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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.
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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.
I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:
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
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
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:
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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 eighteen 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 William Carey 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 William Carey for making it still 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!
KCUMB Students
"Big Robbins" -- RBC / Bleeding
Lectures follow Textbook
QUIZBANK
Metabolic #'s 1-4, 9-24
INTRODUCTION
Serum protein electrophoresis is generally performed to identify patients who have paraproteins. * Future pathologists: Quality assurance and reproducibility Am. J. CLin. Path. 97: 97, 1992.
Although there are many different proteins in human serum, when they are separated electrophoretically by the usual procedures in the hospital lab, this is the pattern you will see in a healthy person.
What's in each peak?
Transthyretin ("retinol binding protein"; "prealbumin")
This is a single protein involved in the transport of thyroid hormones and vitamin A derivatives, worth mentioning because it migrates on the far side of albumin (hence the misleading old name "prealbumin"). It is usually not visible on routine serum protein electrophoresis, but measuring it by a separate assay is usable as an indicator of general health. (Low levels suggest the acute phase reaction, protein malnutrition, or liver disease.)
Albumin (migrates to the anode)
α-1 globulins
α-1 protease inhibitor (α-1 antitrypsin)
* α-1 glycoprotein (* orosomucoid)
α fetoprotein (if present)
high density lipoprotein (HDL)
α-2 globulins
α-2 macroglobulin
antithrombin III
ceruloplasmin
haptoglobin (this is usually the predominant component)
Beta globulins
beta and pre-beta lipoproteins (LDL and VLDL)
C3
C-reactive protein
hemoglobin (free)
plasminogen
transferrin (*"principal component of the beta1 subdivision")
Gamma globulins
Immunoglobulins. (IgM migrates closer to the beta region, IgA between beta and gamma peaks, IgG throughout the gamma region.)
Most of these proteins are familiar to you. α-1 acid glycoprotein ("orosomucoid") and C-reactive protein are important to students of medicine only in connection with serum protein electrophoresis and the acute phase reaction (see below).
*Most serum protein electrophoresis is performed at pH 8.6, and the application point falls in here; it may appear as a "peak".
SERUM ALBUMIN
This is the major protein in the blood. It is routinely measured on the automated chemical profile.
Increased serum albumin does not occur naturally. (Dehydration may produce a relative hyperalbuminemia, or someone may administer too much albumin by vein.)
Decreased serum albumin has several important causes:
protein malnutrition (cachexia, alcoholics, celiac disease, pancreatic duct problems, Crohn's, Whipple's, cystic fibrosis, some hospital diets, etc.; albumin is a good measure of protein nutrition)
hepatocellular disease (decreased synthesis)
nephrotic syndrome (albumin is often very low)
thermal burns, skin disease (loss through skin)
plasma cell myeloma (usual, the mechanism is uncertain)
acute or chronic inflammation (lupus, TB, osteomyelitis, rheumatoid arthritis, etc. This is essentially due the acute phase reaction, and the albumin level will be only slightly low.)
pregnancy (mild decrease)
congenital analbuminemia (this rare genetic causes only mild dependent edema)
*Sometimes the albumin peak is double. If the peaks are the same height, the patient is a heterozygote. If one peak is smaller, you are seeing a drug-albumin complex.
*Slurring of the albumin peak (i.e., too wide and too flat) is generally due to jaundice, since bilirubin binds to albumin.
"THE ACUTE PHASE REACTION" (see NEJM 311: 1413, 1984)
When there is significant ongoing inflammation or tissue necrosis, the body usually responds with increased serum levels of several proteins. (Interleukin-1, from mononuclear phagocytes, probably initiates the reaction.)
α-1 acid glycoprotein, α-1 protease inhibitor, antithrombin III, C3, C-reactive protein, ceruloplasmin, fibrinogen, and haptoglobin increase.
C-reactive protein appears in the serum in 4-6 hours; the other proteins begin to increase in a day or so.
Simultaneously, serum levels of albumin, prealbumin, and transferrin decrease.
Because of differences in half-lives, the drop in prealbumin is seen first, while albumin may take a few weeks to drop significantly.
The erythrocyte sedimentation rate, a test you can order in several forms, increases during the acute phase reaction.
