Types of Anemia

Iron deficiency is the most common and widespread nutritional disorder in the world. As well as affecting a large number of children and women in developing countries, it is the only nutrient deficiency which is also significantly prevalent in industrialized countries.¹

The body needs iron to make healthy red blood cells. Iron-deficiency anemia usually develops over time because your body’s intake of iron is too low. Low iron content (depleted iron stores) can happen because of blood loss, consuming less than the recommended daily amount of iron, and medical conditions that make it hard for your body to absorb iron from the gastrointestinal tract.²

Iron-deficiency anemia is diagnosed by blood tests³ including:

Complete blood count (CBC), RBC differential

Erythrocyte differential and its indices

Reticulocyte (absolute and relative) and CHr

• Ferritin
• Iron
• Total iron-binding capacity
• Transferrin, soluble transferrin receptor (sTfr)

Optional tests:

• Haptoglobin (and Hemopexin)
• Cerulopasmin (Copper Content)

<sub>References
1. WHO/UNICEF/UNU. Iron deficiency anaemia: assessment, prevention, and control. World Health Organization Geneva. 2001;(WHO/NDH/01.3.
2. https://www.nhlbi.nih.gov/health-topics/iron-deficiency-anemia
3. http://www.hematology.org/Patients/Anemia/Iron-Deficiency.aspx</sub>

The most common causes of megaloblastic anemia are deficiency of either cobalamin (vitamin B12) or folate (vitamin B9). Your body needs folate and vitamin B12 to produce enough healthy red blood cells. A diet lacking in these and other key nutrients can cause decreased red blood cell production. Additionally, some people may consume enough vitamin B12, but their bodies aren't able to process the vitamin. This can lead to vitamin deficiency anemia, also known as pernicious anemia.

• A deficiency in vitamin B12 can result in varying degrees of neuropathy or nerve damage. In severe cases, mental changes that range from confusion and irritability to dementia may occur.¹
• Pregnant women need increased folate for proper fetal development because of the added stress of rapidly growing fetal cells. A folate deficiency during pregnancy, especially in the early weeks when a woman might not know she is pregnant, may lead to premature birth and neural tube birth defects (NTDs) such as spina bifida in the child.¹

Vitamin B12 in serum is bound to two proteins: transcobalamin (TC) and haptocorrin (HC). The transcobalamin vitamin B12 complex is called holotranscobalamin (holoTC). HoloTC is also known as active-B12 as it contains the biologically available cobalamin, as only holoTC promotes the uptake of cobalamin by all cells via specific receptors. HoloTC has been shown to be superior to other relevant lab parameters in B12 deficiency, such as serum total cobalamin and methylmalonic acid (MMA), for diagnosing vitamin B12 deficiency.²

Laboratory testing is used to detect a vitamin deficiency, determine its severity, establish it as the underlying cause of someone's symptoms, and to monitor the effectiveness of treatment.¹ Laboratory testing may include:

Complete Blood Count (CBC), incl. granulocyte segmentation

Erythrocyte differential with %Macro and MCV elevation

• Vitamin B12
• Active-B12 (Holotranscobalamin)
• Folate
• Homocysteine
• Methylmalonic acid
• Intrinsic factor antibody
• Gastrin

<sup>References:
1. https://labtestsonline.org/conditions/vitamin-b12-and-folate-deficiencies
2. Valente E et al. Diagnostic Accuracy of Holotranscobalamin, Methymalonic Acid, Serum Cobalamin, and Other Indicators of Tissue Vitamin B12 Status in the Elderly. Clin Chem 57:6, 856-863 (2011)</sup>

Anemia of Chronic Disease (also known as Anemia of Inflammation) is the second most prevalent after anemia caused by iron deficiency.¹ ACD commonly occurs with chronic illness or infections such as viral infections, including HIV, autoimmune diseases such as rheumatoid arthritis, lupus, cancer, inflammatory bowel disease (IBD) and inflammation.¹

