Heme/Onc: understanding anemia

When admitted to the hospital almost all patients will receive a standard battery of blood tests, which includes a Complete Blood Count (CBC).  Often a primary care office will order such work for their patients simply to have a baseline, and many specialists will do so as a means to monitor drug reactions and overall health.  A CBC includes the measurement of many different components of blood, including the number of red blood cells, white blood cells, platelets, hemoglobin, hematocrit, and mean corpuscular volume.  The shorthand of the CBC looks like this:

On the left is the number of white blood cells; on the right- platelets; the H & H is in the middle, referring to the hemoglobin and hematocrit, with the hemoglobin on top.  For anemia the Hemoglobin (Hgb) matters most.  While it doesn't appear in the shorthand form of the CBC, the Mean Corpuscular Volume (MCV) also matters since it allows for an easy classification of anemia.  

Anemia results from a decreased oxygen delivery by the blood.  Symptoms can include many different manifestations including fatigue, lethargy, cold intolerance, and even passing out!  Anyone can address the symptoms, but only in knowing the type and cause of the anemia can one hope for an overall cure.  This does not mean that the anemia can't self resolve.  Many people may become transiently anemic yet never know it, but if seeking medical attention the patient will want as much information as possible.  

Mean Corpuscular Volume refers to the average red blood cell volume.  An anemia will very often affect this number thus allowing for a very simple classification, based on whether the number occurs within normal limits.  The normal value for an MCV ranges between 80 - 100.  The system of classification is as follows:

• Normocytic: MCV between 80 - 100
• Microcytic: MCV less than 80
• Macrocytic: MCV greater than 100

Knowing the type of anemia starts the search for a cause, but in no way gives a definitive answer on its own.  But at least you can sound smart by beginning with a classification of the anemia.  

Microcytic anemias, those with an MCV below 80, often have red blood cells which look pale compared to normal--a phenomenon known as hypochromasia.  Numerous causes exist for a microcytic anemia, but keep in mind that while a microcytic state may point in one direction it is still important to consider causes which typically present as normocytic or macrocytic.  That said, the most typical causes include: 

• Iron deficiency
• Thalassemia
• Sideroblastic anemia
• Anemia of chronic disease

To understand the entities which compromise microcytic anemias requires an understanding of hemoglobin--the oxygen carrying compound in red blood cells.  Hemoglobin has two components:

• Heme: the iron containing molecule of hemoglobin
• Globin chains: four subunit chains defined as either alpha, beta, gamma, or delta

These components must come together correctly in order to have a properly functioning hemoglobin.  While iron deficiency affects heme, it is thalassemia which affects the globin chains.  Thalassemia results from a genetic mutation affecting the formation of the globin chains.  Normal adult hemoglobin has two alpha and two beta chains, and normal fetal hemoglobin has two alpha and two gamma chains; the condition is named for the chain it affects.  Thus alpha thalassemia affects the formation of the alpha chain, and so on.  

One must also understand sideroblastic anemia, a condition which results when the bone marrow makes ringed sideroblasts rather than typical red blood cells.  While it sounds confusing just understand that ringed sideroblasts are basically red blood cells which have nuclei as well as iron deposits.  Any number of things can cause a sideroblastic anemia, but four particular causes to know:

• Alcohol
• Pyridoxine deficiency
• Lead poisoning
• Myelodysplasia

A prussian blue stain, which will pick up the iron, may appear as follows:

Normocytic anemias occur within the normal limits of the MCV value.  Again keep in mind that causes between the different anemias may overlap:

• Aplastic anemia
• Sideroblastic anemia
• Anemia of chronic disease
• Fluid overload

Aplastic anemia occurs when the bone marrow does not respond adequately to the need for new RBC production.  To measure this look at the reticulocyte count, which is normally less than 2.  During times in which the bone marrow must make new RBCs the reticulocyte count should rise above 2, if it does not consider that the bone marrow has not appropriately responded to the stimulus for more production.  

