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 myphysicians.com,
and another at www.afraidtoask.com.
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I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.
Also:
Medmark Pathology -- massive listing of pathology sites
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:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review 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 presently have no sponsor.
This page was last updated February 6, 2006.
During the ten 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!
INTRODUCTION
Joint diseases are distinguished from one another by
the history and physical exam. You can make a diagnosis with
reasonable confidence in most cases without doing any
labs. The lab tests are ancillary, for confirmation
and for monitoring.
Keep this in mind as you work through this confusing unit.
You can do a "sed rate" in your office. ("And get those
temporal arteritis / polymyalgia rheumatica patients on glucocorticoids
now!") For the Westergren,
here's a reasonable "normal range":
Women: < (age+10)/2
Lab tests for the rheumatic diseases: Am. J. Med. 100 (2-A): 16-S, 1996;
South. Med. J. 98: 185, 2005.
SYNOVIAL FLUID (JAMA 264: 1009, 1990, still the best)
The fluid that nourishes and lubricates the joint space is named "syn-ov-ial" because it is "like egg
white" in color and consistency!
It is an ultrafiltrate of extracellular fluid that has passed through the synovial lining, a layer of
more-or-less cuboidal cells that possess neither desmosomes nor basement membrane.
Therefore, synovial fluid is almost identical to the rest of the extracellular fluid, except that the
synovial lining cells add hyaluronic acid.
Indications for tapping and examining synovial fluid are fairly well defined. You'll usually
do it when there is an
acute inflammatory arthritis with an effusion, unless the cause is apparent.
Tests on synovial fluid are old-fashioned but still worth knowing.
Tapping a joint is therapeutic in septic, crystalline, or traumatic arthritis, or when there is a large
effusion. You can use the same tap to inject corticosteroids when this is indicated (but be sure the
joint isn't infected!)
The principal hazard is infection and this is rare. Relative contraindications are infection in the soft
tissues around the joint, sepsis, and bleeding disorder or anticoagulant therapy.
You will learn how to tap a joint in the clinic. Generally the best approaches are on the extensor
aspects of the joints. Be sure to use good sterile technique.
For nice instructions on how to tap each joint in the body, see J. Fam. Pract. 20: 179, 1985.
* One trick to see whether you have synovial fluid is that a droplet will turn toluidine blue dye red.
(Hyaluronic acid does this by lining up the dye molecules along the polymer -- it's called
"metachromasia".)
If you can, send one mL of fluid in each of two tubes:
Even if you get "nothing", send the needle to the Microbiology lab for culture and sensitivity.
SYNOVIAL FLUID CELLS
Healthy synovial fluid contains fewer than 200 cells/mcL, mostly lymphs.
The lab will at least give the total red and white count, and the percentage of the white cells that are
polys.
*If you are performing the count yourself using a counting chamber, remember the white cell
diluting solution you use for blood contains acetic acid, which "clots" synovial fluid. Use saline
instead. Do not use an automatic blood cell counter.
Regardless of the total white count, more than 90% polys strongly suggests septic (bacterial)
arthritis.
Red blood cells in the synovial fluid suggests a traumatic tap.
If you do not think this is the problem, the patient probably has a fracture through the joint surface.
Look for marrow elements in the synovial fluid, though fat by itself is not diagnostic.
*Other possibilities are hemophilic arthritis, traumatic arthritis, or a tumor (i.e., "pigmented
villinodular synovitis").
*Total WBC is not very useful in distinguishing different types of arthritis.
The highest values
(over 100,000/mcL) suggest septic arthritis, TB, or acute gout.
* Of course, determining exactly what kinds of lymphocytes, macrophages,
cytokines, and bacterial and viral antigens are present in the synovial
fluid of study subjects is a major research interest.
SYNOVIAL FLUID CRYSTALS
Crystals found with polys in synovial fluid may establish the diagnosis of gout (uric acid -- if you
try, you can recover crystals in 85% of cases) or pseudogout (calcium pyrophosphate). Unless you
have a special interest, leave crystal identification to the lab.
All synovial fluid contains some small, calcium-rich crystals, and that these are likely to be
numerous in osteoarthritis. * Future pathologists: Alizarin red dye shows these up nicely.
Warning: certain injectable corticosteroid preparations produce needle-shaped crystals that
polarize exactly like uric acid.
