Introduction

What is anaemia?

Anaemia is a condition that reduces the number of red blood cells, percentage by volume of red blood cells within blood (the haematocrit), or the amount of haemoglobin within red blood cells.¹

According to the World Health Organisation (WHO), anaemia is a major public health concern that affects approximately 269 million children (aged between 6 and 59 months) and half a billion women (aged between 15 and 49 years) globally. 

Red blood cells (also known as erythrocytes) transport oxygen from the lungs, carbon dioxide and waste from the tissues, and nutrients across the body. Haemoglobin is the protein that enables oxygen to bind to red blood cells and gives them their characteristic red colour.² 

Image 1: Red blood cells flowing through a blood vessel (Creative Commons CC0 1.0 Universal Public Domain Dedication).³ 

Anaemia can be classified based on its pathogenesis (the cause and development of a disease), red blood cell morphology (structure) and clinical presentation. In clinical practice, anaemia is commonly classified according to red blood cell morphology, specifically the mean corpuscular volume (MCV), the average volume and size of red blood cells.^4,5

Anaemia can be classified into three subtypes based on the MCV. The three classifications of anaemia are:^4,5

1. Macrocytic - the MCV level is above the normal range, more than 100 femtolitres (fL), meaning red blood cells are larger than normal
2. Microcytic - the MCV level is below the normal range, less than 80 fL, meaning red blood cells are smaller than normal 
3. Normocytic - the MCV level is within the normal range, between 80 fL and 100 fL, meaning red blood cells are a normal size

Image 2: The differing size of red blood cells depending on whether they are macrocytic, normal-sized (normocytic) or microcytic. The term discocyte means biconcave disc; red blood cells have a biconcave disc shape (Creative Commons Attribution-Share Alike 4.0 International license).¹²

Overview of normocytic anaemia

Definition

Normocytic anaemia means the size and volume of red blood cells are within the normal MCV range of 80 fL to 100 fL but involves decreased hematocrit.⁴ Normocytic anaemia can involve low haemoglobin, but it can also be described as normochromic, which means the red blood cells have a similar appearance to each other because they contain the normal amount of haemoglobin.^4,6

Normocytic anaemia can be categorised as either haemolytic (relating to haemolysis, the destruction of red blood cells) or non-haemolytic (not associated with the destruction of red blood cells).⁴ Haemolytic normocytic anaemia can occur intravascularly (within blood vessels) and extravascularly (outside of blood vessels), depending on the cause of anaemia, which is discussed in more detail in the ‘causes’ section below.⁴ 

Common symptoms

A majority of people with anaemia are asymptomatic, and the symptoms of normocytic anaemia are slow to develop, dependent on the underlying cause.^6,7 People with normocytic anaemia may experience the following symptoms:^4,6

• Weakness
• Fatigue 
• Dizziness/lightheadedness 
• Headaches 
• Decreased concentration 
• Shortness of breath 
• Exercise intolerance 
• Palpitations 
• Darkened urine 

Causes

The causes of normocytic anaemia can be classified as either hypoproliferative or hyperproliferative.⁶ Hypoproliferative anaemia is where there is a decrease in the production of red blood cells. In contrast, hyperproliferative anaemia refers to when there is an increase in the loss or destruction of red blood cells.

Causes of hypoproliferative normocytic anaemia include:^6,7,8

• Bone marrow hypoplasia/aplasia 
• Myelopathies
• Pure red blood cell aplasia
• Endocrine deficiency disorders
  • Hypothyroidism
  • Addison's disease
  • Adrenal / pituitary insufficiency
  • Hypogonadism
• Liver disease 
• Chronic renal failure 
• Anaemia of chronic disease - the most common normocytic anaemia and the second most common form of anaemia worldwide
  • Infections 
  • Cancer 
  • Autoimmune disorders 

Causes of hyperproliferative normocytic anaemia include:⁷

• Blood loss 
• Hypersplenism 
• Sickle cell disease
• Hereditary spherocytosis
• Autoimmune haemolytic anaemia
• Glucose-6-phosphate dehydrogenase deficiency 
• Thrombotic thrombocytopenic purpura

Classification: acute vs. chronic normocytic anaemia

Acute normocytic anaemia

Acute anaemia refers to the sudden and rapid decrease in the number of red blood cells. Acute normocytic anaemia can be caused by sudden blood loss or haemorrhage due to trauma and hemolysis (the destruction of red blood cells).⁹ 

The symptoms of acute anaemia correspond with the symptoms of hemorrhagic shock and include a fast heart rate, low blood pressure, skin pallor, and an altered mental state.⁹

Chronic normocytic anaemia

Chronic anaemia refers to the gradual decrease in the number of red blood cells over time.⁹ Chronic normocytic anaemia occurs as a result of other conditions, such as anaemia of chronic disease, bone marrow suppression and iron deficiency.^10,11

The symptoms of chronic normocytic anaemia (see the common symptoms section) occur due to the reduced capacity of blood to carry oxygen, resulting in decreased tissue oxygenation.¹⁰

Key differences between acute and chronic normocytic anaemia

The table below summarises the key differences between acute and chronic normocytic anaemia.^9,10

Table 1: The differences in onset, causes, and symptoms in acute and chronic normocytic anaemia.

