Laboratory Tests — Misc. Comments

Today’s post (& next) address a number of subtle & interesting issues about the common tests we all order, the Complete Blood Count (CBC) and Comprehensive Metabolic Panel (CMP).  A number of points have been previously discussed in other contexts, but here it’s all lumped together under “Labs.”

A brief word about “normal” values first.  Each lab should set its own.  High & Low “Normals” should, by definition, mean the points lying 2 standard deviations (S.D.) above & below the population’s mean on a Bell curve.  Of course, we never actually know what “population” our specific labs are referring to, nor how often these values are readjusted.

More important, this definition of “normal” means that purely statistically, 5% of tests should return abnormal (since 2 S.D. in each direction encompasses 95% of a population).  So 2.5% (1 in 40) will be “low,” and another 2.5% “high.”  As such, a person whose test result comes out “low” is more likely to have whatever associated condition or disease than another person whose test is “normal,” but does not necessarily have that condition.  Similarly, a person with a “normal” test may actually have the disease in question.  It’s a matter of probabilities.

Therefore, purely statistically, if you repeat a given test 20 times on the same person, it will probably be abnormal once (1 in 20 = 5%).  Similarly, if you order that same test on 20 different people, one is likely to be abnormal.  And most interestingly, if we order 20 tests on the same person, one is likely to be abnormal by probabilities alone, without meaning that the person has any disease at all.

When do we order 20 tests on a patient?  Whenever we check “Comprehensive Metabolic Panel” on a lab slip.  Try explaining all this to a worried patient — it’s very time-consuming.  It might be easier to explain it to the laboratory’s shareholders, since abnormal results invariably generate more test orders.

With this in mind, let’s discuss some specific tests.

COMPLETE BLOOD COUNT (CBC)

RED BLOOD CELL tests are covered extensively under Anemia – 1.  Here we’ll say a little about White Cells & Platelets.

WHITE BLOOD CELLS (WBCs)  —  The main thing to remember about WBCs is that absolute counts are what matter, not the percentages in the differential.  If absolute counts aren’t reported, you’ll have to multiply the total WBCs by percentages.  We had to do this a lot in the old days, & never bothered to unless the total WBCs were really high or low, or there was a cell type comprising a very unusual percent of the differential.

Neutrophils —  When we say “WBCs,” we usually mean Neutrophils, which can be either too low or too high.  The magic number for too low, Absolute Neutropenia, is an absolute neutrophil count <500/microL.  Some clinicians begin to worry when the count is <1,000, though the real risk for sepsis is <500.  Low absolute lymphocytes (<1,000) is undoubtedly an acute viral infection, though it could be a chronic one.  Repeat in 1-2 weeks, & test for HIV if still low; if patient symptoms are compatible with an AIDS opportunistic infection, test immediately.

Too high:  Studies define leukocytosis as >11,000 WBCs or >8,000 absolute neutrophils.  The 11,000 was the most sensitive parameter for acute appendicitis, though in real life we don’t tend to jump until total WBCs approach 15,000.  Of course, if there’s actually a lymphocytosis, we’d think more about viral infections (like mono) and  pertussis.  Really high absolute lymphs (15 – 20,000 on up) could be pertussis, but we’d need to worry about leukemias.

High neutrophils usually suggests increased bone marrow activity due to bacterial infection, but can also occur from any acute stress due to demargination (non-circulating mature neutrophils clinging to endothelium “margins” get released).  “Stress” means anything that gets lots of epinephrine flowing: M.I., kidney stone, car accident, etc.  Not final exams, nor a break-up.  Total WBCs can also be elevated due to corticosteroids, smoking, and pregnancy.

The way to distinguish acute infection/inflammation from demargination is by a manual differential, which can count bands (immature neutrophils, a.k.a. “segs” and “stabs”).  Over 5% bands gets flagged “abnormal,” though >700 absolute bands is more convincing.  A manual smear can also reveal “toxic granulation,” “Döhle bodies,” and “vacuoles,” all of which suggest acute systemic infection/inflammation.

If platelet clumping is incidentally noticed on a manual smear, Beware.  The automated counter may have accidently counted them as WBCs (spurious leukocytosis).

Eosinophils —  These are conventionally considered high if there are over 500 absolute Eos per microL.  However, lab reports have conventionally flagged >5% as “high.”  Really, never worry about eosinophilia unless the absolute count is >500, & most conditions requiring work-up will have >1,500.  See Eosinophilia for more discussion; the mnemonic for its differential is “NAACP” (Neoplasms, Asthma, Allergies, Connective tissue disease, Parasites).