SYNOVIAL FLUID MUCIN-CLOT ("Ropes test")
This measures how well-polymerized the hyaluronic acid is.
A few drops of synovial fluid are added to 10 mL or so of 5% acetic acid in a beaker and swirled for
a minute. The resulting "clot" is rated:
Inflammation in the joint space damages the hyaluronic polymers, shortening them.
Thus, the "mucin clot" is:
SYNOVIAL FLUID STRING TEST ("Viscosity test")
This test (not to be confused with Ropes, which is a name) measures the polymerization of
hyaluronic acid plus how much it has been diluted by the rapid entry of extracellular fluid into an
inflamed joint.
All the different ways of doing this test involve stringing a drop of the fluid out (from the end of a
syringe, etc., but not between your fingers because of the HIV risk). If you can pull the drop into a
string longer than 3 cm, the test is normal.
Interpretation is the same as for the mucin clot test.
OTHER TESTS ON SYNOVIAL FLUID
Synovial fluid glucose is normally the same as venous glucose in the fasting patient; decreased
values occur when there are many white cells, especially polys, active in the joint space. (In septic
arthritis, synovial fluid glucose is often more than 40 mg/dL below the venous value).
Gram stain will show the causative organisms in around 70% of cases of gram-positive septic
arthritis, and around 30% of cases of gram-negative disease. (When you are getting your cultures
ready, remember to inoculate Thayer-Martin medium.) * We suggest you get a blood culture as
well.
* Complement is often low in active joint disease
caused by autoimmunity (lupus, rheumatoid
arthritis). Again, I cannot recommend spending money on this unless you are a researcher.
In effusions from patients with lupus, you may see an LE cell (not really pathognomonic, but
helpful, and oh, so classic!).
* Rheumatoid factor may be present in effusions from patients with rheumatoid arthritis when it is
not (yet) present in the blood.
*The rice granules of rheumatoid arthritis, which result from failure to clear or organize
a fibrinous
effusion, are usually too large to pass through even a 16-gauge needle.
* There are old claims that, in reactive arthritis (enteropathic, Reiter's, Lyme
disease, rubella, hepatitis B) the lymphocytes from the joint fluid react specifically with the
offending antigen. This remains an experimental technique rather than something
practical for clinical use.
* Of course, Congo Red can help identify amyloid in
dialysis arthropathy.
SERUM RHEUMATOID FACTOR (RF)
Rheumatoid factor is any autoantibody or autoantibodies (IgM, IgG, or IgA) against the Fc portion
of slightly altered IgG.
Probably these contribute to the pathogenesis of joint and vessel disease by forming complexes that
attract and activate killer-T cells, fix complement, and so forth.
* The molecular biology is very complicated, of course.
The antigen on the altered IgG
is Gm(a) or Gm(g); IgG's lacking these antigens can still be recognized by rheumatoid factor if they
are aggregated or bound to antigen; maybe this is why some people produce antibody against these
"non-self" proteins.
Many procedures have been developed to test for the autoantibody. The two usual tests measure
mostly IgM rheumatoid factors.
The current "standard" is based on the agglutination of latex particles coated with IgG.
This "latex slide test" is negative in most people, and titers of 1:80 or less are common in infectious
mono, acute inflammation, and up to 15% of people over age 60. One recent study from Wichita
reviews its sensitivity and specificity in rheumatoid arthritis and in non-inflammatory arthritis, finds
it valuable, and disputes the claim that older people tend to turn positive (Arth. Rheum. 34: 951,
1991).
Depending on your lab, you may be instructed to ignore titers of 1:40 or less if you are considering
the diagnosis of rheumatoid arthritis.
The older Rose-Waaler test is based on the agglutination of sheep red blood cells coated with rabbit
IgG. Some rheumatologists prefer this, or like to get both.
This "sheep red cell tube test" is generally used today as a more specific test to follow the "latex"
test. Normal people have titers 1:16 or less.
The principal indication for ordering a serum "rheumatoid factor" is suspected adult rheumatoid
arthritis.
The majority of adults with rheumatoid arthritis will have significant titers of rheumatoid factor
(1:160 or above) in their serum.
Circulating rheumatoid factor may precede the illness or only appear
later.
The higher the titer (* especially above 1:640), the more likely the patient is to have rheumatoid
arthritis.
However, titers correlate only slightly with severity of the disease, and do not usually drop in
response to treatment.
