Anemia a clinical perspective

Anemia A Clinical Perspective

DAVID STEINBERG

Section of Hematology, Lahey Clinic Medical Center, Burlington, Massachusetts, 01805

T he purpose of this discussion from a clinician is to provide a perspective of anemia as it is seen by the

practicing physician. I think it is valuable for clinical chemists to understand the context in which the laboratory data they generate are used in making diagnostic and therapeut ic decisions, l will s tar t with some com- ments about anemia in general and then discuss specific forms of anemia. I will comment on iron, v i tamin B12, and folic acid deficiencies, anemia due to bone marrow infiltration, anemia of chronic disease, and hemolytic anemia.

I will begin with an a t tempt at a definition of anemia tha t will encompass the full meaning of the word as it is understood by the practicing physician. Let me con- fess, in advance, that I will not succeed; however, ex- plaining why it is difficult to define anemia should give you a bet ter appreciation of what the term means to doctors. According to Wintrobe's venerable hematology text (1), "the te rm anemia as it is general ly used in clinical medicine refers to a reduction below normal in the concentration of hemoglobin or red blood cells in the blood." Will iams' textbook (2) says, "anemia is func- t ionally best characterized by a hemoglobin concen- t rat ion below normal." These definitions, in essence, say a person is anemic when the level of hemoglobin or hematocr i t is below the laboratory 's normal value.

Using case examples, I will show that some pat ients whose hemoglobin value is normal and who, by definition, are not anemic have disorders listed among the anemias. Conversely, some patients are reported with hemoglobin values below normal who, despite our definition, should not be considered anemic.

The first example is a 55-year-old man with t ingling in his fingers and toes, loss of equilibrium, and a sore, swollen tongue. The hemoglobin was 14.2 g/dL and the mean corpuscular volume (MCV), 120 ~m :3. Although this man, by definition, was not anemic, appropriate studies showed he had classic pernicious anemia. He had perturbed red blood cell production, but the manifestations had not yet included frank anemia. By definition, this man was not anemic, but he had a disorder physicians commonly include in any classification of the anemias.

A 38-year-old woman of I ta l ian descent was seen for a routine examination. The hemoglobin was 12 g/dL, and the MCV, 58 ~m 3. Studies proved she had a thai-

Correspondence: Dr. David Steinberg, Lahey Clinic Medical Center, Section of Hematology, 41 Mall Road, Box 541, Burlington, MA 01805.

This paper is based on a presentation by the author at the Joint Congress on Clinical Chemistry, Quebec City, June 26-30, 1983.

assemia t rai t (Mediterranean anemial. Despite the fact tha t by our definition she was not anemic, she also had a disorder classified as a form of anemia.

The third example is a 42-year-old woman with a hemoglobin of 12.3 g /dL and a reticulocyte count of 20q. This woman, by definition, was not anemic, but studies showed she had au to immune hemolytic anemia. The hemoglobin value was normal because she compensated with excess red blood cell production.

The next pat ient i l lustrates the converse. A 31-year-old man had a hemoglobin of 13.5 g/dL, a value lower than the laboratory 's normal of 14 g/dL. By definition, he had anemia; however, numerous tests showed no abnormal i ty in red blood cell production or destruction and he has had a stable hemoglobin level for six years. In this case, we are detecting the small proportion of the population whose value is below our level of normal but who do not have disease. Such pa- t ients can be a great concern to the clinician who has to decide whether or not there is a problem. The nature of anemia as a pa ramete r of disease, as we shall see, makes this an important question.

A 21-year-old woman in the third t r imester of pregnancy had a hemoglobin value of 11.5 g/dL. She was, by definition, anemic, but she was not truly anemic; she had "spurious anemia" due to hemodilution caused by excess plasma accumulated during the third t r imes ter of pregnancy.

A final and perhaps atypical example of a pat ient anemic only by definition is a man with a hemoglobin value of 9.3 g /dL whose case was reported in the medical l i terature. This man had an abnormal hemoglobin, hemoglobin Seattle, with a low affinity for oxygen. His hemoglobin molecule was excessively generous in de- l ivering oxygen to the tissues, and physiologic delivery of oxygen could be mainta ined at a lower than normal hemoglobin level. Red blood cell production and destruction were not abnormal. This low hemoglobin level was physiologically normal; he was not anemic in the usual sense of the word.