• Soluble transferrin receptor (sTfR) has been shown to be an indicator of iron deficiency and is unaffected by concomitant chronic disease and inflammation4 Serum ferritin levels reflect iron stores while sTfR levels reflect the degree of availability of iron for cells. Calculating the sTfR/log ferritin index (sTfR index) from these two measures provides an estimate of body iron over a wide range of normal and depleted iron stores. sTfR and the sTfR index can aid in the diagnosis of iron deficiency anemia (IDA) and in the differential diagnosis of IDA and ACD.²
• The hematologic indices, HYPO (measurement of the proportion of hypochromic red cells) and reticulocyte hemoglobin content (CHr) have also been shown to help differentiate between iron deficiency anemia and anemia of chronic disease. CHr is an early marker of functional ID, as reticulocytes exist in the circulation for only 1–2 days. The usefulness of this index in monitoring erythropoietic function is indicated by studies of the evaluation of iron status in hemodialysis patients, in the diagnosis of ID in children, and in the diagnosis and treatment of various hematologic disorders.³

The combination of the hematologic indices CHr and HYPO with the sTfR-F index provides an attractive tool for diagnosis and therapeutic monitoring of functional ID.³

A number of laboratory tests may be used to determine the underlying cause⁴ including:

Complete Blood Count (CBC)

Reticulocyte count

Erythropoietin

Iron and transferrin (TIBC)

Soluble transferrin receptor (sTfR)

• Blood smear
• Comprehensive metabolic panel (CMP)—used to detect evidence of chronic disorders
• Tests for inflammation such as CRP, BSR, IL-6, procalcitonin (PCT)
• Tests for infections such as PCT, Leukocytosis (Differential), HIV and TB
• Hepcidin

<sup>References:
1. Weiss G et al. Anemia of Chronic Disease. N ENGL J MED 352;10. March 2005
2. Skikne B et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: A prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am. J. Hematol. 86: 923-927, 2011
3. Thomas C and Thomas L. Biochemical Markers and Hematologic Indices in the Diagnosis of Functional Iron Deficiency. Clin Chem 48:7, 1066-1076, 2002
4. https://labtestsonline.org/conditions/anemia</sup>

Anemia is one of the most common complications of chronic kidney disease (CKD), especially in children and is associated with a variety of adverse clinical consequences, including an increased risk for hospitalization and mortality, and the development and progression of cardiovascular disease (CD) risk factors.¹

In renal anemia, the kidney’s ability to produce erythropoietin (EPO) is impaired. Inflammatory cytokines suppress erythropoiesis in the bone marrow and EPO production in the kidney, as a result fewer red blood cells are produced, causing anemia.^1,2

The current management of anemia in patients with advanced CKD consists of a combination of erythropoiesis-stimulating agents (ESAs) with iron supplementation.¹ However, a number of studies have demonstrated that the use of ESAs may be associated with adverse cardiovascular events and increased mortality risk.¹ A novel class of therapeutic agents is currently in development for the treatment of anemia in patients with CKD. These new agents act by inhibiting the enzymes that promote the degradation of hypoxia inducible factors (HIFs), a family of oxygen-sensitive proteins that regulate the cell’s transcriptional response to hypoxia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk–benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.³ 

According to the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice and guidelines⁴ diagnosis of anemia in CKD consists of:

• Diagnose anemia in adults and children >15 years with CKD when the hemoglobin concentration is <13.0 g/dL (<130 g/L) in males and <12.0 g/dL (<120 g/L) in females.
• Diagnose anemia in children with CKD if Hb concentration is <11.0 g/dL (<110 g/L) in children 0.5–5 years, <11.5 g/dL (115 g/L) in children 5–12 years, and <12.0 g/dL (120 g/L) in children 12–15 years.

Investigation of anemia includes:

Complete blood count (CBC), which should include Hb concentration, red cell indices, white blood cell count and differential, and platelet count

Absolute reticulocyte count

Ferritin

Vitamin B12 and folate levels

• Serum transferrin saturation (TSAT)

References:

1. Atkinson M & Warady B. Anemia in chronic kidney disease. Pediatr Nephrol (2018) 33:227-238

2. https://www.niddk.nih.gov/health-information/kidney-disease/anemia

3. Locatelli F et al. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol 2017; 

4 5:187-1994. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the 

Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150.