Especially, patients with rheumatoid vasculitis tend to have higher titers.
Around 25% of adults with clinically obvious rheumatoid arthritis never develop rheumatoid factor
in the serum ("seronegative" RA).
Check synovial fluid for rheumatoid factor if you think your seronegative patient might just be
developing the disease.
* Tests for IgG, IgA, and IgE rheumatoid factors have not proved useful.
Rheumatoid factor is usually absent in patients with arthritis due to one of the following
"seronegative arthropathies"
Other causes of "significant titers" of rheumatoid factor in the serum include:
(You can document clinical improvement in patients with SBE or advanced syphilis by their falling
RF titers.)
*All type II cryoglobulins are by definition an IgM RF, and all type III cryoglobulins contain it.
Even "young normals" can have high titers of RF. Note that the diseases on the above list are those
that tend to feature polyclonal gammopathies.
Lab users: Remember that anemia of chronic disease is
common
in severe rheumatoid arthritis.
ANTI-NUCLEAR ANTIBODIES ("ANA's"): Pathology evidence-based consensus document Arch. Path. Lab. Med. 124: 71, 2000.
*All sorts of information about anti-nuclear antibodies (ANA) is available in the references and the
Path Dept. for the extremely curious student. With the "new biology" (recombinant DNA and
monoclonal antibodies), the various tests for autoantibodies are becoming more sensitive and more
specific for particular diseases. Use these judiciously.
The most helpful test is still your history and physical exam.
Old tests for antinuclear antibodies used fluorescence to detect antibodies stuck to real mammalian
nuclei ("rat liver test"; "mouse kidney test"; newer tests are done on human epithelial cells -- "HEp2
test"). These are still the screening tests. (And they're for screening: Postgrad. Med. 94: 55, 1993).
As you have guessed, differences in substrate account for the great variability between labs.)
New tests for specific antinuclear antibodies are
mostly tube tests.
RULE: In dealing with anti-nuclear antibody tests, the higher the titer, the more likely it is to mean
something.
You already know how to do an LE-cell prep, which begins best with a clumsy phlebotomy. It is a
cheap, easy way to detect a presently-uncharacterized antibody or antibodies against a certain DNA-histone complex.
We think that there is no longer any indication for an LE-cell prep, unless you want to do it yourself
for your own interest. There are rare reports of LE-positive, f-ANA-negative lupus victims,
but tube tests should pick these patients up (Am. J. Clin. Path. 101: 65,
1994).
Fluorescent ANA (f-ANA) titers for the older test:
1:20 or less... "negative"
1:40 to 1:160... infections, "one organ autoimmune diseases", normals (especially oldsters,
and perhaps 10% of healthy children and adolescents: Clin. Ped. 43: 637, 2004),
some "collagen-vascular diseases"
Above 1:160... "collagen-vascular diseases"
The only real indication for an f-ANA is when you have some reason to suspect:
If the f-ANA comes back positive, and you think this is lupus, consider these tests:
(1) an anti-double-stranded DNA antibody (anti-dsDNA. This is the same as anti-native DNA
antibody, anti-nDNA. * You will get either a "Crithidia test" (a leishmania with an easy-to-stain
blobbie of ds-DNA) or a "binding assay", and there are
some differences in interpretation.
These are pathogenic (for example, J. Imm. 151: 1128, 1993; Arth. Rheum. 36: 355,
1993), quite specific for lupus, and are present in high titer in around half untreated systemic lupus
patients. (* Beware: extreme cases where there is antigen-excess or antibody-excess in the serum).
The wire loops have ds-DNA and its antibody in them.
Titer of anti-ds-DNA is a good way to follow disease activity and predict exacerbations; a rise
in titer common precedes a flareup.
* Intriguing study: Dogs owned by lupus patients are much more likely to have anti-dsDNA on board
(Lancet 339: 1378, 1992).
* For some reason, rheumatoid arthritis patients treated with infliximab,
the antibody against tumor necrosis factor, commonly develop anti-ds-DNA
antibodies that however do not seem to produce symptoms (Arthr. Rheum. 43:
2383, 2000.
(2) a serum C3. It should be low in active systemic lupus (it's usually normal in rheumatoid
arthritis). So are C4 and CH-50 (see below) You may use these to follow disease activity.