Macrocytic anemias occur when the MCV has surpassed 100.  When thinking of this type of anemia think of diet induced.  Although not always true it covers the three most important causes:

• Vitamin B12 deficiency
• Folate deficiency
• Alcohol

Thus comes the biggest question: how does one evaluate an anemia after looking at the MCV?  

Simple: order more tests!  

Absolutely standard tests for anemia should include a measure of serum iron, a ferritin level, and the calculated Total Iron Binding Capacity (TIBC), as well as a Serum Protein Electro Phoresis (SPEP), Urine Protein Electro Phoresis (UPEP), and a level of B12 and folate.  

Other tests to order may include a Lactate DeHydrogenase (LDH), which is released during cell destruction and serves as a particularly useful marker for RBC destruction.  

I can go into further detail if anyone would want that.  Just message me.  In the meantime I find an interesting article, which I have cited, in the AMA's Archives of Internal Medicine.  Written in 1958, it describes the clinical application of SPEP, something taken for granted today.  You may find it a waste of time to read, but it is interesting to see how science has progressed!

 

Robert Wall (1958). The Use of Serum Protein Electrophoresis in Clinical Medicine Archives of Internal Medicine, 618-658

The importance of the cardiac physical exam?

If it hasn't seemed apparent enough in the previous posts, I once again want to stress the importance of the physical exam.  By taking the time to thoroughly examine the patient, which includes a thorough history, tragic events like this can be avoided.

Numerous things should happen during any physical exam, but the cardiovascular exam should include: visual examination, palpation, and auscultation; with most of the focus on the neck and chest.

So what to do...

Take a few blood pressures.  Check each arm and one leg, normally the leg will have the higher blood pressure.  If not, add coarctation of the aorta to the differential.

Feel for pulses.  While weak distal pulses does not have to mean pathology, left ventricular hypertrophy is one possible cause.  Keep in mind that LVH occurs due to conditions such as AS, IHSS, AR, MR, and event HTN.

Look at the eyes.  Using the ophthalmoscope check for neovascularization, which suggests the blockage of arteries having resulted in the formation of new ones.  Two important disease entities to consider if you see this: diabetes, and coronary artery disease.

Examine the neck.  This means giving more than a shear glance and looking at the internal jugular vein, which includes checking for differences during inspiration and expiration; and listening for bruits in the carotid arteries.

• Bruit: the turbulent flow of blood past an obstruction, otherwise understood as the abnormal sound blood makes as it passes an obstruction.  Because of the pumping of blood the bruit will make two sounds--the upstroke and the decline.  The importance lies in the speed of the upstroke and the speed of the decline, which together can aid in a diagnosis.
• Rapid upstroke, Rapid decline: aortic regurgitation 
• Rapid upstroke, Delayed decline: IHSS
• Delayed upstroke, Delayed decline: aortic stenosis
• Slow upstroke, Normal decline: atherosclerosis, only occurs in the carotid with the plaque
• Internal Jugular Vein: correlates with pressure in the right atrium.  The pulse should normally be seen around 5 centimeters above the Angle of Louis of the sternum.  To look for this the patient should lay on the table at an incline of 30 to 45 degrees.  For comparison: 10cm from the Angle is the mandible; at 12cm is the ear lobe.  Two important entities need consideration when checking the internal jugular: 
• Hepatojugular Reflux: a sign of right atrial overload, will stay elevated on inspiration and expiration.
• Kussmual's Signs: distention of the internal jugular with inspiration; suggestive of pericardial effusion and impending respiratory failure.

Next, move on to the chest.

Palpate the chest.  Particularly check three areas:

• Apex: should be at the left 5th intercostal space at the midclavicular line, but can vary slightly depending on the heart's deviation.  However, barely feeling it during S4 suggests a small heart, where as a large heart will generally create a sensation across all palpating fingers during S3.
• Sternum: roughly located above the right ventricle.  Normally one will not feel it; only right ventricular hypertrophy is felt.  If felt you should add tricuspid regurgitation to your list, auscultating a systolic murmur in the tricuspid area would only further support this diagnosis.
• Sternal border: correlates well with the left atrium, and just like the right ventricle it will only be felt if enlarged.  With left atrial enlargement consider disease states such as mitral stenosis, mitral regurgitation, and dilated cardiomyopathy.