Monocytes  —  These can be elevated in a variety of infections (TB, brucella, syphilis, etc. etc.) & malignancies; also autoimmune diseases, depression, asplenia, & even pregnancy.  As such, the finding is completely non-specific.  I’ve never heard of anyone working up high monocytes.

Basophils —  These are even less relevant than monocytes.  There are basophilic variants of leukemia, but the total WBCs would strike you first.  Maybe acute hypersensitivity could increase the basophils.  Call Heme for persistent basophils >1% (I’ve never heard of it).

Immature Forms  —  Rarely a metamyelocyte might appear if the bone marrow is really active.  Anything more immature, i.e. myelocytes, promyelocytes, or blasts, undoubtedly means cancer.  I’d even talk to Heme if metamyelocytes appeared on a repeat.

PLATELETS  —  Low platelets equals thrombocytopenia; see our discussion under Bruising / Bleeding.  The main confounder is when platelets clump, meaning the “low” count is spurious.  Never accept a low platelet count without a comment by the lab that they confirmed it by manually looking at a smear [Aside: the jargon doesn’t quite make sense, though we do order “manual smears,” not “visual” ones].  Low platelets require a work-up (like HIV, cirrhosis, etc.), though nobody bleeds until the count falls below 25,000.

Platelets get flagged as “high” when >400,000/microL; we don’t address them until they’re >450,000.  The cause may be an extraneous reason such as bleeding or asplenia.  The first step in work-up should be a repeat; in one study, only 8% of patients remained high within the next 8 months.

Since platelets increase as an acute phase reactant, the differential of thrombocytosis is broadly divided into Reactive vs. Essential.  “Reactive” means due to conditions such as infection or autoimmune disease.  Essential Thrombocytosis invariably winds up being some sort of hematologic malignancy.

Platelet counts over 1 million can cause strokes; we start to worry at 800,000.  Paradoxically, Reactive Thrombocytosis doesn’t cause strokes, and is much more likely to generate such extreme elevations than is Essential.  I had a patient with active Crohn’s disease, & platelets of 1,100,000.  Heme wasn’t interested, shrugged it off as “just reactive”.

Next time I have such a patient, or one with just 800,000 platelets, I’ll still call them.

ERYTHROCYTE SEDIMENTATION RATE  (ESR; Sed Rate)

This is such a non-specific test, that one lecturer I heard commented, “A high sed rate only proves for sure that the lab was open that day.”  Sed Rates can be elevated due to any kind of infection, inflammation, or active malignancy.  In terms of the latter, a normal ESR rules out nothing.

Still, I find it useful in 2 contexts:

• For patients with vague symptoms like fatigue or joint pains, a normal ESR supports a decision not to pursue extensive work-up, provided there is no other clinical reason either (certainly don’t focus on the ESR if there are significant findings like weight loss, etc.).
• Sed Rates that are extremely high, close to or >100, suggest a handful of significant illnesses, such as endocarditis, temporal arteritis, HIV, renal failure, active TB, or multiple myeloma.

Today, the C-Reactive Protein (CRP) seems to have replaced the ESR.  Personally, I prefer the latter, a function of age — my age; I’ve worked with it for so long.  Also, I don’t have a feeling for what represents an “extremely high” CRP, analogous to an ESR of 100.  However, the CRP is fine; equally non-specific.

The Sed Rate, by the way, is a measurement (in mm/hr.) of how fast RBCs settle out in a tube.  Fibrinogen (a product of inflammation) causes RBCs to cling together & stack (“Rouleaux formation”), & thus settle faster (i.e. higher ESR).   RBCs also settle faster in less viscous plasma, so anemia (especially hemoglobins <9) may give falsely elevated ESRs.

The ESR also goes up with age, and is slightly higher in women.  A neat formula (which has been questioned) for a “normal” ESR: 1/2 the age, add 5 in women.

In resource-poor areas, a Sed Rate can be performed by simply drawing a tube of blood & letting it settle for an hour.  For a woman with acute pelvic pain, a high ESR would suggest PID, a normal one perhaps an ectopic.  Flank pain with a high ESR might be Pyelo; vs. a Renal Stone if it’s normal.  Not so relevant with more modern diagnostics, however.

That’s all for today.  Next time: the CMP (comprehensive metabolic panel).