(3) for confirmation, an anti-Sm and/or anti-Ro.
Anti-Sm antibody is a tube test. This is not very sensitive (30%), but quite specific
for lupus (and an indicator of bad prognosis. Anti-Ro is not very sensitive
and not very specific, but warns of photosensitivity, sicca, thrombocytopenia,
and especially heart block in the unborn or newborn child; using the older substrate,
it was used to support
a diagnosis of lupus in old "ANA-negative" cases.
If the f-ANA comes back negative, and you think this is lupus, consider these tests:
Remember this is very uncommon nowadays.
If the lab was using the olf-ashioned test, order an anti-Ro/SSA
and an anti-single-stranded DNA (see below), and consider other tube tests. You'll be using the list
of criteria to make the diagnosis. You may also
order an anti- extractable nuclear antigen (anti-ENA)
assay, a possible lupus marker
that modern ANA testing misses: Medicine 84: 208, 2005; J. Clin. Path. 54:
187, 2001.) Anti-histone antibody is a marker for drug-induced lupus (hydralazine, isoniazid, procainamide,
phenytoin.
This is supposed to be
100% sensitive, but not really specific; up to 70% of patients with regular lupus will have at
least one anti-histone antibody, and they pop up in plenty of other autoimmune diseases (* notably
morphea: Arth. Rheum. 36: 1137, 1993). Plus, how is the test going to help guide therapy?
We don't really recommend doing this?
Over half the patients you put on hydralazine or procainamide will become f-ANA-positive, but only
around 10% will get sick.
* Anti-H3, a different anti-histone autoantibody ("variable large speckles"), seems to define a new
lupus-like syndrome; again, this has not come into common use.
* Anti-ribosomal P antibodies probably cause the psychosis. They are fairly common (Br. J. Rheum.
32: 663, 1993). Again, this is a researcher's tool.
* Anti-DNP
(deoxyribonucleoprotein) is a known
marker for lupus and scleroderma that is not much used except by
researchers.
You can biopsy a piece of normal-looking skin and ask the pathologist to check for
immunoglobulins and complement components along the dermal-epidermal junction (the lupus band
test). This suggests systemic lupus, but interpretation is complex. (See Arthr. Rheum. 27: 382,
1984). Send sun-exposed, non-rash skin if you want a diagnosis.
{33205} positive lupus band test
Whether or not you have established a diagnosis of lupus, a high f-ANA titer or LE-cell in an
effusion suggests the cause is lupus.
If you have established the diagnosis for lupus by any means (remember there are clinical criteria),
"follow the disease activity and its response to your treatment" with serial f-ANA's, C3's, C4's, etc.
ANA and anti-dsDNA titers tend to drop after effective treatment (see Arthr. Rheum. 29: 26, 1986).
Complement components rise to normal levels. However, why are you ordering this?
The classic CH-50 assay for complement was a measure of the titer of complement required to
hemolyze 50% of a standardized preparation of IgM-coated RBC's. Its main use today is to check
for specific complement component deficiencies -- where C3 is normal but CH-50 is very low.
Anti-ribonucleoprotein antibodies (anti-nRNP, anti-U1-nRNP etc.) is always present in high titer in
"mixed connective tissue disease" (anti-U1-nRNP disease, i.e., Raynaud's, swollen fingers, arthritis,
mild myositis). Order it if (and only if) you suspect this illness.
It is often is positive at low titer in systemic lupus, * scleroderma, and even
* healthies (Arch. Derm. 123: 601, 1987). (* If positive in anti-Sm-negative SLE, it indicates a
good prognosis.)
* Components of the nRNP antigen include U1
and U2, which seem linked to MCTD (U1), psoriasis and Raynaud's (NEJM 315: 105, 1986), and
U3 (fibrillarin), which is common in scleroderma.
* Anti-U1RNP can cause neonatal lupus, just like anti-Ro can (Arch. Derm. 128: 1490, 1992). It is
less severe. Anti-U1RNP heart block in adults: Arth. Rheum. 32: 1170, 1989.
In adults, the presence of anti-U1RNP is a predictor of aggressive, eroding arthritis (Br. J. Rheum.
29: 345, 1990).
* Anti-nucleolar antibodies of various specificities are present in most scleroderma patients and in
occasionally in other "autoimmune" diseases (Ann. Rheum. Dis. 45: 800, 1986), and are presently
being characterized; they have not found their way into
clinical practice. Anti-centriole antibody strongly suggests scleroderma, though only some
patients are positive. Again, these are for research interest.
