A FRAMEWORK FOR DIAGNOSING ANEMIA

The patent is fatigued and has a low hemoglobin. That certainly suggests anemia, but what form? This system for classifying and identifying the various anemias will shorten the search for the final diagnosis.  By Lawrence S. Cohn. MD

DR. COHN is attending physician, department of medicine. Harbor-UCLA Medical Center, Torrance, Calif.

 

A reduction in hemoglobin and hematocrit values below the normal range is, by definition, anemia. Reduced hemoglobin generally indicates that red cell mass is also reduced, but there are exceptions. In the anemia or pregnancy, the red cell mass may actually increase, but the plasma volume increases still more, reducing the ratio of red cell mass to plasma volume and therefore reducing hematocrit and hemoglobin. Occasionally, patients with congestive heart failure may also have sufficient expansion of the plasma volume to produce a fall in hematocrit and hemoglobin, despite a normal red cell mass. Conversely, a drop in red cell mass may not be reflected by a corresponding drop in hematocrit if blood loss is acute and a compensatory rise in plasma volume has not yet taken place.

The clinical signs and symptoms of anemia include fatigue, dyspnea, pallor, and tachycardia.  The degree of symptomatology depends not only on the magnitude of the fall in blood counts, but also on the rapidity of the fall, the adequacy of physiologic corrective mechanisms, and the presence of associated diseases. If the onset is gradual, a normal individual can tolerate a 50% Call in hemoglobin with only minimal symptoms. On the other hand, a 30% drop in red cell mass can produce shock if it occurs rapidly in an acute bleeding episode.

 

A DIAGNOSTIC CLASSIFICATION SYSTEM

What follows is a framework to assist you in classifying anemia using just the red cell indexes and the reticulocyte count (table). If an anemia can be classified as microcytic hypochromic or macrocytic, the differential diagnosis is limited to only a few kinds. The normochromic normocytic group, however, includes many types. For this group, the reticulocyte count is useful to subclassify the anemia. A normal or low count suggests that the anemia is due to underproduction of red cells. An elevated count suggests that it is due to rapid destruction of red cells or to acute blood loss.

 

MICROCYTIC HYPOCHROMIC ANEMIAS

The common denominator of all the microcytic hypochromic anemias is impairment of hemoglobin synthesis within the developing RBC. Hemoglobin consists of heme moieties attached to a globin molecule; the heme moiety in turn consists of iron attached to a porphyrin. If the red cell lacks iron or is unable to synthesize the porphyrin or the globin properly, it will be unable to produce hemoglobin at a normal rate. The result will be cells that are hypochromic because of decreased hemoglobin concentration. Such a decrease in turn increases the cell division during maturation, resulting in smaller-than-normal mature red cells (microcytosis).

There are three types of microcytic hypochromic states: iron deficiency anemia, where there is a lack of total body iron; thalassemia, where production of globin is impaired; and sideroblastic anemia, where production of porphyrin is impaired.

A SYSTEM FOR CLASSIFYING ANEMINA

 

TYPE OF ANEMIA                        INDEX

Microcytic hypochromic                              low MCV and MCHC

Iron deficiency

Thalassemia.

Sideroblastic

 

Macrocytic                                                      increased MCV

Megaloblastic

B₁₂ deficiency

Folate deficiency

Chemotherapy

Normoblastic

(Nonmegaloblastic)

Some hemolytic and acute

Blood loss anemia due to

Increased reticulocytosis

Liver disease

Hypothyroidism

 

Normochromic normocytic                         Normal MCV and MCHC

Underproduction                                           Normal or low reticulocyte count

Chronic disease

Renal failure

Liver disease

Hypothyroidism

Myelophthisic anemia

Aplastic anemia

Refractory anemia

Increased red cell destruction                      Elevated reticulocyte count

(hemolysis)

Hereditary hemolytic anemias

Acquired hemolytic anemias

 

MCV = Mean corpuscular volume

MCHC = Mean corpuscular hemoglobin concentration

 

Iron deficiency anemia. Although indexes may be within normal limits in very early iron deficiency anemia, it is usually associated with distinct microcytosis.  Hypochromia is generally the most readily recognizable finding on the peripheral smear, but microcytosis will also be seen when the anemia is of at least moderate degree.  The smear may also reveal ovalocytosis which can be profound in severe iron deficiency.

