- ACRONYMS
- AHA - Autoimmune hemolytic anemia
- AI - Anemia of inflammation
- C3 - Complement component 3
- CAHA - Cold autoimmune hemolytic anemia
- CDC - Centers for Disease Control and Prevention
- CHr - Content of hemoglobin in reticulocytes
- CKD - Chronic kidney disease
- DIC - Disseminated intravascular coagulation
- ESA - Erythropoietin-stimulating agents
- Hg - Hemoglobin
- HUS - Hemolytic uremic syndrome
- IRIDA - Iron-refractory iron deficiency anemia
- ITP - Immune thrombocytopenia
- MCV - Mean corpuscular volume
- PNH - Paroxysmal nocturnal hemoglobinuria
- RBC - Red blood cell
- SLE - Systemic lupus erythematosus
- TCD - Transcranial doppler ultrasound
- TSAT - Transferrin saturation
- TTP - Thrombotic thrombocytopenic purpura
- USPSTF - U.S. Preventive Services Task Force
- VTE - Venous thromboembolism
- WAHA - Warm autoimmune hemolytic anemia
- DEFINITIONS
- Acanthocytes (spur cells) - acanthocytes are RBCs that have spikes along their membrane at irregular intervals. Acanthocytes occur because of abnormalities in the composition of the cell membrane. Acanthocytes may be seen in a number of conditions including liver disease (increase in membrane lipids) and vitamin deficiencies. (acanthocyte illustration)
- Anisocytosis - anisocytosis means the observed RBCs have varying sizes. Anisocytosis is common in anemia. The red cell distribution width (RDW) is a measure of anisocytosis with higher values indicating greater anisocytosis.
- Antibody screen - an antibody screen is a test that detects antibodies to surface antigens on RBCs. Antibodies to the main A and B red blood cell antigens occur naturally depending on a person's blood type. Antibodies to other RBC antigens occur through exposure to foreign RBCs, primarily through blood transfusions or pregnancy (mother-baby incompatibility).
- Apoferritin - apoferritin is a protein that resides in cells. It's primary function is to bind iron that has entered the cell at which point it becomes ferritin. Ferritin is the main storage form of iron accounting for 15 - 30% of total body iron.
- Apotransferrin - apotransferrin is a protein that binds iron in the plasma and intestines. The apotransferrin-iron complex is called transferrin, and it is the main form in which iron is transported around the body. Apotransferrin is mixed with bile and secreted into the small intestine where it binds free iron and iron-containing compounds like hemoglobin and myoglobin in meat. The apotransferrin-iron complex (transferrin) is then absorbed by the intestine. See iron homeostasis below.
- Basophilic stippling - "basophilic" means something that is readily stained with basic dyes. In histological terms, "stippling" means small dots. Basophilic stippling is a term that means small dots of basophilic ribosomes and RNA are speckled throughout an erythrocyte. Basophilic stippling occurs when there is incomplete ribosome degradation during the latter stages of erythropoiesis, which may occur in heavy metal toxicity (e.g. lead poisoning) and hemoglobinopathies such as thalassemia and sickle cell disease. (basophilic stippling illustration) [30]
- Bilirubin - bilirubin is a compound formed from the metabolism of hemoglobin. After macrophages consume hemoglobin, they break it down into iron and bilirubin. Bilirubin is released back into the bloodstream where it is removed by the liver and secreted into the bile. See RBC life cycle below.
- Bite cells (also called blister cells) - bite cells are RBCs with irregular membranes. Bite cells are formed when macrophages remove Heinz bodies from RBCs. Bite cells are a sign of G6PD deficiency. (Heinz body and bite cell illustration)
- Blood - blood is composed of plasma and formed elements (e.g. WBCs, RBCs, platelets). Plasma is blood minus all the formed elements, and serum is plasma minus the clotting factors. The average adult has 5 liters of blood.
- Carbon monoxide - carbon monoxide is a gas that binds almost irreversibly to hemoglobin and renders it unable to carry oxygen. Carbon monoxide poisoning is treated acutely with high-flow oxygen.