Anti-Scl-70 antibody (* anti-DNA-topoisomerase I) is an antibody against an alkaline, nonhistone
nuclear protein. It is positive only in about 20% of patients with diffuse scleroderma. It is very
specific, and suggests a relatively bad prognosis. Consider ordering this if
you believe your patient is coming down with scleroderma.
* Anti-RNA polymerase (anti-RNAP I, II, and/or III) are common in
diffuse scleroderma
and may come into clinical use (Arth. Rheum. 42: 275, 1999; Arth. Rheum. 52:
2425, 2005).
Anti-centromere antibody (* really "anti-kinetochore antibody") is a sensitive and (in high titer)
specific marker for CREST syndrome (Mayo Clin. Proc. 59: 708, 1984).
With today's f-ANA substrates, the anti-centromere pattern is obvious and there is probably
no need for a tube test.
Anti-SSA antibody ("anti-Ro", is an anticytoplasmic
autoantibody that occurs in nearly all patients with Sjogren's syndrome;
high titers can cause a
vasculitis. Low titers occur in other autoimmune diseases and normals.
Neonatal lupus (i.e., rash/heart block) is caused by Mom's anti-SSA/Ro. See NEJM 312: 98, 1985;
Arthr. Rheum. 30: 1232, 1987; Am. J. Med. 83: 793, 1987; Ped. Dis. Clin. N.A. 15: 335, 1989).
Anti-Ro is also the key player in subacute cutaneous lupus.
One intriguing study from Sweden suggests that around 1/3 of "healthy" older adults have some
complaints of dry eyes / dry mouth, and that these patients are more likely to have higher levels of
anti-Ro and anti-La on board. Stay tuned (Arth. Rheum. 35: 1492, 1992).
Anti-Ro can produce a multiple-sclerosis-like picture. Nobody really understands how.
Anti-SSB antibody ("anti-La"): is an anticytoplasmic autoantibody that is seen in patients with
primary Sjogren's. Patients with anti-SSB always have anti-SSA. The new version of this test
appears to be quite sensitive and specific for primary Sjogren's.
Anti-Jo-1 and several other markers for polymyositis-dermatomyositis are antibodies against transfer
RNA synthetases for specific amino acids (new additions: J. Immunol. 144: 1737, 1990).
Unfortunately, the group is represented in only 50% of cases, and in occasional non-PM-DM
patients.
Anti-Jo is a fair marker for dermatomyositis lung disease, and a good marker for the subluxing
arthropathy (Arth. Rheum. 33: 1640, 1990). Consider ordering this if you suspect or have diagnosed
polymyositis / dermatomyositis.
* High titers of anti-single stranded DNA antibody seems to be a marker for saber-cut scleroderma
and morphea (as above, also Arch. Derm. 123: 350, 1987). Modest titers in juvenile arthritis,
lupus (70% of cases), etc. You will not make a diagnosis based on this.
* Antibodies against proliferating cell nuclear antigen (anti-PCNA) is common in SLE.
It's not used clinically.
* The antibody anti-RA33, promoted as very specific for rheumatoid arthritis,
has not proved to be helpful (Annals of Rheum. Dis. 60: 67, 2001).
*Anti-DEK is an up-and-coming autoantibody
that seems to be specifically responsible for the iridocyclitis that is such a
problem in some patients with juvenile rheumatoid arthritis (Clin. Exp. Imm. 119: 530, 2000;
Arth. Rheum. 41: 1505, 1998).
*Anti-HSP90 (anti-heatshock protein 90) and other heatshock autoantibodies
are seen in various autoimmune diseases
but despite some claims for various specificities, nothing has panned out.
* Anti-nuclear matrix antibody is an autoantibody against a protein
peptidase. It is common in a variety of autoimmune diseases, notably MCTD. It's not much in use.
*In certain cancers (notably hepatocellular carcinoma), anti-nuclear antibodies are likely to appear
(Cancer 71: 26, 1993). Interesting, can you suggest reasons? {29557} ANA, speckled pattern
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Houston Pathology -- loads of great pictures for student doctors
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Walter Reed -- surgical cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta
Pathology Images --hard-core!
