Continuing Education Activity

Normocytic normochromic anemia is the type of anemia in which the circulating red blood cells (RBCs) are the same size (normocytic) and have a normal red color (normochromic). Most of the normochromic, normocytic anemias are a consequence of other diseases; a minority reflects a primary disorder of the blood. Management depends primarily on treating the underlying cause of anemia. This activity will focus on the role of the interprofessional team in the diagnosis and management of normocytic normochromic anemia.

Objectives:

• Identify the etiology of normocytic normochromic anemia.
• Explain the pathophysiology of normocytic normochromic anemia.
• Summarize the management of the normocytic normochromic anemia-related disease.
• Outline the role of the interprofessional team in the diagnosis and management of normocytic normochromic anemia to ensure the best patient outcomes.

Introduction

Anemia is a condition marked by a decrease in the number of red blood cells (RBC), the proportion of hemoglobin, or the collective volume of packed RBCs (hematocrit). The main function of RBCs, or erythrocytes, is to carry oxygen from the lungs to the body tissues and carbon dioxide as a waste product from the body tissues to the lungs back. This process is facilitated by hemoglobin (Hb). A decrease in the number of RBCs transporting oxygen and carbon dioxide in anemia decreases the body’s capacity for proper gas exchange. The impairment may result from blood loss, an increase in the destruction, or reduced production of RBCs. Traditionally, the decrease is quantified by the ratio of packed RBCs to blood volume, called hematocrit and hemoglobin concentration.[1][2]

Anemia can be classified according to mean corpuscular volume (MCV), a measure of the average volume of RBCs in a specimen. Low MCV indicates microcytic, normal MCV indicates normocytic, and high MCV indicates macrocytic.[3] Anemia is generally defined as hemoglobin of less than 13.0 g/dL in men and less than 12.0 g/dL in premenopausal women[4]

Normocytic normochromic anemia differs from other forms of anemia because the average size and hemoglobin content of the RBCs are typically within normal limits. RBCs typically appear similar to normal cells under microscopic examination, though in some cases, there may be variations in size and shape that equalize one another, resulting in average values within the normal range. Normocytic normochromic anemia most commonly occurs as a result of miscellaneous chronic infections and systemic diseases. Most normocytic anemias appear to be the outcome of the impaired production of RBCs.[5]

Etiology

Most of the normochromic, normocytic anemias are a consequence of other diseases; a minority reflects a primary disorder of the blood. This may be due to anemia of chronic disease (inflammation, neoplasia), renal failure, endocrine failure (hypothyroidism, hypopituitarism), marrow failure (pure red-cell aplasia, aplastic anemia, infiltration), acute blood loss, and polymyalgia rheumatica.[6]

The etiology of normocytic normochromic anemia depends on whether the anemia is hypoproliferative (i.e., corrected reticulocyte count <2%) or hyperproliferative (i.e., corrected reticulocyte count >2%).[7][8]

Normal/Decreased Reticulocyte Count

Normal Bone Marrow

• Anemia of chronic disorders (neoplastic, infections)
• Anemia of renal failure
• Endocrinopathy (myxedema, Addison disease, hypothyroidism, panhypopituitarism)
• Anemia of liver disease
• Early iron-deficiency anemia

Abnormal Bone Marrow

• Marrow infiltration (leukemia, myelofibrosis, metastasis)
• Hypoplastic anemia
• Aplastic anemia
• Medication side effect

Increased Reticulocyte Count

Hemolysis

1. Intrinsic: Inherited defects of hemoglobin, RBC membrane, or enzyme; paroxysmal nocturnal hemoglobinuria
2. Extrinsic: Autoimmune hemolytic anemia, microangiopathic hemolytic anemia, disseminated intravascular coagulation (DIC). 

Hemorrhage

Epidemiology

Epidemiologic data are not available for all conditions associated with the normocytic normochromic anemia, taking together the most common cause of normocytic normochromic anemia is anemia of chronic disease; a summary by Wiess et al. shows the estimated prevalence percentage of underlying causes of anemia of chronic disease (infections 18% to 95%, cancer 30% to 77%, autoimmune 8% to 71%, chronic rejection after solid organ transplantation 8 to 71% and chronic kidney disease and inflammation 23% to 50%. Nevertheless, the prevalence of normocytic normochromic anemia in patients with less common causes like an endocrine failure, marrow failure, acute blood loss, etc. is not well defined.[9]

Pathophysiology

The pathogenetic mechanisms of normocytic normochromic anemia vary; specifics depend largely on the etiological cause. Each of several individual factors will play a role in the cumulative cause of the anemia. Since anemia of chronic disease constitutes a major percentage of normocytic normochromic anemia cases and has common pathophysiology with other causes of normocytic normochromic anemia, in the following section, we will refer primarily to the common pathways involved in anemia of chronic disease, along with other associated conditions.