Diagnostic Approach

History and physical examination

The first step of diagnosis involves a healthcare professional taking a medical history. During your appointment, your doctor will ask you questions about your: ^1,6

• Diet
• Medications
• Family history of hemoglobinopathies, sickle cell disease, thalassemia
• Blood loss (such as menstruation history, rectal bleeding, presence of  hemorroids, melena) 
• History of cancer and autoimmune diseases
• Surgical history 

In addition to considering your symptoms, your doctor will also conduct a physical examination during which they will be looking for:¹

• Pallor of the conjunctiva, lips, nail beds, palmar creases and skin 
• Skin that feels cool to the touch
• Postural/orthostatic hypotension 
• Jaundice 
• Bone pain 
• Enlarged spleen 
• Rapid breathing 
• Swollen lymph nodes 

Image 3: The different appearance of skin, tongue and conjunctival pallor on various skin tones (Creative Commons Attribution-Share Alike 4.0 International license).¹³

Laboratory tests

There are a few blood tests and analyses that are needed to help diagnose normocytic anaemia, these include:^1,6

1. Full Blood Count (FBC) with differential: This test, also known as a Complete Blood Count (CBC), measures the number of different cells and components in the blood, including red blood cells, white blood cells, and platelets
2. Mean corpuscular volume (MCV): This is part of the FBC and measures the average size and volume of red blood cells. Normocytic anaemia is characterised by an MCV between 80 fL and 100 fL
3. Peripheral blood smear: This is the analysis of blood cells spread on a glass slide, examined under a microscope. Examination of a peripheral blood smear may reveal the presence of specific cell types, such as large polychromatic ‘shift’ cells and spherocytes, which indicate normocytic anaemia
4. Reticulocyte count: This test measures the number of reticulocytes (immature red blood cells) and helps determine the underlying cause of anaemia. Namely, an increased reticulocyte count indicates hemolysis, whereas a decreased reticulocyte count indicates a hypoproliferative cause of anaemia

Image 4: A blood smear of a healthy adult showing the appearance of red blood cells (red cells), white blood cells (large purple cells) and platelets (small purple cells) under a microscope (Creative Commons Attribution-Share Alike 3.0 Unported license).¹⁵

Further investigations

Normocytic anaemia most frequently occurs due to an underlying chronic non-haematological disease, so further investigations may be needed to determine the underlying cause. These investigations may include screening for renal insufficiency, autoimmune diseases, subclinical infections and neoplasia.¹⁴ 

Further investigations may include the following tests:^1,6

• Blood Urea Nitrogen (BUN)
• Creatinine 
• Erythropoietin 
• C-reactive protein
• Erythrocyte sedimentation rate (ESR)
• Thyroid function tests
• Serum and urine electrophoresis
• Bone marrow biopsy
• Tests for infections such as Human Immunodeficiency Virus (HIV), Epstein-Barr virus (EBV), and hepatitis

Management

Anaemia itself is a sign of an underlying condition, so its treatment, correction, and management focus on addressing the underlying cause of anaemia.⁷

For example, the management of acute normocytic anaemia may focus on stopping bleeding (following blood loss) or surgical interventions and medications (to address haemolysis). Alternatively, the management of chronic normocytic anaemia may aim to address different chronic diseases using erythropoiesis-stimulating agents, corticosteroids, anti-inflammatories, blood transfusion, and iron supplementation.^4,6

FAQs

What is the difference between normocytic anaemia and other types of anaemia? 

Normocytic anaemia refers to red blood cells with a normal mean corpuscular volume, which means they have an average size of 80-100 fl. This differs from macrocytic and microcytic anaemia in which the red blood cells are larger (>100 fL) or smaller (<80 fL), respectively.⁴

What is the prognosis for normocytic anaemia? 

While normocytic anaemia is typically not a very serious illness, it can be indicative of a serious underlying condition, which may progress, and the prognosis depends on the underlying condition. For example, the prognosis for underlying conditions such as cancer may be worse compared to anaemia due to acute blood loss.⁶

What is the difference between acute and chronic normocytic anaemia? 

The main difference between the two is related to onset. Acute normocytic anaemia develops suddenly and rapidly, whereas chronic normocytic anaemia develops gradually and over time. The symptoms of and treatment for acute and chronic normocytic anaemia also differ.^9,10

Summary

• Anaemia is a major public health concern and refers to the decrease in the number of red blood cells, amount of haemoglobin or hematocrit
• Normocytic anaemia is characterised by a mean corpuscular volume between 80 fL and 100 fL
• Acute normocytic anaemia has a sudden and rapid onset, while chronic normocytic anaemia has a gradual onset that occurs over time, often as a result of an underlying condition
• A past medical history, physical examination, and blood tests can be used to diagnose and differentiate between acute and chronic normocytic anaemia.