Cornell
Image Collection -- great site
Bristol Biomedical
Image Archive
EMBBS Clinical
Photo Library
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
WebPath:
Internet Pathology
Laboratory -- great site
My team:Ed Lulo's Pathology Gallery
Bryan Lee's Pathology Museum
Dino Laporte: Pathology Museum
Tom Demark: Pathology Museum
Dan Hammoudi's Site
Claude Roofian's Site
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
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
We comply with the
HONcode standard for health trust worthy
information:
verify
here. 
Men: < age / 2
When the diagnosis is obvious clinically (i.e., symmetric small-joint arthritis),
you might not even want to bother ordering a rheumatoid factor.
RIM PATTERN
Probably anti-dsDNA.
Your patient probably has systemic lupus.
HOMOGENEOUS PATTERN
Probably anti-histones.
Your patient probably has drug-induced lupus.
SPECKLED PATTERN
Could be anti-Sm and/or
anti-Ro/SSA and/or anti-La/SSB and/or
anti-U1RNP and/or any of several others.
You'll certainly want to continue your workup!
CENTROMERE PATTERN
An especially fine speckling
with little background staining. This is anti-centromere,
the marker for CREST / pulmonary hypertension.
NUCLEOLAR PATTERN
anti-Th
or anti-fibrillarin / anti-U3RNP
or anti-U17RNP. Think of
scleroderma, though most scleroderma patients
don't show the nucleolar pattern.
HOWEVER... Using the new substrates, as many as 5% of "normal" people will have a titer of 1:160 or higher.
The classic rim pattern doesn't work, and the new substrates
do pick up anti-centromere
and anti-Ro, which the older tests missed.
Anti-nuclear antibodies
Crithidia
More on lupus testing:
* Anti-topoisomerase II is especially common in localized scleroderma
More anti-nuclear antibody subtypes:
{33154} ANA, rim pattern
{33248} ANA, nucleolar pattern
{08457} ANA, nucleolar pattern
| Test |
|
|
|
Tapping the joint |
Consider doing this especially when there is a hot joint with an effusion | Heparin tube for crystals and CBC-diff;
Plain tube(s) for viscosity, mucin clot, complement, glucose, gram stain, and culture
|
|
* Synovial fluid complement |
Acute lupus, acute RA |
Likely to be low in active autoimmune disease.
|
|
* Synovial fluid RF |
Early adult RA |
Becomes positive before serum RA. Limited usefulness.
|
|
Serum rheumatoid factor |
Adult RA |
75% of adult RA's will be positive Many positives in old age, SLE, SBE, syphilis Negative in juvenile arthritis, osteoarthritis, others
|
|
* Serum IgG RF |
Adult RA |
Available. Of doubtful value.
|
|
* Serum anti-RANA |
Adult RA |
Old test based on the idea that Epstein-Barr virus causes many cases of rheumatoid arthritis, an idea that is still floating around after decades.
|
|
Serum f-ANA |
Those multi-organ autoimmune diseases |
Screening test. Titers 1:20 to 1:160 are nonspecific. Rim: Classic lupus Speckled: Classic lupus, Sjogren's, MCTD Homogeneous: Drug-induced lupus Nucleolar: Scleroderma
|
|
Serum anti-dsDNA |
SLE |
Same as anti-nDNA and anti-DNA. Higher titers are very specific for lupus. Rising titers predict an exacerbation. Titers fall on successful treatment. Now being seen after infliximab therapy also. Stay tuned.
|
|
Serum C3 |
SLE |
Usually low in lupus; of course this is not specific. Value rises to normal on successful treatment
|
|
Serum anti-Sm |
SLE |
Very specific for lupus, positive in 30% of cases.
|
|
Serum anti-histone |
Drug-induced lupus |
Most patients with this antibody remain asymptomatic. A negative value pretty much rules out drug-induced lupus.
|
|
Lupus band test |
SLE |
Requires skin biopsy. Becoming obsolete
|
|
Serum anti-nRNP |
Mixed CT disease |
All MCTD's positive, low titers in other diseases. Ask whether the lab can give you just an anti-U1.
|
|
* Serum anti-centriole |
Scleroderma |
Promoted as positive in some patients with scleroderma; not much used nowadays
|
|
Serum anti-centromere |
CREST |
High titer defines CREST syndrome
|
|
Serum anti-SSA (-Ro) | Sjogren's |
Often positive but not specific. This is the autoantibody that causes neonatal lupus with heart block.