The most useful tests to confirm the diagnosis of iron deficiency are for serum iron and total iron-binding capacity (TIBC).  The serum iron is classically low (less than 50 mg/dL), and the TIBC capacity is high or at the upper limits of normal (greater than 450 mg/dL).  In addition, low serum ferritin supports the diagnosis.  Normal ferritin supports the diagnosis.  Normal ferritin ranges are 20-365 ng/mL for men; and for women, 7 to 102 ng/mL premenstrually and 13 to 200 ng/mL postmenstrually.  For children from 6 months to 15 years of age, the range is 7 to 140 ng/mL.  When all other criteria are equivocal, a bone marrow examination may be helpful since the sine qua non of iron deficiency is the absence of storage iron in the bone marrow.  If storage iron is present, the patient cannot be iron deficient, regardless of what other findings may suggest.

You can also confirm the diagnosis by a trial of iron therapy.  This should increase the reticulocyte count within approximately four days, followed by a gradual rise in hemoglobin and hematocrit over several weeks.

Once iron deficiency is diagnosed, the cause must always be considered. In pregnancy, there may be insufficient dietary iron to supply the rapidly expanding red cell mass as iron shifts to the fetus. Otherwise, dietary deficiency as the sole cause of iron deficiency is quite unusual concept in children under 4 years.

Perhaps the most common cause is menstrual blood loss in women who have a significantly heavy flow - in excess of 100 ml, of blood per cycle compared to the average 30 to 50 mL. In postmenopausal women and adult males, iron deficiency must be assumed to result from overt or occult gas­trointestinal bleeding. A GI work-up is mandatory even when no other signs or symptoms of dis­ease have appeared.

Malabsorption is a possible cause. Specific malabsorption of iron occurs in patients who have had a Billroth II procedure for peptic ulcer disease. Malabsorp­tion of iron may also be associated with generalized malabsorption syndromes.

Thalassemia. A low mean cor­puscular volume (MCV) coupled with a normal serum iron level suggests thalassemia. Although thalassemia major is a rare disease, thalassemia minor is relatively common. It is not unusual for specialists to see patients who have been treated with iron for many years under the mistaken belief that they have iron deficiency anemia when in fact they have thalassemia. The condition is due to defective synthesis of the globin portion of hemoglobin. Each globin molecule consists of two a chains and two p chains. Production or either may be defi­cient, but b-thalassemia (deficien­cy in the b chains) is much more common in this country. It is the type found in people of Mediterra­nean descent and in most blacks who have thalassemia.

The degree of microcytosis is greater in thalassemia than it is in iron deficiency. In fact, it is not unusual to diagnose thalassemia in a patient with a normal hematocrit who, nevertheless, has microcytosis. In thalassemia the peripheral smear shows hypochromia and microcytosis, as it does in iron deficiency, but target cells are usually numerous. In addition, basal cell stippling is common, whereas it is quite uncommon in iron deficiency. The most helpful test is hemoglobin electrophoresis. In b-thalassemia, hemoglobin A₂, hemoglobin F, or both will be elevated.

Sideroblastic anemia. By far the least common microcytic hypochromic anemia, the sideroblastic variety is not a single entity but rather a syndrome defined by the so-called ring sideroblast, seen on iron stains and bone marrow smears. Nucleated red cells show iron-containing particles arranged in a ring around the nucleus. When a metabolic defect has been identified, it has been in porphyrin synthesis. Ordinarily, the porphyrin and iron will join to form heme within the mitochondria, where heme is synthesized. When porphyrin synthesis is deficient, iron accumulates within the mitochondria, producing the siderotic particles.

Sideroblastic anemia may occur as a rare congenital disorder, as an acquired idiopathic bane marrow disorder, or as a secondary phenomenon - most commonly as­sociated with alcoholism. Other possible underlying causes include lead poisoning, isoniazid therapy, rheumatoid arthritis, carcinoma, and other disorders. A minority of the congenital and acquired idiopathic anemias respond to pyridoxine.

