Hypo-proliferative Anemias

I. Problem/Condition.

Hypo-proliferative anemia is an anemia where the bone marrow’s response, the production of reticulocytes, is absolutely low, or low for the degree of anemia (Reticulocytopenia). It is possible to have a hemolytic anemia or blood loss (a ‘hyper-proliferative anemia”) simultaneously, in which case the hemoglobin level will fall more rapidly.

II. Diagnostic Approach

A. How to approach a hypo-proliferative anemia

The most common error in approaching anemias is to think of all the causes that come to mind and try to fit one to the situation. Forgetting uncommon diagnoses, missing simultaneous multiple etiologies or simply being overwhelmed by the possibilities are all common outcomes. Fortunately, the evaluation of anemia lends itself to a systematic approach.

Anemias are either hypoproliferative (relative or absolute bone marrow failure) or hyperproliferative (increased loss or destruction with a resultant shortened red cell survival). In a patient with a stable but inappropriately low hemoglobin, this is most easily assessed by the reticulocyte count. There are three possibilities:

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  • A high reticulocyte count or rapidly falling hemoglobin as seen with shortened red cell survival

  • Low reticulocytes or inappropriately normal reticulocyte count as seen with a bone marrow failure.

  • Both. The reticulocyte count may be elevated, consistent with a shortened red cell survival (e.g. autoimmune hemolytic anemia) but not as elevated as one would expect (e.g. due to the underlying lymphoma causing the hemolysis).

Hyperproliferative anemias is discussed in a separate section.

If the reticulocyte count is inappropriately low then the bone marrow production of red blood cells (RBCs) is inadequate. Bone marrow failures can be segregated by red cell size – the mean cellular volume (MCV). The MCV is tightly regulated and even modest variation of this commonly ignored lab result is of clinical significance.

Microcytic anemia

Usually due to either iron deficiency or a thalassemia; although lead poisoning, congenital sideroblastic anemia, severe chronic disease anemia, or rare hereditary fragmentation syndromes can present this way.

Macrocytic anemia is due to:

  • Something interfering with normal nuclear maturation, e.g. B12 / Folate deficiency, chemotherapy-like agents (myelosuppressive chemotherapy), immunosuppressive drugs (e.g. azathioprine, cytoxan) or myelodysplasia.

  • Specific dyslipidemias which enlarge the RBC lipid bilayer membrane – liver disease, ethanol use, severe hypothyroidism.

  • Other “artefacts” including cold agglutinins (red cell clumping) or the missed diagnosis of severe reticulocytosis.

Normocytic anemia

Normocytic anemia is by far the most complex anemia to sort out and may be:

  • Mixed macrocytic and microcytic process (e.g. B12 with atrophic gastritis causing iron deficiency)

  • Chronic disease anemia

  • Transfused patients

  • Renal or liver disease related

  • Endocrine related

  • Intrinsic bone marrow disease including: myeloma, aplastic anemias, lymphoma, infections and metastatic non-hematologic malignancies. This is less overwhelming than it sounds since the diagnosis is usually in the bone marrow biopsy.

The approach to a hypo-proliferative anemia depends on the MCV with a few wrinkles. We are interested not only in the absolute MCV but in the change in the MCV. For example, a patient with a thalassemia trait may have a very low MCV (e.g. 70) but a normal hemoglobin. An “improved” MCV of 75 with a new anemia reflects a macrocytic process (e.g. B12 deficiency or new ethanol use). Similarly, a normal MCV in a chronic alcoholic or a patient with liver disease may reflect new iron deficiency or a different microcytic process.

B. Diagnostic approach to hypo-proliferative anemias

Particularly in patients with a severe anemia, a normal MCV may reflect a combined macrocytic and microcytic process.

Microcytic anemia

This is most likely iron deficiency or thalassemia. A quick review of patient’s hemoglobin and MCV can guide further workup when differentiating between thalassemia or iron deficiency as a cause of microcytic anemia. In iron deficiency, the MCV falls progressively as the anemia worsens. In thalassemia however, even a patient with the trait and a normal hemoglobin will have severe microcytosis. So a well maintained hemoglobin with microcytosis is likely to be thalassemia trait.

Always check the iron studies first since iron deficiency may mask beta-thalassemia trait. Note that normal iron studies with an MCV under 77 is almost certainly thalassemia. If the hemoglobinopathy panel is “normal” then it must be alpha-thalassemia trait which does not show up on that study.