Nothing is different about the red cells. The increased fibrinogen and other globulins in the plasma alter blood physics to cause red cells to sink more rapidly.
Part of the secret is that the relatively electropositive globulins partly neutralize the zeta potential, causing the red cells to stack. Fibrinogen molecules also line up and help streamline the sinking of red cell stacks.
*This effect was known to Hippocrates.
The "sed rate" is increased in anemia (there is a correction factor), in the presence of a paraprotein (see below), and during normal pregnancy and menstruation.
*(Future lab directors: "Sed rates" will increase greatly if there is heavy construction near the lab causing vibrations!)
The "sed rate" is decreased in polycythemia and when there is much poikilocytosis (sickle cell disease, hemoglobin C disease, hereditary spherocytosis, etc.)
Whatever its limitations, the "sed rate" can rule out uncomplicated hypochondriasis and can be used to monitor the course of an illness.
Remember its usefulness in detecting temporal arteritis and polymyalgia rheumatica.
PARAPROTEINS ("M-proteins")
Greatly increased amounts of some normally-undetected serum protein is called paraproteinemia, and the abnormally-increased protein is called a paraprotein or M-protein.
("M" means both monoclonal and myeloma, the usual cause of an M-protein.)
Most often, the paraprotein is all or part of an immunoglobulin molecule.
Especially if the paraprotein is light chains, it may spill into the urine ("Bence-Jones proteinuria").
You can test urine for Bence-Jones protein by yourself, using a test tube and a Bunsen burner. Bence-Jones protein precipitates on heating (around 40-60), then redissolves just before the urine boils.
Paraprotein appears as a sharp peak (a "spike"), most often in the gamma region, though it may be anywhere.
Such a peak indicates the presence of a monoclonal gammopathy
A majority of detected monoclonal gammopathies are the result of plasma cell myeloma. These patients typically have depression of other gamma globulins and albumin.
Some other causes of monoclonal gammopathies include:
Waldenstrom's macroglobulinemia
heavy chain disease
cryoglobulinemia (some cases, i.e., *types I and II)
CLL, lymphoma, amyloidosis (occasional cases)
*Sometimes, patients with diseases in which there is long-term increased production of immunoglobulins (tuberculosis, leprosy, chronic active hepatitis, sarcoidosis, primary biliary cirrhosis, collagen-vascular disease) may develop a superimposed monoclonal gammopathy.
A substantial minority of detected monoclonal gammopathies are apparently unrelated to any disease.
These usually occur in older patients. The quantity of paraprotein in the blood is less than 2.0 gm/dL, Bence-Jones proteinuria (rarely present) is less than 60 mg/L, and there is no suppression of other immunoglobulins or albumin.
These patients are said to have "benign monoclonal gammopathy", "monoclonal gammopathy of uncertain significance", "MGUS", etc.
Most do not go on the develop plasma cell myeloma or amyloidosis B, though a large minority do.
A few of these folks have an IgM directed against a myelin glycoprotein, and get a peripheral neuropathy (J. Neuro. 243: 34, 1996.
Once a paraprotein it detected, it may be characterized by immuno-electrophoresis, a technique with which you are familiar from your course in immunology.
The hospital lab routinely checks the patient's serum with antisera to detect α, gamma, and mu heavy chains and kappa and lambda light chains.
Remember that a precipitation band including both the normal serum components and a large amount of paraprotein will appear bent. (Why?)
These pretty teaspoons are rapidly being replaced by immunofixation electrophoresis in most labs (Pathology 21: 35, 1989). While it is more expensive, it is much easier to read, and picks up secondary paraproteins readily.
Don't be fooled by these other causes of a "spike" on serum protein electrophoresis:
α-2 macroglobulin (α-2 region, nephrotic syndrome)
haptoglobin (α-2 region toward the beta side; acute phase reaction)
transferrin (beta region; iron deficiency or late pregnancy)
SERUM PROTEIN ELECTROPHORESIS
Indications for this interesting study include:
symptoms or findings suggestive of plasma cell myeloma (i.e., a patient over age 40 with bone pain, a pathologic fracture, unexplained anemia, infection, Rouleaux formation, hypercalcemia, low albumin, high globulin, etc.)
symptoms or findings suggestive of paraproteinemia (i.e., cryoglobulinemia, hyperviscosity syndrome, Bence-Jones proteinuria)
looking for, or monitoring levels of, a paraprotein in plasma cell myeloma or any other B-cell tumor ("tumor marker")
?? evaluating protein abnormalities revealed by routine screening
Interpretation requires knowledge of common patterns.
