arteriovenous channels and closure of precapillary sphincters.

      Long-mysterious, it's now pretty clear that it's a small-fiber neuropathy (Arch. Derm. 139: 1337, 2003; Brain 126: 567, 2003).

      Lack of nutritive blood flow contributes to the pain, while the excess non-nutrative blood flow causes a burning sensation. Victims spend much time with affected areas socking in ice water.

      Erythromelalgia most often involves the feet and maybe hands. There are familial forms, or the disease can simply appear, usually sometime during adult life.

        Hard-to-treat, one group reports success in children using sodium nitroprusside (Arch. Dis. Child. 87: 229, 2002).

ATHEROSCLEROTIC AORTIC ANEURYSMS

Aneurysms I
From Chile
In Spanish

Aneurysms II
From Chile
In Spanish

    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
{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

Aortic aneurysm
Autopsy finding
KU Collection

Abdominal aortic aneurysm
Urbana Atlas of Pathology

Aortic aneurysm
WebPath Photo

Coronary Artery Aneurysm
Classic drawing
Adami & McCrae, 1914

    Syphilis causes ischemic damage (by 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.

      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
{18716} syphilitic aneurysm

Syphilitic aneurysm
Classic patient photo
Adami & McCrae, 1914

Syphilitic aortitis

Yutaka Tsutsumi MD

Syphilitic aortitis
Disrupted elastica
KU Collection

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 of * Erdheim", actually there are no cysts and no necrosis, just diminished elastic and maybe a little extra mucoid goo).

      Think of the blood acting as a chisel under the strokes of the heart.

    Aortic dissection
    Classic drawing
    Adami & McCrae, 1914

    Dissecting aneurysm
    Photo and mini-review
    Brown U.

    "Cystic medial necrosis"
    WebPath Photo

    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.

      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).

      * 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, also exist. "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
{18718} dissecting aneurysm
{20222} dissecting aneurysm
{25747} dissecting aneurysm

Aortic dissection
Pittsburgh Pathology Cases

Aortic Dissection
Pittsburgh Illustrated Case

Aortic dissection
WebPath Photo

Aortic dissection
WebPath Photo

Double-barrel dissection
WebPath Photo

Aortic dissection
WebPath Photo

Dissection up carotid
WebPath Photo

Aortic dissection
WebPath Photo

Dissection tear
WebPath Photo

Dissection tear
WebPath Photo

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.

    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 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.

        Looks similar: post-thrombophlebitis syndrome, with stasis changes due to damage to the valves after an episode of deep-vein thrombosis.

        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).

      You already know from physiology about esophageal varices and hemorrhoids as evidence of portal hypertension.

      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 group A.) You'll see red streaks running along an extremity, etc.

    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.