|
|
Serum anti-SSB (-La) | Sjogren's |
Often positive but not specific
|
|
* Serum anti-adrenal |
Autoimmune Addison's |
Helps rule out other causes of Addisonism. The antigen is (at least usually) 21-hydroxylase.
|
|
* Serum anti-islet-cell |
New or impending DM type I |
Usually positive, doubtful clinical usefulness
|
|
Serum anti-insulin receptor |
Type II diabetes variant |
Insulin resistance caused by blocking autoantibody
|
|
Serum anti-sperm antibodies |
Infertility |
Husband or wife
|
|
Serum anti-AchR |
Myasthenia gravis |
Anti-acetyl cholinesterase receptor. The first test to order in suspected MG. * False positives occur in patients injected with bungarotoxin (cobra venom, quack remedy)
|
|
Serum anti-AchR Blocking Ab |
Myasthenia gravis |
Order in suspected MG if Anti-AchR is negative
|
|
* Serum anti-striational ab's |
Myasthenia gravis, thymoma |
If negative in MG, some surgeons will not remove thymus
|
|
Serum anti-GBM |
Goodpasture's |
A few false negatives. If the pathologist who does the test isn't experienced, there will be lots and lots of false positives.
|
|
Serum anti-tubular BM |
Renal interstitial disease |
Anti-TMB disease is an important, under-recognized cause of acute interstitial nephritis.
|
|
*Serum anti-intrinsic factor |
Pernicious anemia
|
Probably worthless, less sensitive and less specific than a Schilling test
|
|
*Serum anti-parietal cell abs |
Pernicious anemia |
Probably worthless, less sensitive and less specific than a Schilling test
|
|
Schilling test |
Pernicious anemia etc. |
Step 1: Give your patient radioactive vitamin B12 by mouth. See how much
comes out in the urine. If very little comes out in the urine, your patient can't absorb straight
vitamin B12 (pernicious anemia, fish tapeworm, or ileal disease).
Step 2: If your patient just proved he or she cannot absorb straight vitamin B12, repeat the test by administering a mix of vitamin B12 and intrinsic factor. If, this time, the patient excretes more of the vitamin B12 in the urine, you have established the diagnosis of addisonian pernicious anemia. Check your protocol. You'll probably want to administer an injection of vitamin B12 before the test, since you don't want the patient actually storing the radioactive substance.
|
|
Platelet-associated Ig |
Immune thrombocytopenia |
Idiopathic thrombocytopenic purpura, also SLE, AIDS
|
|
Serum anti-skin |
Blistering diseases |
Inter-epithelial antibodies: Pemphigus vulgaris Dermal-epidermal junction: Bullous pemphigoid Reticulin: Dermatitis herpetiformis (biopsy it instead!)
|
|
*Serum anti-reticulin *Serum anti-endomysium *Serum anti-gliadin |
Sprue / dermatitis herpetiformis |
Nowadays some clinicians omit small bowel biopsy
when these are positive, and move right to
the gluten-free
diet trial.
|
|
* Anti-collagen (I, IV, etc.) | Various joint diseases | Research interest only; nothing's really come of these in humans despite decades of work. |
|
Serum anti-smooth muscle |
Lupoid hepatitis 1 |
Only high titers are significant, low titers occur in many diseases
|
|
Serum anti-LKM1 ("liver kidney microsome") |
"Lupoid hepatitis" 2 | Defines the illness
Anti-liver-kidney-microsome disease.
|
|
Serum anti-mitochondrial |
Primary biliary cirrhosis |
Sensitive and specific, but only high titers are significant health threats
|
|
* Serum anti-myocardial |
"Dressler's" |
Completely out of use. The existence of Dressler's is very much in doubt anyway.
|
|
Serum anti-streptococcal |
Sequelae of strep infection |
Glomerulonephritis, rheumatic fever. Several tests are available, ask you lab ("ASO", "anti-hyaluronidase" are popular). They will be positive by the time your patient has rheumatic fever or glomerulonephritis.
|
|
* Serum anti-teichoic acid |
Staph infections | This used to be
used to monitor the treatment of osteomyelitis, but is now completely out of
use which is fine (Ped. Inf. Dis. J. 17: 1021, 1998)
|
|
Serum anti-neutrophil cytoplasmic antigen |
Wegener's, polyarteritis |
Anti-myeloperoxidase (p-ANCA, p-ACPA) causes many cases of polyarteritis nodosa (the "small vessel" variant). You'll also see it in most patients with the combination of sclerosing cholangitis and ulcerative colitis.