Listen to the heart.  Listen for heart sounds and check for murmurs.  Focus on the four main areas:

• Aortic: the right 2nd intercostal space
• Pulmonic: the left 2nd intercostal space
• Tricuspid: the left sternal border
• Mitral: the left 5th intercostal space at the midclavicular line

And of course: always take a good history! 

More on heart sounds and cardiac history taking later...

Unfortunately the physical exam has lost its importance to many practitioners.  

In lieu of looking, listening, and palpating CT, MRI, US, and XR have come in as replacements.  While radiographic and ultrasonographic imaging have benefits, they have downsides as well.  After all, a physical exam doesn't expose the patient to radiation, require a contrast medium, or cost any more money than the salary to employ the practitioner.  But in a society clamoring for big money lawsuits clinicians need to protect themselves, and imaging modalities can provide conclusive answers without the subjectivity of the clinician's skills.  

Some medical schools require their students to do rotations in rural areas, which often lack the bells and whistles of large cities.  It is unfortunate that the bodies which govern medical education across the board don't mandate such training.  Only when one must go without reliance on imaging will he or she learn to appreciate a good physical exam.  

Jauhar, S. (2006). The Demise of the Physical Exam New England Journal of Medicine, 354 (6), 548-551 DOI: 10.1056/NEJMp068013

Cardiology: Murmurs!

The stethoscope has practically become the icon of healthcare.  To wear a stethoscope suggests that a person has some sort of clinical knowledge.  After all, why else would a person have a stethoscope on their person if they did not actually know how to use it?  A stethoscope amplifies sound to make very subtle noises audible to the human ear.  Thus the sounds of the hearts valves closing, the movement of air into and out of the lungs, the bowels doing their thing, and so on get recognized clinically with the use of a stethoscope.  Without an understanding of what the sounds actually mean such information proves useless, allowing the stethoscope to serve as nothing more than a mere piece of jewelry.

When putting the stethoscope to the chest one can look at the chest as having four separate areas in which to listen for heart sounds:

• Aortic: the right second intercostal space adjacent the sternum
• Pulmonic: the left second intercostal space adjacent the sternum
• Tricuspid: the left third and fourth intercostal spaces adjacent the sternum
• Mitral: the left fifth intercostal space in the mid-clavicular line, often the point of maximal intensity

The location of a heart sound allows for the listener to determine the significance of a murmur based on the clinical picture.  Some of the sickest patients may have a murmur which needn't be addressed while some of the healthiest patients can have murmurs which signify the presence of a silent killer.   This means that the clinician wields a heavy tool in his or her stethoscope.  

Just as a jugular venous pressure wave shows the cardiac cycle of systole and diastole, the stethoscope auscultation, or listening to the heart provides an audible representation of heart function.  Normally two sounds, or beats get heard: S1 and S2.  When someone describes the heart as making a lub dub noise, they are referring to S1 and S2.

• S1 is the sound of the bicuspid and tricuspid valves closing during systole, the aortic and pulmonic valves should be open
• S2 is the sound of the aortic and pulmonic valves closing during diastole, the mitral and tricuspid valves should be open

To learn mumurs, which usually sound like a whoosh instead of or after a beat, it's easiest to think of them in terms of whether they occur in systole or diastole.  Knowing their location helps to limit the differential.

Systolic murmurs are those which occur during systole, and can be further classified upon when the murmur actually occurs.