These cases i l lustrate that when a laboratory gener- ates a hemoglobin or a hematocri t value, a decision whether or not a pat ient has a disorder tha t we commonly include among the anemias involves consid- erat ion of factors other than simply the hemoglobin level. The hemoglobin is only a s tar t ing point the clinician considers in a wider context.

From a clinical perspective, the most important con- cept concerning the nature of anemia and one tha t every practicing physician mus t unders tand to avoid disaster is tha t anemia is a signal of d i s ea se - - an emia is a sign tha t something is wrong, but it is not a disease

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itself. Pat ients have suffered devasta t ing consequences because mild degrees of anemia were neglected. A man who has 12.8 g /dL of hemoglobin is not going to be symptomat ic from this. It will not make him tired, and it will not threa ten his life. However, the presence of anemia means tha t "something" is wrong. That "something" can be a duodenal ulcer, a cancer of the colon or kidney, rheumatoid arthrit is , bacterial endocarditis, or any one of hundreds of diseases. The physician taking care of an anemic pat ient must determine the basic cause of the problem. The good hematologist should also be a good general internist. Anemia can be the present ing manifestat ion of a disorder in vir tual ly any organ system.

In one of our laboratories is a nicely designed table depicting abnormal blood tests in the various anemias. Although this may be a helpful guide, it gives a limited picture of how the practicing physician approaches anemia. The house staff often talk of ordering "an anemia workup" when they see an anemic patient, as if there were such a thing. The t ruth is that the workup of anemia does not begin with a bat tery of laboratory tests. The evaluation of anemia begins with the history and physical examination. As we discuss the various anemias, it will be apparent tha t critical clues often come from simply ta lking with the pat ient and from the physical examination. These influence the workup of anemia before there are any laboratory data. A few il lustrat ive examples follow.

A 22-year-old woman was iron-deficient a year ago and only briefly and inadequately took iron pills. She is still having heavy periods and is again anemic. From her story we can assume she probably has iron deficiency. If we learn she is sucking on ice cubes Imore about this later), the diagnosis of iron deficiency is vir- tual ly confirmed before doing any additional laboratory tests.

An elderly anemic person who has painful sensations in the extremities, a sore, swollen tongue, and is off balance when walking will probably have v i tamin B12 deficiency. A person of I tal ian or Greek descent with a family history of anemia is likely to have thalassemia. A pat ient whose father, uncle, and brother had splenec- tomy because of anemia is likely to have heredi tary spherocytosis. I f a pat ient has telangiectasia of the skin and mucous membranes , which is typical of Osler- Weber-Rondu disease, you will suspect s imilar telangiectasia in the gastrointest inal tract. These bleed and cause iron deficiency. The physical examinat ion in such a pat ient provides a major clue to the cause of anemia.

The physician's perspective of anemia, therefore, begins with the maneuvers he makes as he evaluates the problem, and these are dictated not by a flow sheet or his notion of an anemia workup but by the signals he detects from ta lk ing with and examining the patient. The laboratory evaluation of anemia is not the s tar t ing point.

I r o n deficiency

Iron deficiency may be the commonest heal th problem in the world today. Iron is the only major deficiency

disease still prevalent in our prosperous western society. Let me begin with some basic physiology.

Body iron exists in several forms. Hemoglobin in blood and myoglobin in muscle are iron-containing compounds that bind and deliver oxygen. Certain en- zymes contain iron. h'on is stored as ferritin and hemosiderin.

