Anemia - NOTE: DRAFT ARTICLE

last authored: March 2012, David LaPierre
last reviewed:

 

 

Introduction

Anemia, a condition characterized by low hemoglobin, is an extremely common problem worldwide, with a prevalence of approximately 25% (WHO, 2008).

Anemia can have significant consequences for individuals and populations. In fact, the World Health Organization (WHO) has classified anemia as a severe public health problem in 68 countries, given it's high prevalence among children and pregnant women (WHO, 2008). The majority of disease is in Africa and South-East Asia.

 

Anemia is technically defined as a reduction in red blood cell concentration, hematocrit, or hemoglobin, two standard deviations below that of the normal values. In men, this is below 140 g/L in men and 120 g/L in women.

 

There are many causes of anemia, which is not technically a disease on it's own. While one of the commonest causes is iron deficiency, it is a mistake to conclude that all iron anemia is due to this condition. Where available, simple diagnostic tools can be very helpful in identifying the cause.

 

 

The Case of Ben T.

Ben is a 44 year-old man with no medical conditions who has been feeling increasing fatigue, to the point that he becomes breathless while working at his job at a factory. He presents to his family physician for evaluation. As a component of his assessment, his physician orders bloodwork that shows, amongst other results, a hemoglobin of 68 g/L.

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Causes and Risk Factors

There are a number of ways of categorizing the causes of anemia. One of the most helpful is according to the MCV, or mean corpuscular volume. The MCV describes how large the red blood cells (or corpuscules) are, and varies according to the underlying cause. The MCV is normally between 80-95 fl (femtoliters) for men and  80-100 fl for women.

  • microcytic
  • normocytic
  • macrocytic
  • hemolytic

Microcytic

Microcytosis is characterized by erythrocytes with an MCV of less than 80.

 

This is usually due to problems with heme or globin synthesis, remembered by the acronym TAILS:

  • thalassemia
  • anemia of chronic inflammation (can be slightly low or normal)
    • T 1/2 of RBC goes down as the pass through injured tissue
    • phagocytes hold onto iron
    • chronic infections, CRF, malignancy, connective tissue diseases
  • iron deficiency anemia (can be very low, into the 40s)
  • lead poisioning (often 50s)
  • sideroblastic anemia - congenital or acquired problems with iron incorporation into heme (usually above 50s)

Normocytic

 

hyperproliferative (increased reticulocyte count) - appropriate bone marrow response

  • early iron deficiency
  • acute blood loss
  • hemolysis (see next tab)
  • splenic pooling

 

hypoproliferative - (decreased reticulocyte count) - inappropriate bone marrow response

  • hypothyroidism
  • Addison's disease
  • chronic renal disease - loss of erythropoietin production
  • chronic liver disease
  • anemia of chronic disease
  • aplastic anemia
  • bone marrow replacement (leukemia, myeloma, metastasis)
  • testosterone deficiency

Normocytic anemia can also be an early presentation of microcytic or macrocytic anemia, or a combination of the two.

Macrocytic

Macrocytosis is characterized by erythrocytes with an MCV of greater than 100.

 

Causes include:

  • megaloblastic anemia (vitamin B12/folate deficiency)
  • ethanol abuse
  • hypothyroidism
  • liver and lipid disorders
  • drug-induced (antiretrovirals, antimetabolites, anticonvulsants)
  • reticulocytosis
  • other endocrine disorders
  • hemorrhage
  • hemolysis (see next tab)
  • bone marrow disorders: myelodysplastic syndrome, multiple myeloma

Hemolytic anemias

Hemolysis is an increased rate of RBC destruction, and can result in anemia if destruction exceeds production.

 

There are many causes of hemolysis.

Immune-mediated

 

Micoangiopathic hemolytic anemia

RBC defects (membranes, enzymes, or hemoglobin)

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Pathophysiology

Anemia can result from disorders in RBC production, maturation, or destruction. Please read about red blood cell biology for more details on these cells.

 

Anemia is normal in infants during the first 6-12 weeks of life, as erythropoiesis ceases in the new oxygen-rich environment and blood volume increases. The nadir (lowest point) is ~100 g/L, though can be lower with premature infants.

 

Disorders of red cell production can be due to bone marrow failure. This can occur with:

Impaired erythropoetin production is seen in:

Impaired erythrocyte maturation can result from problems in the nucleus (vitamin B12 or folic acid deficiencies) or the cytoplasm (iron deficiency, thalasemia, sideroblastic anemia, lead poisoning).

 

Red cell destruction can be seen with defects in hemoglobin or the RBC membrane. Problems of RBC metabolism can be due to many enzyme systems, ie G6PD. Destruction can be antibody mediated, ie following a viral infection, or due to mechanical or thermal injury or perturbation, ie mechanical heart valve.

Extravascular hemolysis occurs outside the vessels, and accounts for 90% of hemolytic events. Macrophages of the reticuloendothelial system, especially the spleen, are usually involved. Hemoglobin is degraded, rather than being released into the circulation. Hemoglobin splits into CO2, iron, which is reutilized, and biliverdin, which is transformed into unconjugated bilirubin and released into the plasma.

Intravascular hemolysis occurs within the vessels. It usually results from damage to the RBC membrane. Free hemoglobin is released into the circulation, where it breaks down into alpha-beta dimers. This can cause hemoglobinuria or hemosiderinuria.