Anti-proteinase 3 (c-ANCA, c-ACPA) is closely linked to Wegener's granulomatosis. You can see these in various systemic autoimmune diseases; whatever the "underlying systemic vasculitis. Certain nonspecific ANCA's probably result from longstanding inflammation, as in rheumatoid arthritis (Art. Rheum. 36: 994, 1993).
|
|
Serum C' esterase inhibitor |
Hereditary angioedema |
Ask for both level and functional assay
|
|
Serum complement components |
Deficiency states |
Deficiencies of C1q, C1r, C1s, C4, C2, C5, and/or C8 simulate SLE
Deficiency of C6, C7, C8 have recurrent neisserial infections In seeking out genetic birth defects, ask for both level and functional assay. You can of course also use C3 and C4 to monitor the course of lupus.
|
|
Serum CH-50 |
Screening test for all complement component deficiencies ("titer that hemolyzes 50% of the test red cells") |
Has also been used to follow the course of SLE
|
|
Serum anti-cardiolipin |
SLE, AIDS, aborters, clotters |
Newly recognized major disease, with thrombosis and abortion. Also called anti-phospholipid. Biochemically similar (but not identical to) "lupus anticoagulant" and the lupus biologic false positive for syphilis.
|
|
Nitroblue Tetrazolium test |
Chronic granulomatous disease (i.e., the neutrophil killing defect) |
Hereditary immunodeficiency syndrome with defective killing of staphylococci by polys
|
|
Serum anti-allergen IgE |
Food or penicillin allergy |
"RAST", supposed to replace skin tests, expensive.
|
|
* Raji cell assay |
Circulating immune complexes |
Limited usefulness
|
|
HLA-B27 |
Ankylosing spondylitis, etc. |
Classic example of a result that is unlikely to affect patient management
|
|
* Von Willebrand factor |
Vasculitis |
In patients who do not have von Willebrand's disease but who do have some kind of serious systemic vasculitis (lupus, polyarteritis nodosa, Wegener's, Henoch-Schonlein, and so forth), levels of vWFAg are likely to be elevated (why? Arch. Dis. Child. 70: 40, 1994)
|
|
* Thrombomodulin |
Vasculitis |
Endothelial thrombin receptor. Serum levels increase in vasculitis (Am. J. Clin. Path. 101: 109, 1994)
|
|
Complement 3 nephritic factor |
Membranoproliferative glomerulonephritis types I and (now) II |
Pathogenic; helps establish the diagnosis
|
|
"Heterophile antibodies" |
Many inflammatory diseases |
Agglutinate sheep red cells. Nobody orders this test.
|
|
Forsmann antibodies |
Many inflammatory diseases |
Heterophile antibodies that are absorbed by guinea pig kidney but not by beef RBC's. Nobody orders this test.
|
|
Mono test ("Mono-spot") | EB-virus infectious mono |
Heterophile antibodies that are absorbed by beef RBC's, not by guinea pig kidney. Cheap test, sensitive and specific, but often remains negative for many weeks, often never turns positive in children
|
|
Serum IgG anti-EBV capsid |
EBV infection, past/present |
Expensive, high titers suggest current infection. This is the test to order
if the "Mono-spot" is still negative but you still suspect EBV mono.
|
|
Serum IgM anti-EBV capsid |
Current EBV infection |
Sensitive and specific, very useful in children
|
|
EBV "early antigens" |
Early or chronic EBV disease |
Ask your infectious disease expert whether these tests are useful.
|
|
CMV, toxoplasmosis, HIV tests |
Remember these too in "infectious mononucleosis"; "post-viral fatigue syndrome"
|
| Visitors to www.pathguy.com reset Jan. 30, 2005: |
Ed says, "This world would be a sorry place if
people like me who call ourselves Christians
didn't try to act as good as
other
good people
."
Prayer Request
Teaching Pathology
PathMax -- Shawn E. Cowper MD's
pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic
Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification
Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science
Trivia Quiz -- have a chuckle!
Rudolf
Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
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Taser Video 83.4 MB 7:26 min |