Anemia of chronic disease is usually mild to moderate normocytic normochromic anemia; it evolves with time to become hypochromic and, more rarely, microcytic. Less than 25% of normocytic normochromic anemia cases progress to microcytic hypochromic anemia, in which case the mean corpuscular volume is rarely less than 70.[9] This measure stands in contrast to iron deficiency anemia, which is mostly microcytic. The hemoglobin concentration is usually 8 g/dL to 9.5 g/dL (mild to moderate anemia) and rarely drops to below 6 g/dL. In cases of severe anemia, other causes of red cell loss or destruction should be strongly considered. Anemia of chronic disease may be secondary to infections, malignancies, autoimmune disorders, or chronic renal failure. 

The pathophysiology of normocytic normochromic anemia is complex but typically relates to three broad causes, each related to an increase in pro-inflammatory cytokines and a subsequent increase in hepcidin levels. In addition, inappropriate erythropoietin (EPO) levels, a decreased response to erythropoietin, and decreased RBC survival contribute to normocytic normochromic anemia. This is the underlying mechanism most commonly seen in patients with acute renal failure.

1. Increase in Pro-inflammatory Cytokines and Iron Dysregulation: This increase is associated with a variety of disease states, including infection, neoplasm, chronic kidney disease, as well as autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus. Hepcidin is the main modulator of iron metabolism, giving it a key role in the pathophysiology of anemia of chronic disease. An acute-phase protein, the upregulation of hepcidin is facilitated by interleukin-6 (IL-6) and other proinflammatory cytokines. Hepcidin binds to the iron export protein, ferroportin, which is present in macrophages, hepatocytes, and enterocytes. Increased hepcidin levels lead to iron trapping within macrophages and hepatocytes, resulting in low levels of circulating iron. Through negative feedback stimulated by increased iron stores, hepcidin causes enterocytes and macrophages to degrade ferroportin, thus reducing absorption and promoting storage, respectively.[10][11]
2. Inappropriate Erythropoietin (EPO) Levels or Less Response to Erythropoietin: In a healthy individual, erythropoietin circulates in the bone marrow to assist in the production of RBCs, thereby improving oxygen concentration in the blood and relieving hypoxia. Recent studies have identified a number of cytokines that inhibit hemopoiesis in the bone marrow and contribute to a subnormal erythropoietin response, varying by the degree of anemia. For example, in patients with chronic kidney disease, anemia is mainly due to a deficiency of EPO. Because kidney function plays an important role in hepcidin clearance, kidney dysfunction leads to decreased hepcidin clearance and consequent hepcidin storage, resulting in hyposideremic anemia development.[12] Several inflammatory proteins, as well as the inflammatory cytokine, especially IL-6, have been linked to this diminished response to erythropoietin. These cytokines downregulate the expression of the SLC4a1 gene in late erythroid precursors and thereby reduce hemoglobin synthesis. This process results in the escalation of the hepatic synthesis of hepcidin.[13][14]
3. Decreased RBC Survival and Bone Marrow Infiltration: Several studies have identified a mild shortening of the red-cell lifespan in normocytic normochromic anemia cases, which appears to be due to an extracorpuscular factor or intrinsic abnormality of the red cells. The RBC survival is usually not markedly shortened, and marrow function should compensate for the reduced survival. In hemolytic anemias, the etiology of premature erythrocyte destruction is diverse and can be due to conditions such as intrinsic membrane defects, abnormal hemoglobin, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism. Hemolysis may also be intramedullary, occurring in cases when fragile red blood cell (RBC) precursors are destroyed in the bone marrow before their release into the circulation.[15] Bone marrow changes also lead to physical obstruction and destruction of the bone marrow microenvironment.

Anemia secondary to cancers occurs via these common mechanisms: decreased production of RBCs, increased RBC destruction, blood loss, or miscellaneous etiologies. However, in some cases, significant anemia has also been observed in the absence of marrow invasion or deficiency of vital nutrients. This signifies that other pathways may be important in the pathogenetic processes leading to anemia, cancers, or marrow changes that lead to physical obstruction and destruction of the bone marrow microenvironment.[16]

Histopathology

The average size and hemoglobin content of the RBCs are within the normal range in typical normocytic normochromic anemia cases. Under microscopic examination, RBCs usually appear similar to normal cells. However, in some other cases, remarkable variations in each cell size and shape may be detectable, causing normal average values.[17]

Bone marrow morphology can help us differentiate various types of anemia:

1. Normal morphology: Secondary anemia (inflammation, renal disease, renal disease, endocrine deficiency, etc.)
2. Hypoplastic: Aplastic anemia
3. Infiltration/fibrosis: Leukemia, myelofibrosis, metastases
4. Dyserythropoetic: Myelodysplasia

History and Physical

Taking a medical history is one of the first things required of a health care provider to diagnose anemia. Symptoms of normocytic anemia can be slow to develop depending on the causation.