When evaluating iron studies in hospitalized or ill patients, some authors will recommend checking ferritin, iron and transferrin or total iron binding capacity (TIBC). In inflammatory states the ferritin is often normal with a microcytic, iron-responsive anemia suggested by a saturation under 10%. A low ferritin is always iron deficiency (except in the very rare congenital aferritinemia).

It is possible to have both iron deficiency and thalassemia in the same patient. this is more likely in the patients with thalassemia trait with history of chronic blood loss. This is often obvious due to severe/worsening microcytosis or worsening anemia.

Thalassemia is usually obvious because of the normal iron studies and chronic microcytosis with or without anemia. Rarely, with hematologic malignancy, you can see acquired thalassemia.

Iron deficiency is discussed at length but remember:

Identify the source. If not menorrhagia then it is likely gastrointestinal (GI) blood loss – refer to GI regardless of the fecal occult blood testing (FOBT). Dietary insufficiency/malabsorption are unlikely the sole etiology since little iron is excreted normally. After repletion, confirm normalization of the anemia. Malabsorption, non-compliance and secondary causes of anemia need to be dealt with.

Rarely, microcytic anemia will be lead poisoning. A lead level is diagnostic. It may be seen in patients due to occupational or home exposure (needs to be inhaled or ingested). Heavy construction, plumbing, and battery production are a few examples of professions at higher risk of lead exposure. These patients require chronic lead chelation to be started as soon as possible after increased exposure.

Congenital sideroblastic anemia is uncommon but often microcytic – when presenting in the adult it is typically mild and stable. The more common myelodysplastic syndrome (MDS) sideroblastic anemia is usually macrocytic. Very rarely, congenital RBC fragmentation syndromes may present with marked microcytosis but the smear makes it obvious.

Macrocytic anemia

There is a limited differential here, so the approach is quite straight forward. A good history will help evaluate the most common causes of macrocytic anemia. Liver disease (which should also be showing other manifestations-hypoalbuminemia, transaminitis, thrombocytopenia) and alcohol (ETOH) use (which may be quite occult – “only an occasional glass of wine” confirmed by the family is common in patients who will later be seen to be significant ETOH users). A trial of complete abstinence from Alcohol may resolve macrocytosis during follow up labs. It is often worth repeating full history and review of all medications since often patients will forget them because they think of them as rheumatologic/GI or dermatologic drugs.

B12 level is very helpful, but can be functionally deficient with low normal levels (perhaps even up to 300). If the B12 is above 200 but below 300 without other explanation for macrocytosis, then check a methylmalonic acid which is dependent on B12 for its metabolism and will be elevated if the B12 is functionally deficient. A peripheral smear can be useful in creating a strong suspicion of a megaloblastic anemia. Hypersegmented neutrophils and oval macrocytic RBCs are suggestive but can also be seen in MDS, chemotherapy and in septic patients, so ultimately, the answer is in the B12 level.

Folate deficiency is very uncommon since folate was added to our food (ca 1996) but may still be seen in the rare patient with malabsorption. A recent study at a single US institution looked at the serum folate level testing between 2003 and 2013 and found an extremely low rate of folate deficiency. A recent choosing wisely article concluded that Folate levels in North American population are highly unlikely to be low in the post fortification era. At risk patients should be started on folate supplementation regardless of the serum folate levels.

Hypothyroidism can cause macrocytosis but usually the thyroid disease is so severe as to be clinically obvious.

If the above evaluation doesn’t provide an answer, especially in someone over 50 years of age (when the risk begins to increase), then myelodysplasia should be considered and a bone marrow aspirate and biopsy ordered. A well-evaluated smear (a laboratory done smear is often not subtle enough nor “goal directed” enough to be of value here) can be very helpful but will not obviate the need for a bone marrow evaluation.

The smear may show RBC fragments (which may be confused with schistocytes), nucleated RBCs or other odd RBC forms; neutrophils may be hypogranulated, hypolobulated (with only 2 segments rather than the usual 3 or more) or hypersegmented (as with B12/folate deficiency) or simply odd with clover leaf or other unusual nuclear patterns. Immaturity, even to blasts, may be seen. Platelets may be decreased (or rarely increased) in number and may be large or hypogranulated.

Normocytic anemia

This is the most difficult sub-group of the anemias to approach. Lab testing will usually take you to the diagnosis with micro and macrocytic anemias but normocytic often reflects an underlying medical illness and a thorough H and P may be needed.