The small amount of iron lost from the body is usually lost with the desquamation of epithelial cells in the gastrointest inal tract. Very little iron is lost in the urine. A normal adult man, and a nonmens t rua t ing adult female, lose only about 1 mg of iron a day 10.6 to 1.6 mg). To absorb this amount of iron, the diet must contain about 10 mg of iron. This is because iron absorption is incomplete. It is est imated tha t in the Amer- ican diet there is about 6 mg of iron for every 1,000 calories consumed. It is vir tual ly impossible for an adult man or a nonmens t rua t ing female to become iron- deficient simply because of a poor diet. It can be a lethal mis take to ascribe iron deficiency in an adult man or a nonmens t rua t ing female to a poor diet. h'on deficiency due solely to a poor diet is so unusual that such cases are reported in the medical l i terature. One such pat ient was a 58-year-old retired schoolteacher with a psychiatric disorder. For a period of 27 years his diet consisted of a doughnut and coffee for breakfast , milk or orange juice o1" perhaps a sardine for lunch, and some thin clear soup for supper. During these 27 years he denied any significant mea t o1" egg intake. He became iron-deficient because of a bad diet; such examples are, however, extremely rare.

The si tuation is different in mens t rua t ing women. The average menst rua l blood loss is considered to be about 40 mL of blood per cycle but is greater than 80 mL in 10c~ of women. Incidentally, it has been shown tha t women are a poor judge of the amount of their menstru- al blood loss. It is est imated tha t most women require about 2 mg of iron a day to mainta in normal iron balance. This amount is not always available in the diet and explains why iron deficiency anemia is common in mens t rua t ing women.

There are a few interest ing historical explanations for a suspected recent increase in the incidence of iron deficiency anemia. The amount of iron in the diet is roughly comparable to the amount of calories consumed. Years ago the physical labor demanded of women was more than it is now, and women consumed more calories. More calories mean t more iron. Also in the past, some persons cooked in iron pots, which leached iron and were an added source of dietary iron. A theory tha t qualifies as a historical curiosity states tha t during periods in history when women wore t ight corsets there was an increased incidence of anemia. Theories postulated to explain why the wearing of corsets caused anemia included reflux of gastric contents causing bleeding and such abdominal t ightness tha t iron-rich foods, such as meat , were not consumed.

There are other physiologic si tuations where there are increased demands for iron. Excess iron is needed in infancy and adolescence to make blood. During pregnancy, mate rna l iron is diverted to produce fetal red blood cells. Iron is also lost during lactation; as much as 30 mg of iron can be lost each month in breast milk.

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In the underdeveloped world iron deficiency is an especially critical problem because dietary iron is more limited, and in many poorer countries there is wide- spread parasit ic infection, such as hookworm, which results in blood loss. Loss of blood, of course, entai ls loss of iron since every milli l i tre of red blood cells contains 1 mg of iron.

In the absence of physiologic drains on iron the diagnosis of iron deficiency means there has been bleeding. There are other causes of iron deficiency, such as real- absorption, which can be due to disease or resection of the small bowel, or to total or partial gastric resection. Also, you can have iron loss with hemoglobinuria. A good general rule, however, is that , until proven other- wise, the diagnosis of iron deficiency means there has been bleeding. It means bleeding even if the pat ient is not aware of any bleeding. It means bleeding even if the stool is chemically negative for blood. Bleeding from the gastrointest inal t ract can be subtle, and it can be intermit tent . Many lives have been saved or lost de- pending on whether or not the diagnosis of iron deficiency was interpreted as a clue to bleeding.

A precise diagnosis of iron deficiency is critical. If I make the diagnosis of iron deficiency in a 55-year-old man, I must study his gastrointest inal t ract for a source of bleeding. This can involve many x-rays and con- ceivably the insertion of tubes into the lower and upper gastrointest inal tract. I would not want to do all this to someone if I were not certain of the diagnosis.

How, then, does the clinician establish the diagnosis of iron deficiency anemia? I have already alluded to clues in the history. A mens t rua t ing woman, a history of bleeding, use of such drugs as aspirin which often cause hemorrhagic gastritis, symptoms of an ulcer, or prior surgical removal of small bowel or stomach all hint at iron deficiency. A very helpful diagnostic clue is pica, which is a perversion characterized by abnormal eat ing habits. Hippocrates noted this centuries ago when he wrote "a craving to eat ear th is associated with corruption of the blood." Of the various forms of pica, one is the eat ing of starch lamylophagia~. Starch inges- tion leads to iron deficiency because starch provides calories without iron. Clay eat ing Igeophagia), a common habit in Iran, Egypt, and Turkey, is also associated with iron deficiency because certain clays interfere with iron absorption. Perhaps the commonest perversion I see is eat ing ice (pagophagia). Many pat ients are re luctant to discuss this habit because they do not unders tand its origin, and they think they are doing something odd and bizarre. On more than one occasion pat ients have been amazed when I ask if they have been sucking on ice cubes. I have also seen a var ian t of p a g o p h a g i a - - a woman who sucked on slush made by freezing Pepsi-Cola. Other picas have been described; many involve potato chips, carrots, and pretzels. Re- cently, the perversion of eat ing raw potatoes (geo- melophagia) was described. Pica usually subsides when iron deficiency is treated.