Common Symptoms

• Fatigue
• Dizziness or lightheadedness
• Dyspnea
• Exercise intolerance
• Generalized weakness
• Palpitation
• Headaches
• Decreased concentration

Important History Questions

• Diet
• History of abdominal pain, reflux disease, peptic ulcer disease
• Medications, including frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs)
• History of autoimmune conditions, malignancies
• Blood loss including menstrual history (e.g., hematochezia, melena stools, gross hematuria, hematemesis)
• Family history of thalassemia or sickle cell disease [18]
• Medications

A physical exam may help confirm the diagnosis. The first signs of normocytic normochromic anemia or any type of anemia are usually generalized weakness and a pale complexion.

Physical Exam Signs

• The pallor of the skin, conjunctivae, lips, palmar creases, and nail beds
• Postural hypotension secondary to intravascular volume loss
• Jaundice caused by hemolytic anemia
• Bone pain and/or organomegaly with an infiltrative disease of the bone marrow
• Splenomegaly secondary to hemolysis, lymphoma, leukemia, myelofibrosis [19]

Evaluation

The common workup required to diagnose normocytic normochromic anemia includes the following:

• CBC with differential - repeat if there is an acute drop; also, rule out any dilutional effect - usually observed in a patient receiving a substantial amount of fluids in a short period of time, and is associated with an equal drop in other cell lines.
• Mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)

Reticulocyte count must be obtained to determine the pathophysiologic mechanism of anemia. Increased reticulocyte count demonstrates hemolysis; other evidence related to increased RBC destruction, e.g., increased LDH, increased indirect bilirubin level, decreased haptoglobin, etc., should also be taken into consideration. A decreased reticulocyte count is associated with a hypoproliferative state like aplastic anemias, kidney disease, hypothyroidism, etc.

• Corrected reticulocyte count = percent reticulocytes x (patient's HCT/normal HCT)
• Peripheral smear - Erythrocyte morphology (shape and size; absence of schistocytes rules out microangiopathic hemolysis; microspherocytes indicate hemolysis; rouleaux formation relates to multiple myeloma.
• LDH, haptoglobin, bilirubin - to rule out hemolysis
• Iron panel (iron, ferritin, TIBC, transferrin saturation)[8]   

If normocytic normochromic anemia with a secondary cause is suspected, the following tests should be done as per diagnosis/clinical suspicion:

• Renal failure: BUN/creatinine, erythropoietin level (end-stage renal disease)
• Autoimmune causes: ANA, ESR, CRP, and other studies depending on symptoms and signs
• Hypothyroidism: Thyroid function tests
• Multiple myeloma: Serum and urine electrophoresis, serum and urine free light chains
• Aplastic anemia: Drug exposure, infections (EBV, hepatitis, CMV, HIV, parvovirus), hematologic malignancies, and paroxysmal nocturnal hemoglobinuria (PNH)
• Pure red cell aplasia: Test for parvovirus B19, exclude thymoma[20]

Treatment / Management

The management of normocytic normochromic anemia depends primarily on treating the underlying cause of anemia. Blood transfusion remains an important short-term management option, especially in individuals with severe anemia (Hb <7 g/dL), those who are symptomatic or have associated cardiac disease.[21]

• Anemia of Chronic Disease: Treatment of the anemia of chronic disease requires treating the underlying disorder. Anemia of chronic disease is usually mild anemia, but approximately 20% of patients may have hemoglobin <8 g/dl. In these more severe cases, clinicians should rule out additional concurrent causes of anemia, such as iron deficiency anemia. The use of erythropoiesis-stimulating agents, blood transfusion, and iron supplementation with treating the underlying diseases are the most important treatment options. If patients have low or inappropriately normal erythropoietin levels, they may respond to injections of erythropoietin or darbepoetin. Patients with appropriately elevated EPO levels (especially >500 mU/ML) do not respond. The anemia of chronic disease is often mistaken for iron deficiency anemia.[22][23] It is crucial to differentiate normocytic normochromic anemia from iron deficiency anemia since iron overload may result in undesirable consequences such as liver necrosis, seizures, cardiogenic shock, and even coma.[24]

• Acute Blood Loss: Treated with efforts aimed at stopping bleeding, and supportive measures such as IV fluids, crossmatched packed red blood cells, and oxygen support. 