• Early to mid systolic murmurs
• Pulmonic Stenosis (PS)
• Tricuspid Regurgitation (TR)
• Atrial Septal Defect (ASD)
• Idiopathic Hypertrophic Subaortic Stenosis (IHSS)
• Mitral Regurgitation (MR)
• Mid to late systolic murmurs
• Mitral Valve Prolapse (MVP)
• Aortic Stenosis (AS)
• Holocystolic--occurring throughout all of systole
• Tricuspid Regurgitation (TR)
• Mitral Regurgitation (MR)
• Ventricular Septal Defect (VSD)

Notice that TR and MR can occur as either early/mid systolic as well as pan-systolic.  The difference being that something acute occurs early, where as a chronic condition happens throughout.  

Diastolic murmurs also occur, albeit considerably less to know than the list of 10 systolic murmurs.  Often one auscultates these best in the neck, and can quantify them based on the sound they make: a rumble vs. a blow.

• Diastolic Rumbles
• Tricuspid Stenosis (TS)
• Mitral Stenosis (MS)
• Austin Flint 
• Diastolic Blows
• Aortic Regurgitation (AR)
• Pulmonic Regurgitation (MR)
  

Once the clinician has auscultated a murmur he or she must somehow differentiate the type.  An echocardiogram can effectively diagnose problems with valves and septa (the plural for septum, not the transit authority).  However, since not always practical or available, the practitioner should remember a few fundamentals to accurately diagnose a murmur by physical exam.  Since the heart handles systemic circulation, look at the heart as a dual circuit: the right side of the heart receives blood from the venous circulation, anything which increases venous return will increase a murmur on the right; the left side of the heart pumps blood into arterial circulation, anything which increases the arterial blood pressure will increase a left sided murmur.  

• Inspiration & leg raising: increase the amount of blood from venous circulation returning to the heart, this increase in preload leads to an increase in the duration of right sided murmurs
• Squatting: increases the amount of blood returning to the heart as well as the systemic arterial blood pressure, this increase in both preload and afterload results in increased duration of right and left sided murmurs
• Hand grip: constriction of the radial and ulnar arteries leads to a backup of arterial blood which increases the arterial blood pressure, this increase in afterload causes an increase in left sided murmurs
• Valsalva & standing: leads to a decrease in both preload and afterload, ultimately reducing the duration of both right sided and left sided murmurs

One very important exception exists to these rules: IHSS

• Duration increases with valsalva
• Duration decreases with squatting

In considering the pathophysiology of IHSS, it makes sense.  Because of the hypertrophy of the subaortic area of the left ventricle blood will have a difficult time getting from the left ventricle into the aorta.  However, if the pressure in the arterial circulation increases it will lead to an increase in left ventricular pressure in order to compensate.  Where as this will increase the effect of most left-sided pathologies and thus increase their associated murmurs, in IHSS the pressure increase will push against the hypertrohpied tissue and essentially push it out of the way such that blood will move by easier and result in a diminished murmur.  Following the same logic the opposite is also true.  

Some people could not help themselves and insisted on putting their namesake to a diastolic murmur.  Nonetheless three particularly important ones exist:

• Carey Coombs Murmur: the diastolic murmur of mitral stenosis heard as a result of rheumatic heart disease
• Graham Steell Murmur: the diastolic murmur of pulmonic valve regurgitation
• Austin Flint Murmur: the diastolic murmur heard best in the mitral area associated with severe aortic regurgitation compressing against a normal mitral valve

Although not very recent, a 1990 study showed that in diagnosing pediatric murmurs the clinical skills of an experienced cardiologist have a sensitivity of 96% and specificity of 95%.  While it may seem great, just ask yourself this: how many doctors today rely on their physical exam skills as much as those who practiced decades ago?  Just how many doctors today actually qualify as experienced as determined by that article?  Since the article left out such criteria I cannot know, but I suspect the number would be considerably less. 




John F. Smythe MD, Otto H. P. Teixeira MD, Peter Vlad MD, Pierre Paul Demers MD, & William Feldman MD (1991). Initial evaluation of heart murmurs: Are laboratory tests necessary? The Indian Journal of Pediatrics, 58 (2), 231-231 DOI: 10.1007/BF02751126