- Cold agglutinins - cold agglutinins are IgM antibodies that bind the I/i antigen on RBCs. They are most reactive between 39 and 70° F, hence the name "cold." If their concentration is high enough, they can cause RBC agglutination and fixation of C3 to the RBC membrane. C3-tagged RBCs may undergo intravascular hemolysis if the complement system is completed, but more commonly, they are removed by macrophages in the spleen and liver. Cold agglutinin antibodies are present at low titers in almost all humans, and they only become clinically significant at higher titers. Cold agglutinins may form secondary to an underlying condition (e.g. cancer, Mycoplasma pneumonia, mononucleosis), or they may be secondary to a clonal low-grade B-cell lymphoproliferative disorder. See cold autoimmune hemolytic anemia for more. [58]
- Direct Coombs test (direct antiglobulin test) - the direct Coombs test is an assay that looks for antibodies (IgG, "gamma globulins") and complement components (C3, "beta globulins") attached to RBCs. IgG attached to RBCs is consistent with WAHA. C3 attached to RBCs can occur with WAHA, but it is more common in CAHA. CAHA is caused by IgM antibodies that attach to the surface of RBCs and fix complement (C3). IgM can detach from RBCs and is not commonly detected on the direct antiglobulin test, but the presence of C3 fixation is a strong indicator of the presence of IgM antibodies. These autoimmune antibodies can lead to hemolysis and RBC destruction. See autoimmune hemolytic anemia for more.
- Deoxyhemoglobin - deoxyhemoglobin is hemoglobin that does not have oxygen bound to it.
- Echinocytes (Burr cells) - echinocytes are RBCs that have regularly spaced spikes along their membrane. Echinocytes occur when plasma abnormalities affect membrane morphology. Echinocytes can be seen in kidney disease, liver disease, and as an artifact of treating blood samples with EDTA to prevent clotting. (echinocyte illustration)
- Erythropoietin - erythropoietin is a hormone that stimulates RBC production in the bone marrow. 90% of erythropoietin is produced in the kidneys and 10% in the liver. Erythropoietin release is stimulated by tissue hypoxia, and it takes about 5 days after an increase in production before new RBCs are seen.
- Ferritin - ferritin is formed when iron binds the protein apoferritin inside of cells. Ferritin is the main storage form of iron iron accounting for 15 - 30% of total body iron. The serum ferritin level is directly proportional to tissue concentrations which makes it a good measure of total body iron stores. Ferritin is also an acute phase reactant and may be elevated in inflammatory conditions. See ferritin for more.
- Folate/Folic acid (Vitamin B9) - folate is a naturally-occurring vitamin found in dark leafy green vegetables, citrus fruits, and liver. Folic acid is a synthetic version of folate that is found in supplements and fortified foods such as breads and cereals. Folic acid is essential for the production of DNA. Folic acid deficiency causes RBCs to develop abnormally leading to enlarged RBCs called macrocytes. Macrocytes carry oxygen normally, but they are not as pliable as normal RBCs and their lifespan is decreased by 30 - 50%. See folic acid deficiency for more.
- Haptoglobin - haptoglobin is a protein produced by the liver that binds directly to hemoglobin in the blood and prevents the release of highly reactive heme. Haptoglobin-hemoglobin complexes are quickly removed by macrophages. Elevated LDH levels in combination with a haptoglobin < 25 mg/dL is 95% specific for the presence of hemolysis while a normal LDH and haptoglobin > 25 mg/dL are 92% sensitive for the absence of hemolysis. Low haptoglobin levels may also be seen in vigorous exercise, liver disease, transfusion therapy, and ahaptoglobinemia, a rare genetic disorder that affects 0.1% of whites and as many as 4% of blacks. Haptoglobin is also an acute phase reactant, and it may be normal or elevated despite significant hemolysis in patients with infections and other inflammatory states.
- Heinz bodies - Heinz bodies are clumps of denatured hemoglobin that appear in RBCs. They are not seen on standard blood smears, but can be visualized with supravital staining. Heinz bodies form under conditions that cause oxidative stress (e.g. G6PD deficiency), and they often lead to hemolytic anemia. When macrophages remove Heinz bodies from RBCs, the RBCs can develop an irregular border which gives them the name "bite cells" or "blister cells." (Heinz body and bite cell illustration)
- Hemosiderin - hemosiderin is an insoluble storage form of iron that normally makes up a small percentage of iron stores. If apoferritin stores are exhausted, hemosiderin production may increase and large clusters may form in cells. If these clusters are in the skin, something called "hemosiderin staining" can occur in which the skin appears hyperpigmented or darkened. Hemosiderin staining of the skin may occur in areas of trauma, bleeding, edema, and ulceration.
- Hemosiderinuria - in severe hemolysis, urinary hemoglobin is reabsorbed by renal tubular cells and processed to hemosiderin. Hemosiderinuria is the presence of hemosiderin in sloughed renal epithelial cells.