Sometimes the laboratory diagnosis of iron deficiency is easy, and sometimes it is not. First, a philosophic consideration: In general, the more tests done, the more certain our diagnosis. We pay for increased cer ta inty because tests cost money, they are uncomfortable, and

some of them are hazardous. In making any diagnosis the physician must use clinical judgment and decide how much to do to establish a diagnosis. ! will review the various ways the diagnosis of iron deficiency can be established.

A 25-year-old heal thy woman with heavy menst rua l periods is seen with a hemoglobin value of 10 g/dL. A year ago her hemoglobin level was 12 g/dL. How should the physician proceed? This clinical set t ing strongly suggests tha t iron deficiency due to menst rua l blood loss is the most likely diagnosis. A reasonable approach in such a pat ient would be to t rea t with iron pills and to measure the hemoglobin in a few weeks. If the hemoglobin rose with iron t r ea tment the diagnosis probably was iron deficiency; this may not solidly establish a diagnosis of iron deficiency, but in certain si tuations it is an easy, cheap, and reasonable thing to do.

If a hematologist were seeing the pat ient he would probably look at the pat ient 's blood smear. Un- fortunately, the blood smear is not a perfect way to diagnose iron deficiency. In one study the diagnosis was missed after looking at blood smears in 51% of proven cases of iron deficiency; 6~ of normals were called iron- deficient. The blood smear, al though clearly not perfect, is an inexpensive and valuable tool tha t is often over- looked. It should be par t of the evaluation for every anemia. You can, for example, see spherocytes and make a diagnosis of au to immune hemolytic anemia or heredi tary spherocytosis. You can see schistocytes and make a diagnosis of microangiopathic hemolysis. In iron deficiency the blood smear may be normal if the iron deficiency is mild. The typical findings in more severe iron deficiency are pale cells with a reduced hemoglobin concentration Ihypochromial and small red blood cells Cmicrocytosis). There also is var ia t ion in size and shape of the red blood cells and an increase in elliptical red blood cells.

The mean corpuscular volume (MCV), which is now routinely available, is a very helpful tool in hematology. A low MCV suggests iron deficiency. In iron deficiency the mean corpuscular hemoglobin (MCH) and the mean corpuscular hemoglobin concentration (MCHC) may also be reduced, especially if the anemia is severe. A woman with a hemoglobin of 11 g /dL who has a MCV of 76 ~m :' may well have iron deficiency anemia. A low MCV can be a helpful clue.

At this point, let me digress and discuss an impor tant differential diagnosis, iron deficiency v s thalassemia. Tha lassemia t rai t is an extremely common problem af- fecting millions of persons. The red blood cells in both iron deficiency and tha lassemia are hypochromic and microcytic. A helpful differential point is tha t the reduction in MCV is much more severe for the same degree of anemia in tha lassemia than it is in iron deficiency. A woman with a hemoglobin of 11 g /dL and a MCV of 72 ~m 3 is likely to have iron deficiency. A woman with a hemoglobin of 11 g/dL and a MCV of 58 ~m 3 is likely to have tha lassemia because the population of very small red blood cells brings down the value for MCV. The MCV can occasionally also be low in anemia of the chronic disease type.

The test most commonly used to establish the diagnosis of iron deficiency is measu remen t of serum iron and


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total iron binding capacity (TIBC). In typical iron deficiency the serum iron is low, and the TIBC is high. The saturat ion is usually 15% or less. An example is a 50-year-old man who has a hemoglobin value of 12 g/dL. His peripheral blood smear shows minimal hypo- chromia and minimal microcytosis and is not very helpful. Since iron deficiency would imply bleeding and dic- tate the need for x-rays and perhaps other tests, I would be reluctant to accept a diagnosis based on a good guess or a therapeutic trial with iron. If the serum iron were 20 ~g/dL and the TIBC 500 ~g/dL, the diagnosis of iron deficiency anemia would be well established.