Sideroblastic anemias consistently produce hypochromia on the peripheral smear. However, most individuals with the acquired syndrome have a normal or high MCV. The peripheral smear may also show target cells and ovalacytes. The serum iron is classically elevated but may be nor­mal; serum ferritin is normal or high. A bone marrow examination is necessary for specific diagnosis. It will demonstrate the diagnostic hallmark, the ring sideroblast, in addition to normal-to-increased iron storage.

 

MACROCYTIC ANEMIAS

This group is defined by an increase in the MCV above 100. They may be divided into anemias associated with a megaloblastic bone marrow (folic acid deficiency, vitamin B₁₂ deficiency, and those in which the bone marrow shows normal erythroid maturation or is normoblastic (hemolysis, acute blood loss, liver disease, hypothyroidism, aplastic anemia, refractory anemia).

Megaloblastic macrocytic anemias.  A morphologic bone marrow abnormality caused by impaired maturation of the nucleus ac­counts for this group. There is nuclear/cytoplasmic dissociation, since the maturation of the nucleus is delayed but maturation of the cytoplasm is not. This produces red cell precursors with larger nuclei and less clumping of chromatin than would be expected for the stage of development that the appearance of the cytoplasm suggests. There is also skipping of nuclear divisions, resulting, in large-than-normal precursor and mature red cells.

Abnormalities in white cell maturation also occur-in the bone marrow, there are giant bands and metamyelocytes; in the peripheral blood, hypersegmentation of the polymorphonuclear leukocytes. The latter is the most helpful finding on the smear, since it is the most specific. The most characteristic red cell abnor­mality is the macro-ovalocyte. In severe forms of this anemia, leukopenia and thrombocytopenia are also seen.

Accurate radioimmunoassays for serum folate and serum vitamin B₁₂ are now readily available and may make a bone marrow examination unnecessary. Macrocytosis, in conjunction with a characteristic peripheral blood abnormality and with the finding of a low serum vitamin B₁₂ or folate level, can frequently establish the diagnosis. If folic acid or vitamin B12 deficiency is the cause.  It Is also necessary to establish the cause of the deficiency.

Folic acid deficiency is much more common than vitamin B12 deficiency. Dietary lack can cause either, but since the daily requirement for vitamin B12 is only 1 mg and the body stores large amounts of it, and since it is available in all animal foods (including diary products), a dietary deficiency is quite unusual and appears almost exclusively in strict vegetarians.  Even without any intake of vitamin B12, it takes three to four years to exhaust the body's stored supply.

The best sources of folic acid are fresh green vegetables and liver. If no folate is taken in, the body’s stores of this vitamin will be exhausted in only two to three months.  Folic acid deficiency is therefore quite common in malnourished individuals, particularly alcoholics who also show some interference with folic acid absorption.  Malabsorption can also be the basis for deficiency of either vitamin.  It is by far the most common reason for  vitamin B12 deficiency, though lass common than dietary lack in causing folic acid deficiency.  It can be part of any generalized malabsorption syndrome and also occurs in alcoholics and patients on diphenyl-hydantoin.

Pernicious anemia, in which atrophic gastritis diminishes production or intrinsic factor, causes malabsorption of B₁₂. Production of intrinsic factor may also be decreased or absent after a subtotal or total gastrectomy. In sprue and in regional enteritis, disease of the terminal ileum results in malabsorption of B₁₂ despite normal production of intrinsic factor 0ther potential causes of vitamin B₁₂ malabsorption include fish-tapeworm infestation and the blind-loop syndrome. In the former, the parasite consumes the vitamin B₁₂; in the latter, bacterial action results in dissociation of the vitamin B₁₂ intrinsic factor complex. The Schilling test will not only diagnose vitamin B₁₂ malabsorption but will also define the mechanism.