α-1 protease inhibitor deficiency: much decreased α-1
Acute phase reaction: decreased or N albumin, increased or N α-1, increased α-2
*(This is sometimes called the "immediate response". If the process has been going on long enough to generate an antibody response, you see increased gamma, and may call this the "delayed response". These terms are not in wide usage.)
Sarcoidosis is known for producing the "sarcoid steps", with a small increase in α-1 and progressively greater increases in α-2, beta, and gamma. (This is no substitute for finding a non-caseating granuloma in a biopsy of some part of your patient's body....)
Protein-losing enteropathy: much decreased albumin, increased α-2, decreased gamma
Nephrotic syndrome: much decreased albumin, much increased α-2, much decreased gamma
Much of the α-2 increase is due to α-2 macroglobulin, which is greatly increased in this condition. This second-largest of the plasma proteins is retained while smaller molecules are lost into the urine.
Chronic liver disease: decreased albumin, much increased gamma with "beta-gamma bridging" (caused by IgA)
Polyclonal gammopathy: much increased gamma without any "spike"
"Polyclonal gammopathy" occurs in chronic liver disease (see above), SBE, sarcoidosis (see above), collagen-vascular disease, AIDS
An increase in proteins lying between the beta and gamma regions ("beta-gamma bridging") may be seen in polyclonal gammopathy of any etiology, though it is best known for its association with liver disease.
* Oligoclonal bands here suggest AIDS or autoimmune disease.
Plasma cell myeloma: decreased albumin, much decreased gamma except for "spike" (increased to much-increased)
At presentation, 80% of patients with plasma cell myeloma have a serum "spike". All but 1-2% of the rest will have Bence-Jones proteinuria, and light chains may appear in the serum as well, especially as renal function goes.
Benign monoclonal gammopathy: N gamma except for "spike" (increased to much increased)
See above. Up to 3% of older people will have a "monoclonal gammopathy of uncertain significance". You may be doing them a favor by not discovering it. Order serum protein electrophoresis with discretion!
CRYOGLOBULINS (Arch. Path. Lab. Med. 123: 119, 1999; Am. J. Clin. Path. 117: 606, 2002)
These are proteins that reversibly precipitate in serum left overnight (or for 72 hr.) in the refrigerator. (Cryofibrinogens can be checked simultaneously; they're only in plasma.)
"Cryoglobin"/"cryoglobulin" refers to a physical property, not a distinct protein.
Some of these are M-proteins. If it's not an M-protein, we speak of "mixed cryoglobulinemia".
Most of the rest are rheumatoid factors bound to IgG.
Occasionally they are other antigen-antibody complexes, for example, hepatitis B or C (NEJM 330: 751, 1994, many others) virus and antibodies.
Indications for and interpretation of this study are not well defined.
Cryoglobulins are common in patients with lymphoproliferative disorders, monoclonal gammopathies, chronic infections, autoimmune disease, idiopathic Raynaud's syndrome, and are found in perhaps 1% of healthy people.
They may cause otherwise-unexplained purpura, vasculitis, or kidney problems.
PROBLEMS:
1. What would a classic immunoelectrophoresis look like if the sample is urine containing Bence-Jones protein?
2. What would a classic serum immunoelectrophoresis look like if the patient has only Bence-Jones protein in the blood?
3. What would a classic serum immunoelectrophoresis look like if the patient has α heavy-chain disease?
4. What would a classic serum immunoelectrophoresis look like if the patient has an IgD spike?
5. The common patterns seen on serum protein electrophoresis are fairly characteristic of various diseases. For which diseases does do you think it really helps make the diagnosis?
BIBLIOGRAPHY / FURTHER READING
I urge anyone interested in learning more about serum proteins 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!
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