Free hemoglobin can also bind haptoglobin, a protein with high affinity for free Hgb. This mops up free Hgb and transports it to the liver for removal. Intravascular hemolysis thus can lead to decreased or absent haptoglobin.

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Signs and Symptoms

Obvious symptoms are not seen in younger people until hemoglobin has fallen below 70-80 g/L (hematocrit falls below 20-25%), or below 100-120 g/L in older patients.

  • history
  • physical exam

History

When approaching a patient with anemia, it is important to ask about:

  • age
  • gender
  • race/ethnicity - many hemoglobinopaties and enzyme deficiencies are genetic

 

History of present illness

Anemia's effects on the body are determined by its severity, speed of onset, and the overall health of the patient. Common symptoms of anemia include:

  • fatigue
  • weakness
  • shortness of breath, chest pain with exertion
  • presyncope

With more pronounced anemia, exercise capacity becomes markedly reduced, and exertion is accompanied by palpitations, dyspnea, pounding headache, and rapid exhaustion. Exercise intolerance is a result of the oxygen-dissociation curve's ability to respond to modest reductions of hemoglobin, but not in situations of increased demand.

 

Some specific anemias also have specific symptoms:

  • iron deficiency - ice craving in adults, dirt eating in children
  • sickle cell anemia - lifelong, episodic bone and joint pain
  • folate/B12 deficiency - sore mouth, difficulty swallowing
  • retroperitoneal bleeding: abdominal pain, flank bruising

Infants with anemia can have difficulty feeding, needing to break off or not able to fully suckle.

 

 

past medical history

  • prior history of anemia
  • gastrointestinal bleeding: past history, risk factors, and signs of blood in the stool.
  • menstrual history: excessive bleeding?
  • medications
  • infections: malaria, HIV, parasites, viral

 

social history

  • poor nutrition
  • alcohol abuse
  • occupational or environmental exposure to toxic chemicals

 

family history/past history, especially of anemia or other blood diseases

 

Physical Exam

 

  • pallor, especially in conjunctiva, mucous membranes, nail beds, and palmar creases
  • mouth: glossitis, cheilosis
  • tachycardia
  • jaundice in extravascular hemolytic anemia
  • fingernail spooning (iron deficiency)

chronic anemia:

  • forceful apical impulse
  • wide pulse pressure
  • tachycardia with exertion
  • frequent flow murmurs secondary to blood turbulence as mid- or holosystolic murumrs at apex or along sternal border, with radiation to neck

lymph nodes for malignancy or infection

abdominal exam for hepatomegaly or splenomegaly

neurologic exam to assess for viamin B12/folate deficiency

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Investigations

  • lab investigations
  • diagnostic imaging

Lab Investigations

Always look to past lab values to compare

  • CBC is the most important test to identify and evaluate anemia
  • reticulocyte (immature cell) count: marker for RBC proliferation
    • high: consider hemorrhage, hemolysis, medication
  • iron studies identify iron deficiency and anemia of chronic disease
    • low ferritin: iron deficiency suggested

depending on the results of the MCV, you may also consider:

  • TSH (hypothyroidism)
  • liver enzymes (chronic liver disease
  • serum B12 and RBC folate
  • hemoglobin electrophoresis (sickle cell and thalassemias)
  • peripheral blood smear to evaluate RBC shape
  • fecal occult blood testing (FOBT) if iron-deficiency is noted
  • bone marrow biopsy if indicated

If anemia is due to hemolysis, the following may be seen:

  • decreased haptoglobin (will decrease with binding of hemoglobin, but is an acute phase reactant and may also increase)
  • hemoglobinuria
  • hemosiderinuria
  • free hemoglobin
  • reticulocytosis
  • increased lactate dehydrogenase (LDH), an enzyme abundant in RBCs
  • increased unconjugated bilirubin

Anemia detection in low-resource settings provides additional challenges that are discussed here (PATH, 1997).

Diagnostic Imaging

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Treatments

Acute management

If anemia is severe, resulting in hemodynamic instability (hypotension, tachycardia, decreased oxygen saturation), provide oxygen, intravenous fluids, and blood transfusion.

 

Chronic management

Corrective therapy begins with adequate iron, folate, and B12 in the case of deficiency.

 

Transfusion may be useful in patients who are anemic but stable. There is no clear threshold for transfusion, though indications are looser if patients have chronic disease.

 

In patients with chronic renal disease, erythropoietin can be used.

 

In patients with ischemic heart disease, management of anemia is especially challenging. As hematocrit drops, mortality increases. However, the presence of cardiovascular disease poses a serious risk for transfusion. There is thus a trade-off between risk and benefit (Wu et al, 2001).

 

Anemia should be identified and treated in the months before surgery is scheduled so that it can be corrected ahead of time.

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Consequences and Course

Iron deficiency anemia can have marked consequences on cognitive and behavioural development in children if left untreated.

 

Anemia can worsen ischemic complications, including angina and claudication, and can precipitate heart failure in patients with underlying heart disease.

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Additional Resources

PATH. 1997. Anemia Detection Methods in Low-Resource Settings: A Manual for Health Workers.

University of Utah's WebPath provides microscope slides of various anemias.

Wu et al. 2001. Blood transfusion in elderly patients with acute myocardial infarction. NEJM. 345(17):1230-6.

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Topic Development

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