The serum iron and TIBC are not perfect tests. One problem, as with every laboratory test, is the borderline value. What if the serum iron were 50 ~g/dL and the TIBC 333 ~g/dL with the saturation 15%? These borderline values leave an element of uncertainty. The serum iron and TIBC are not good tests in a sick population. A patient who is anemic and has rheumatoid arthritis, malignant disease, or other chronic disorder typically has a low serum iron, but in contrast to iron deficiency, the TIBC is low, not high. In chronic disease, the iron might, for example, be 20 jxg/dL and the TIBC 207 }xg/dL. In this situation you cannot be certain that the anemia is due to another illness or whether there is also iron deficiency.

In the setting of chronic diseases we often need another way to gauge body iron stores. This can be done by looking at the iron stores in the liver or bone marrow. In fact, when we biopsy the bone marrow, for whatever reason, we always stain a slide for iron. Patients with chronic disease accumulate iron in the marrow reticu- loendothelial cells. In iron deficiency there is no iron. A look at bone marrow separates anemia due to chronic disease from iron deficiency. However, there are pitfalls to the bone marrow examination. You must have an adequate number of marrow particles on the smear and must be careful only to look at granules of iron and not artifact. In some instances where the amount of iron is borderline, it is difficult to be certain there is no iron deficiency.

A small amount of ferritin, a storage form of iron, circulates in blood. The serum ferrit in level often re- flects body iron stores and can, if low, be useful in making a diagnosis of iron deficiency. Unfortunately, the ferrit in value may not be helpful when we need help the most. Ferr i t in can be elevated falsely in leukemia, in chronic disease, and when there is acute or chronic inflammation, especially of the liver.

Megaloblastic anemia

The next important category of anemia is megaloblastic anemias; these are almost always due to deficiency of vi tamin B12 or folic acid. The best known cause of vi tamin B12 deficiency is pernicious anemia.

In the megaloblastic anemias, the typical abnormal- ity is a delay in maturat ion of the cell's nucleus. When we look at matur ing red blood cells in the bone marrow, we see a large, young, open nucleus in a cell whose cytoplasm has matured often to the point of being pink with hemoglobin. There is a lag in the development of the nucleus. The ability of only 1 Ixg a day of vi tamin

B12 to prevent these abnormalities has led some to call vi tamin B12, on a weight basis, the most potent drug in medicine. Its ability to cause nuclear maturat ion has been noted by researchers in cancer and leukemia who seek ways to coax young, immature, malignant cells to mature. Might there be something that will cause leu- kemic cells to mature, the way vitamin B12 caused the maturat ion of the very abnormal cells in vitamin B12 deficiency?

White blood cell series development is also affected in megaloblastic anemia with large, so-called giant bands and large metamyelocytes. In the peripheral blood there are large macrocytes, often oval in shape, aniso- cytosis, poikilocytosis, and hypersegmentation of the polymorphonuclear leukocytes. Excess lobulation of the polymorphonuclear leukocytes, six lobes or more, usually means megaloblastic anemia. An average lobe count greater than 3.5 has a similar significance. These nuclear perturbations affect other tissues; patients with pernicious anemia may have a smooth, swollen tongue and severe, often crippling, nerve damage. It is tragic that, although thousands of persons get vi tamin B12 injections without any good medical indication, there are persons who suffer progressive neurologic dis- ability because needed vitamin B12 is not given.

What are the common causes of vitamin B12 and folic acid deficiency? These can best be appreciated after a brief review of some relevant physiology. Vitamin B12 is absorbed in the small bowel, specifically the terminal ileum. Its absorption is facilitated by intrinsic factor, which is secreted by the stomach. Folic acid is also absorbed in the small bowel. Body stores of vitamin B12 can last about three to five years. Stores of folic acid are less ample.