Normoblastic macrocytic anemias.  Usually only mild degrees of macrocytosis are associated with this group. Since the reticulocyte has an MCV of 120, a disorder that significantly increases reticulocytes may cause some degree of macrocytosis. This is true of some hemolytic anemias or when reticulocytosis follows an episode or acute bleeding. Only rarely is the degree of reticulocytosis sufficient to produce an MCV greater than 115.

In the other causes of normoblastic macrocytic anemia, the degree of macrocytosis is quite mild, and the MCV usually does not exceed 108. The diagnosis is made by the' usual clinical criteria of liver disease or hypothyroidism or both, or by the finding of aplastic anemia or refractory anemia on bone marrow examination.

 

NORMOCHROMIC NORMOCYTIC ANEMIAS

Underproduction of RBC’s. it the reticulocyte count is normal or low, the cause or normochromic normocytic anemia is generally underproduction of red cells as found in chronic disease, renal failure, liver disease, hypothyroidism, and in myelophthisic, aplastic, and refractory anemia.

The anemia of chronic disease - infection, inflammation, or a malignant lesion - is characterized by low serum iron, low TIBC normal or increased serum ferritin, and normal or increased bone marrow iron stores.

Anemias of renal disease, liver disease, and hypothyroidism are diagnosed by the usual clinical and laboratory manifestations of these disorders. Note that in both liver disease and hypothyroidism, the anemia may be associated with macrocytosis.

The definitive diagnosis of myelophthisic, aplastic, and refractory anemias is made by bone marrow examination, although clues may be present on the peripheral smear. The myelophthisic anemias are due to replacement of marrow by malignant lesions or by myelofibrosis.

In metastatic carcinoma and myelofibrosis, the peripheral smear commonly shows a leukoerythroblastic reaction that consists of a combination of nucleated red cells and early white cells (metamyelocytes, myelocytes, and occasionally promyelocytes and myeloblasts.

In aplastic anemia, pancytopenia on the peripheral smear is associated with a marked increase in cellular elements and increased fat in the bone marrow.  Aplastic anemia is generally normochromic normocytic, but it may be mildly macrocytic.  The reticulocyte count is frequently zero.

Refractory anemia refers to a group of idiopathic disorders in which bone marrow dysfunction results in underproduction of red cells and sometimes of white cells and platelets.  The primary bone marrow dysfunction is not morphologically hypoplastic.  Often the bone marrow is actually hyperplastic, in striking contrast to aplastic anemia.  The anemia is due to failure of the cells to mature properly within the bone marrow; and in many instances, there is intramedullary cell death (ineffective erythropoiesis).  Sometimes refractory anemias represent preleukemic states.

Increased red cell destruction.  An elevated reticulocyte count suggests the basis of anemia is reduced red cell survival because of acute blood loss or hemolysis.  The latter will frequently be manifested by decreased haptoglobin, increased indirect bilirubin, and increased lactate dehydrogenase, in addition to the elevated reticulocyte count.  The peripheral smear will show polychromatophilia and sometimes a basophilic stippling.  The latter abnormalities are due to the increased RNA content of the young RBC’s, the same cells that would be seen as reticulocytes with special staining.

The hemolytic anemias can be divided into those that are hereditary and those that are acquired. Hereditary hemolytic anemias will frequently be discovered in childhood, although the diagnosis may not be made until adulthood. Among them are the hemoglobinopathies, spherocytosis, and nonspherocytic hemolytic anemias.

Most common are the hemoglobinopathies. The abnormal hemoglobins that are usually seen in this country are hemoglobins S and C, appearing most often but not exclusively in blacks. Homozygotes and mixed heterozygotes become anemic, but heterozygotes do not.

Sickle cell anemia is a homozygous SS disease. A similar but milder syndrome results from the mixed heterozygous state - SC disease. In addition, mixed heterozygosity for hemoglobin S and for thalassemia (SThal) produces a syndrome that may be as severe as homozygous SS disease and clinically identical to it. In all three syndromes, the peripheral smear will usually suggest the diagnosis by showing sickled cells. Target cells also are generally present. The most important diagnostic tool is hemoglobin electrophoresis.