• Rheumatoid Arthritis: Anti-TNF-a antibody has been shown to lessen the severity of anemia.[25]

• End-stage Renal Disease (ESRD): Usually due to decreased renal erythropoietin-stimulating agents, goal Hb being 10.5-11 g/dl in ESRD patients with Hb<10 g/dl. ESRD patients with transferrin saturation ≤30% and ferritin ≤500 ng/ml require iron supplementation, preferably with intravenous rather than oral iron.[26]

• Primary Bone Marrow Failure: Conditions such as aplastic anemia require immunosuppression therapy, bone marrow transplantation, etc.[27]

• Hemolytic Anemia: If caused by faulty mechanical valves (macroangiopathic hemolytic anemia), these will need replacement. Hemolytic anemia due to medications requires the removal of the offending drug. Hemolytic anemia due to inherited causes is treated depending on the type of disorder. Persistent hemolytic anemia may require splenectomy.

• Hemoglobinopathies: Simple blood transfusions, exchange transfusions, hydroxyurea.

• DIC: The removal of the offending stimulus. Patients with life-threatening bleeding require the use of antifibrinolytic agents along with blood product transfusions (platelet, plasma, cryoprecipitate).[20]

Differential Diagnosis

Anemia may not instantly be evident on laboratory testing in acute blood loss from trauma, since the fluid shifts have less time to normalize the circulating volume and dilute the number of remaining RBCs. 

Significant hemodilution due to large volume fluid resuscitation and phlebotomy hemolysis are a few other reasons that lead to a falsely low red cell count.[28]

• Iron deficiency anemia: At earlier stages, it can appear as normocytic normochromic anemia.
• Other causes of microcytic anemia: Thalassemia, sideroblastic anemia, and lead poisoning
• Macrocytic anemia with B12/folate deficiency
• Liver disease: Usually macrocytic anemia
• Acute blood loss anemia, esp. upper or lower gastrointestinal bleed

Prognosis

Normocytic normochromic anemia is not typically severe, although it can progress with time and with the evolution of the underlying cause. Prognosis is worse when accompanying certain chronic conditions, such as bone marrow failure, autoimmune conditions, or malignancy. Similarly, the prognosis may be altered by a comorbid condition like coronary artery disease, especially in older patients. Likewise, anemia due to acute blood loss, if treated early, has a good prognosis. Mortality rates are low in hemolytic anemias. The etiology of the hemolysis and the underlying disorder, such as sickle cell anemia or malaria, determine morbidity.

In general, the underlying disease is the strongest indication of the prognosis of normocytic normochromic anemia.[29]

Complications

Most normocytic anemias appear to be the result of impaired production of red cells or a deficiency of erythropoietin in cases of renal failure. As in the case of anemia associated with chronic infections or various systemic diseases, the symptoms are usually connected to those of the underlying condition, although sometimes anemia may be the most prominent sign. Likewise, the complications will differ according to the complication of the underlying disease. These include:

• Hypoxia (hypoxic respiratory failure, end-organ damage)
• Renal osteodystrophy (in chronic kidney disease, through secondary hyperparathyroidism)
• Cardiorenal anemia syndrome: Severe anemia causes a decline in blood perfusion to the kidneys, causing additional kidney damage[30]
• Cardiovascular disease
• Multiorgan failure
• Hepatomegaly, splenomegaly
• Jaundice

Anemia Causes

• Cardiovascular compromise
• Shock
• End-organ dysfunction
• Functional limitation

Consultations

The patient should be consulted with a hematologist, particularly when a bone marrow disorder or bleeding is the case. A nephrologist consultation is crucial if anemia of chronic disease due to renal failure is suspected.

Deterrence and Patient Education

Populations at high risk should be considered for interprofessional evaluation. Patients should work with their healthcare provider to treat the underlying disease and address any acute condition like hemorrhage and adopt healthy habits. Patients should also receive adequate education about their underlying disease and possible complications of normocytic normochromic anemia.

Enhancing Healthcare Team Outcomes

The diagnosis and management of normocytic normochromic anemia require an interprofessional team that includes a primary care provider, an internist, and, if relevant, a hematologist, a gastroenterologist, a gynecologist, a surgeon, and a nurse practitioner as well as other professional teams. The key is to find the underlying disease and, if already diagnosed, the treatment and management of the underlying disease. After the diagnosis of the underlying disease, appropriate treatment, in most cases, attenuates the anemia and prevents complications.