Pernicious anemia, the best known cause of vi tamin B12 deficiency, is ul t imately a disorder of the stomach and probably an autoimmune disease. Antibodies against parietal cells of the stomach and antibodies against intrinsic factor are often detected. In pernicious anemia there is a lack of intrinsic factor which, in turn, leads to malabsorption of vitamin B12.

Part ial or total resection of the stomach is also a cause of vi tamin B12 deficiency due to decreased intrinsic factor. A history of prior stomach surgery should alert us to possible vitamin B12 deficiency. Small bowel disease, such as Crohn's disease (regional enteritis), is another significant cause of vitamin B12 deficiency. Extensive surgical resection, for example, after small bowel infarction, can leave insufficient surface area for normal vi tamin B12 absorption. In malabsorption syn- drome the small bowel cannot normally perform its ab- sorptive function. An often quoted but not often seen Cat least not in this part of the world) cause of vi tamin B 12 deficiency is the fish tapeworm, Diphyllobothrium latum, which consumes vitamin B12 and leaves its host vi tamin B12-deficient. The t rea tment for this disease is to purge the worm and replace the patient 's vi tamin B12.

Many people worry about becoming vitamin B12- deficient because of poor eating habits. I assume that is why so many vitamins containing vitamin B12 are sold and so many vi tamin B12 shots are given. However, the only people who become vitamin B 12-deficient solely on


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ANEMIA -- A CLINICAL PERSPECTIVE

the basis of diet are vegans--vegetar ians who also avoid all animal products, including milk and eggs. Unless you are a vegan, vitamin B12 deficiency will not develop on the basis of diet alone.

What about folic acid deficiency? Although the requirement for vitamin B12 is about 1 or 2 ~g a day, the requirement for folic acid is about 50 ~g a day. Folic acid deficiency is the commonest anemia specifically due to poor eating habits. Folic acid deficiency is commonly seen in alcoholics who drink but do not eat, and also in elderly persons, many of whom are senile, live alone, and subsist on an inadequate diet of tea and toast. Folic acid deficiency is also seen when there are increased folic acid requirements, such as in chronic hemolytic anemia Ifolic acid required for excess blood production), chronic leukemias (folic acid utilized by an increased mass of tissue), lactation and pregnancy, and patients on dialysis tfolic acid lost into the dialysis fluid). Disorders and resections of small bowel can also cause folic acid deficiency by limiting absorption.

Although the hematologic manifestations of folic acid and vitamin B12 deficiency are the same, neurologic disease is usually seen only with vitamin B12 deficiency. Treat ing a patient who has vitamin B12 deficiency with folic acid may correct the hematologic de- fects but can lead to progressive crippling neurologic disease. It is, therefore, critical to distinguish folic acid deficiency from vitamin B12 deficiency.

The MCV, as I have already mentioned, is an important clue in the evaluation of anemia and, when it is increased, suggests megaloblastic anemia. We often see an elevated MCV even before there is anemia. Al- though an elevated MCV makes it critical to exclude a deficiency of vitamin B12 or folic acid, an elevated MCV is also seen in liver disease, especially tha t due to alcohol. Reticulocytes are large cells. An increased reticulocyte count can cause an increase in MCV. I recently saw a 90-year-old woman with a hemoglobin of 6.0 g/dL. Her MCV was elevated to 130 ~m 3. She had poor position sense and poor balance. It seemed likely that she had pernicious anemia. However, her reticulocyte count was 30% and that elevated the MCV. Her peripheral blood contained spherocytes, and the direct Coombs' test was positive. She had autoimmune hemolytic anemia and not pernicious anemia. The increased MCV was not due to megaloblastic anemia. Other conditions where the MCV can be increased include the postsplenectomy state, myxedema, cancer chemo- therapy, bone marrow malignancies, sideroblastic anemia, and other myeloproliferative diseases. Some persons have a mildly elevated MCV without apparent cause.

There has been such emphasis on the increased MCV it has recently become necessary to report that megaloblastic anemia due to a deficiency of vi tamin B12 or folic acid can exist with a normal MCV. This is seen when thalassemia or iron deficiency exists with vitamin B12 deficiency. A normal MCV and vitamin B12 deficiency have also been reported with infection and inflammation. A normal MCV, therefore, makes vitamin B12 or folic acid deficiency unlikely but does not exclude it.