1. Historical information important in the diagnosis of normocytic anemia. Past medical history:

  • Previously treated or diagnosed anemias unmasked by non-compliance (iron, B12, Addison’s disease) or aging (congenital anemia, monoclonal gammopathy)

  • Medical problems which are now beginning to worsen i.e. liver disease, renal disease, chronic infectious diseases such as HIV, TB, syphilis

  • Previous malignancies now with relapse, recurrence or secondary malignancies

  • Blood transfusions with hepatitis C

  • History of radiation therapy

2. Current medications:

  • Certain drugs associated with marrow suppression (chemotherapy, HIV, anti-epileptic drugs)

  • Medications prescribed but not being taken

  • Herbal/Alternative therapies

3. Current Illness with particular attention to:

  • Duration of anemia (Current or previous diagnosis)

  • Recent transfusions

  • Liver disease (or pancreatitis with malabsorption)

  • Hypothyroid or hypoadrenal symptoms

  • Fevers, weight loss, fatigue or other symptoms of chronic inflammation or malignancy

  • Adenopathy which may be waxing and waning

  • Diarrhea (infection, malabsorption)

  • Neurologic changes (neuropathy, possible spinal cord lesions, sub-acute combined degeneration, dementia)

III. Laboratory tests that are likely to be useful in diagnosing normocytic anemia

Check a reticulocyte count/index.

The smear may be of value here in looking for mild, early or combined causes of anemia:

  • Megaloblastic changes suggesting B12, folate

  • Early changes of iron deficiency (although lab testing will be more valuable)

  • Target cells and round macrocytes suggesting liver disease

  • Changes suggesting myelodysplasia, especially since the bone marrow may be non-diagnostic in up to 50% of patients initially

  • Immature neutrophils, nucleated RBC and teardrop RBC’s are a “leukoerythroblastic” picture and mandate a bone marrow biopsy early in the evaluation

If the patient has pancytopenia then a bone marrow biopsy is more likely to be needed to look for aplastic anemia, myelofibrosis, primary hematologic malignancies, etc.

Chemistry panel should be obtained to evaluate for renal or hepatic disease and to check the globulin levels (total protein – albumin = globulin) which should be 4 or less. A common error is to fail to look at the globulin in this setting. Hyperglobulinemia is common in renal and hepatic diseases, but when anemia is also present with hyperglobulinemia it warrants further evaluation to rule out monoclonal gammopathy with a serum electrophoresis and/or urine electrophoresis (SPEP/UPEP). Bone marrow biopsy will be ultimately required for diagnosis of multiple myeloma but it can miss up to 5% of the cases due to patchy involvement.

  • B12 and iron studies to look for combined etiologies.

  • TSH and random cortisol since a mild anemia can be seen in this setting.

  • ESR and/or CRP (which is less impacted by delayed evaluation if lab sending out samples) may help by increasing your suspicion for occult inflammation/malignancy.

A. Management of hypoproliferative anemia

The details of managing each specific diagnosis are discussed in separate sections.

If the patient is unstable, at risk or the rate of fall of the hemoglobin is rapid, then the patient should be admitted and transfused. Most information can be retrieved after the transfusion but it is very helpful to obtain a direct Coombs, iron study, B12 study, lactate dehydrogenase (LDH) and a peripheral smear prior to the transfusion if possible. Be cautious in transfusion since chronically anemic patients may be in high output failure and may also increase their plasma volume, putting them at increased risk for volume overload.

If, in the setting of a hypoproliferative anemia, the patient also has: a globulin greater than 4, renal failure, severe bone pain, neurologic symptoms, or severe neutropenia (absolute neutrophil count less than 1000); then you are dealing with a possible medical emergency and a hematologist should be involved immediately without waiting for lab results to return.

Evaluation of microcytic or macrocytic anemia usually reveals a diagnosis. Normocytic anemias are often occult even after a bone marrow biopsy. In that case, supportive care and re-evaluation over a period of time will almost always be revealing. In patients over 50, the diagnosis will often be myelodysplasia but be aware of occult malignancies. If a patient with an unexplained anemia then develops other, even mild, focal symptoms, they should be further evaluated immediately.

**The original source for this chapter was Dr. Brad Lewis. The chapter was revised for this program by Dr. Nargiz Muganlinskaya and Dr. Tahir Mehmood.