Hereditary spherocytosis produces a syndrome that may range from a severe anemia recognized in infancy to a mild anemia not recognized until adulthood. Splenomegaly is usually present. Large numbers of spherocytes on the peripheral smear usually will suggest the diagnosis; the osmotic fragility test can confirm it.

Hereditary nonspherocytic hemolytic anemias are uncommon. Most are due to red cell enzyme deficiencies. Tests for the two most common, glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency, are fairly widely available.

Acquired hemolytic anemias include those due to hypersplenism, the Coombs'-positive anemias, microangiopathic hemolytic anemias, and paroxysmal nocturnal hemoglobinuria. Hypersplenism probably produces the most common acquired hemolytic anemia.  Splenomegaly from any cause can result in splenic hyperfunction and thus give use to this form of anemia. It generally is relatively mild₁ with reticulocyte counts not above 6%. If the degree of hemolysis is significant, leukopenia and thrombocytopenia will usually be present.  The peripheral smear does not reveal any characteristic red cell abnormalities.  The diagnosis is based on splenomegaly in association with evidence of a hemolytic process.

Coombs'-positive hemolytic anemias are the next most common group. The direct Coombs’ test detects globulin on the surface of red cells; and in these hemolytic anemias, the globulin is either an antibody or complement. A Coombs'-positive hemolytic anemia is diagnosed when at least a moderately strong direct Coombs’ test is associated with a hemolytic anemia. If the Coombs' test is only weakly positive, it may not be clinically significant.

Coombs'-positive hemolytic anemias, in turn, can be divided into the warm-antibody hemolytic variety and cold-agglutinin disease.  The former are generally due to IgG antibody.  The presence of IgG on the red cells, sometimes in combination with complement, accounts for the positive Coombs’ test results.  Occasionally, complement may be present without the IgG.

Warm-antibody hemolytic anemias may be either idiopathic or secondary to collagen vascular diseases, lymphoproliferative disorders, and viral infections.  They may also be drug-induced, notable by a-methyldopa.  As many as 30% to 40% of patients taking this drug will have a positive Coombs' test, although only 1% to 2% have significant hemolysis.  Hemolysis will cease in two to three weeks after the drug is withdrawn, but the Coombs’ test may remain positive for as much as a year or longer.  Quinidine and penicillin can also cause a warm-antibody hemolytic anemia.

Most cases of cold-agglutinin disease are due to an IgM anti-body. The IgM itself is generally not detected on the red cell. A positive Coombs' test is due to complement that remains on the cell surface after the IgM has been eluted from the cell.  This disease may be identified by an elevated cold-agglutinin titer in addition to the positive Coombs' test. Cold-agglutinin disease may be idiopathic or secondary to viral and mycoplasmal infections and lymphoproliferative disorders.

The microangiopathic hemolytic anemias are characterized by large numbers of red cell fragments (schistocytes) on peripheral smear. The causes include a wide variety of diseases in which fibrin is deposited within small blood vessels: collagen vascular diseases, disseminated intravascular coagulation, and many forms of kidney disease including malignant hypertension. The red cells fragment when they impinge on the fibrin strands in the vessels. The schistocytes are able to reseal their surfaces and continue to circulate. Their presence in large numbers on the peripheral smear establishes the diagnosis. Patients with artificial heart valves, can also have fragmentation of red cells and a similar hemolytic process.

Paroxysmal nocturnal hemoglobinuria is a rare form of acquired hemolytic anemia.  The name suggests its usual clinical presentation: however, it may appear as anemia without grossly recognizable hemoglobinuria. It is not unusual for leukopenia and thrombocytopenia also to be present. The diagnosis should be considered if a patient with hemolytic anemia gives a history of hemoglobinuria or if leukopenia and thrombocytopenia are also present. If the diagnosis is suspected, it can be confirmed with the readily available sucrose hemolysis test

 

 

 

If you would know about suffering. study your patient his eyes. his voice. how he moves. what he says how he says it Then from here you build up the whole structure of your care, a broad structure. as broad as the measure of his desires. Surely this is no denial of medical science. but its fulfillment

 

-Dickinson W. Richards MD(1895-1973)