The most specific way to confirm vitamin B12 or folic

acid deficiency is to measure their levels in serum. Un- fortunately, these assays are not perfect. Some kits have contained "R-proteins," which have measured in- active cobalamin analogs and have given spuriously high values. There have been reports of some patients with unaccountably low vitamin B12 levels in the absence of disease. Vitamin B12 levels can also be low in the absence of true deficiency when there is multiple myeloma, pregnancy, oral contraceptive usage, trans- cobalamin I deficiency, and folic acid deficiency. The interpretat ion of vitamin B12 levels can, therefore, be confusing, especially since vitamin B12 levels are often ordered when vitamin B12 deficiency is unlikely. The neurologist, for example, has a low threshold for ordering vitamin B12 levels in patients with undefined neuropathies.

The reliability of the folate assay is limited because the folate level can be low due to clinically unimportant changes in folate intake. It can be low, for example, in the absence of megaloblastic anemia in patients with anorexia or alcoholism. Red blood cell folate levels show a better correlation with megaloblastic abnormalities than do serum levels, but this also is not a perfect test.

When the vitamin B12 level is borderline or inexpli- cably low, we often look for corroborating data and ex- amine the bone marrow, perform a Schilling test, or look for intrinsic factor antibodies. The bone marrow typically shows erythroid hyperplasia, delayed nuclear maturation, and cloverleaf-like nuclear abnormalities. The Schilling test measures the absorption of radioactively-labeled vitamin B12. Patients must re- liably collect all their urine for 24 hours and have normal kidney function. In classic pernicious anemia the Schilling test is abnormal without intrinsic factor and corrects with intrinsic factor. Prior t rea tment with vitamin B12 does not affect the Schilling test. Antibodies to intrinsic factor are present in about 50% of patients with pernicious anemia, and false positives are rare. This is probably an underutilized test.

Vitamin B12 and folic acid deficiency are favorable diagnoses because they are easily treated. Mal- absorption of vitamin B12 is treated with monthly injections of vi tamin B12, usually 100 ~xg. Folic acid deficiency is t reated with folic acid, usually 1 mg per day.

Iron, folic acid, and vitamin B12 deficiencies can be viewed as nutri t ional anemias. They can also be viewed as examples of ineffective erythropoiesis. There is exu- berant red blood cell production in the bone marrow, but few reticulocytes emerge. Red blood cell production in the bone marrow is flawed and ineffective. I will now discuss two other categories of anemia with decreased bone marrow production of red blood ce l l s - -anemia due to bone marrow infiltration and anemia of the chronic disease type.

Anemia due to bone marrow infiltration includes some ominous disorders, such as multiple myeloma and acute leukemia. The patient is anemic because the bone marrow is replaced by abnormal cells.

What clues suggest this diagnosis? One is pan- cytopenia. The patient is not simply anemic but also has low granulocyte and platelet counts. There is often a left shift in the white blood cell differential count with band forms, myelocytes, metamyelocytes, promyelo-


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cytes, and even an occasional blast cell. Nucleated red blood cells are also seen in the blood smear. The combi- nation of a left shift in the young white blood cells and nucleated red blood cells is called a leukoerythroblastic blood picture and suggests something abnormal in the bone marrow.

What do we find in the bone marrow? The list includes myelofibrosis, multiple myeloma, lymphoma, metas ta t ic carcinoma, and leukemia. Often there are clues to the diagnosis. A pat ient with multiple myeloma may have bone pain or a protein spike in the serum. A pat ient with lymphoma may have a big spleen, enlarged lymph nodes, or lymphocytosis. Often you suspect you are going to find something in the marrow; sometimes you are surprised. In puzzling cases of anemia the bone marrow has to be examined.

A 50-year-old man had lost weight. There was some increase in bone density, which might have been be- nign. There was no definite abnormali ty on chest x-ray. The hemoglobin was 9 g/dL. The peripheral blood smear was normal. The serum iron, v i tamin B12, and folic acid levels were normal. The reticulocyte count suggested ineffective or decreased bone marrow production. A bone marrow biopsy showed metas ta t ic carcinoma. The pat ient was anemic because he had bone marrow carcinoma. Subsequent sputum cytology showed tumor cells. He had carcinoma of the lung.

Anemia result ing from disease not directly involving the bone marrow is called the anemia of chronic disease. The pat ient is anemic because he is sick. Some- t imes the underlying illness is subtle and hidden, and it is anemia tha t first alerts the clinician that something is wrong.

A 40-year-old woman was tired. The hemoglobin was 10 g/dL. The MCV, blood smear, white blood cell count, differential, platelet count, iron, v i tamin B12, and folic acid levels, and the bone marrow aspiration, and biop- sies were all within normal limits. The cause of the anemia was obscure and not pr imari ly due to a blood disease. A search for the underlying problem revealed a low serum thyroxine level and hypothyroidism. She was t reated with thyroid, and her hemoglobin slowly returned to normal. The first sign of endocrine deficiency was anemia.

A 52-year-old man presented with a hemoglobin of 11.2 g/dL. Similar studies were all normal. He was also anemic because he was sick, but the underlying disease was obscure. A large tumor in the right kidney was resected. Anemia was the first and only clue to kidney cancer.

An 82-year-old woman had a hemoglobin of 10.7 g/dL and no complaints. She had a low reticulocyte count, normal iron, v i tamin B12, and folic acid levels, and a normal bone marrow. After repeated questioning she described headaches. The sedimentat ion rate was very high. Biopsy of the temporal ar tery revealed giant cell arterit is .

Hemolytic anemia

lytic anemia, red blood cell survival is shortened. The bone marrow compensates by making more red blood cells. This is reflected in an increased reticulocyte count. When hemolysis is severe the bone marrow cannot compensate adequately and anemia results.

The clinician often bases the diagnosis of hemolytic anemia on inference. A pat ient with persistent anemia despite a persistent reticulocytosis, who is not bleeding, is likely to have hemolytic anemia. If reticulocytes re- flect excess blood production and the hemoglobin does not rise, tha t blood must be lost someplace, and it may be being destroyed.

The major differential diagnosis for hemolytic anemia is bleeding. I have seen numerous tests carried out for exotic hemolytic disorders when the pat ient was simply bleeding. Anemia with increased reticulocytes can be seen in both bleeding and hemolytic anemia.

When red blood cells are destroyed in the circulation there are typical laboratory abnormalit ies. Hemoglobin released from the red blood cell binds to haptoglobin, leading to low haptoglobin levels. Excess hemoglobin then binds to albumin and forms methemalbumin . When a lbumin -hap tog lob in binding is saturated, hemoglobin is excreted into the urine where some of it becomes hemosiderin. Free hemoglobin may also be found in the serum.

We can divide hemolytic anemia into two large g r o u p s - - i m m u n e and nonimmune. In immune hemolytic anemia, red blood cell destruction is mediated by an antibody, which can usually be detected by an anti- globulin test. The Coombs' test is performed using anti- sera directed against complement and IgG. If there is complement or antibody on the red blood cell, there probably is immune hemolytic anemia. If not, we must consider one of the nonimmune hemolytic disorders.

I will s imply list some of the major categories of nonimmune hemolytic anemias. Abnormali t ies of the hemoglobin molecule (hemoglobinopathies), such as sickle cell anemia, can cause hemolysis. Millions of persons are affected by red blood cell enzyme disorders (enzymopathies); the commonest one is glucose-6- phosphate dehydrogenase deficiency. Abnormal hear t valves or small blood vessel disease can damage red blood cells (microangiopathic hemolysis}. Heredi tary spherocytosis is yet another cause of nonimmune hemolysis.

I hope I have given you at least a partial view of the complex and interest ing world of anemia as it is seen by the practicing physician.

References

1. Wintrobe MM. Clinical Hematology, 7th Ed. Philadel- phia: Lea and Febiger, 1974.

2. Williams WJ. Hematology, 2nd Ed. New York: McGraw- Hill, 1977.

3. Steinberg D. Anemia, Philadelphia: W. B. Saunders Paperbacks, 1982.

Hemolytic anemia is another large category of anemia. The normal red blood cell lives 120 days. In hemo-


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Anemia a clinical perspective