- Hepcidin - hepcidin is a hormone released by the liver that is involved in iron homeostasis. Hepcidin blocks iron absorption in the intestines and inhibits iron release from the liver and macrophages. Hepcidin levels increase in response to high levels of circulating iron and elevated ferritin stores, and release is suppressed by tissue hypoxia, erythropoiesis, low levels of circulating iron, and decreased ferritin. Hepcidin is also an acute phase reactant, and conditions causing prolonged inflammation can raise levels and lead to anemia of chronic inflammation.
- Howell-Jolly bodies - Howell-Jolly bodies are nuclear remnants (clusters of DNA) seen in circulating RBCs. Under normal circumstances, RBCs expel all of their nucleus before they leave the bone marrow, but a small portion may remain. The spleen removes any remaining nuclear remnants from circulating RBCs. Howell-Jolly bodies are seen in patients with hyposplenia and asplenia. They may also be present in megaloblastic anemia and hemolysis. (Howell-Jolly body illustration)
- Inclusion bodies - inclusion bodies are clumps of precipitated proteins that form inside RBCs. They may occur from abnormal hemoglobin, lead poisoning, and abnormal erythropoiesis.
- Iron - iron is an element found throughout the body that has many important functions. Iron binds loosely to oxygen in hemoglobin so that RBCs can transport oxygen throughout the body. Iron is also found in myoglobin (protein that stores oxygen in muscle cells), and it plays an important role in enzymatic reactions (e.g. cytochromes, catalase, peroxidase). Iron is stored in tissues throughout the body, and excess iron is primarily stored in the liver. See iron homeostasis below.
- Lactate dehydrogenase (LDH) - lactate dehydrogenase is an enzyme involved in anaerobic metabolism that is found in almost every cell in the body. When cells are damaged or destroyed, they release LDH. An elevated LDH level is a sensitive measure of RBC hemolysis, but it is not specific. LDH enzymes have subtypes, and subtypes 1 and 2 are seen in RBCs. Subtypes 1 and 2 are also seen in the kidneys, stomach, pancreas, and heart muscle. LDH levels can be used in combination with haptoglobin to detect hemolysis. Elevated LDH with a haptoglobin < 25 mg/dL is 95% specific for the presence of hemolysis while a normal LDH and haptoglobin > 25 mg/dL are 92% sensitive for the absence of hemolysis.
- Mean corpuscular volume (MCV) - the MCV is the average volume of RBCs in a blood sample. It is typically calculated by a machine called a hemolyzer. A normal MCV is 80 - 95 fL in adults.
- Methemoglobinemia - methemoglobin is hemoglobin with the iron in the ferric state (Fe+3) as opposed to the normal ferrous state (Fe+2). Methemoglobin cannot bind oxygen, and it causes the remaining subunits of normal hemoglobin to bind oxygen more tightly; this prevents the delivery of oxygen to tissues. Under normal conditions, methemoglobin makes up < 1% of hemoglobin. Levels above 1% are abnormal and consistent with methemoglobinemia. Methemoglobinemia can be congenital or it can be acquired from certain chemicals and/or medications (e.g. nitrates, local anesthetics, antibiotics, antimalarials). Methemoglobinemia is typically treated with methylene blue, a dye which rapidly converts methemoglobin to hemoglobin.
- Oxyhemoglobin (HbO2) - oxyhemoglobin is hemoglobin that has oxygen bound to it
- Plasma - plasma is the liquid component of blood that does not contain the formed elements (e.g. RBCs, WBCs, platelets). The average adult has about 2.75 liters of plasma. Plasma is 93% water and the rest is dissolved or suspended solutes. Plasma must be frozen to preserve the clotting factors.
- Plasmapheresis - plasmapheresis is a procedure where a patient's plasma is exchanged for donor plasma
- Poikilocytosis - poikilocytosis is a term that means irregularly-shaped RBCs. Poikilocytosis can occur in a number of disorders including anemia and thalassemia to name a few.
- Polychromasia - polychromasia is a term that means there is a abnormally high number of reticulocytes in the circulation
- Red blood cells (RBCs) - RBCs (also called erythrocytes) are a type of blood cell that have the primary function of transporting hemoglobin to body tissues so that oxygen may be delivered to the cells. RBCs also contain carbonic anhydrase, an enzyme that serves as the main acid-base buffer in the body. Healthy red blood cells are very pliable and are able to squeeze their way through capillaries. All bones produce RBCs in their bone marrow up until the age of 5 years, after which, production primarily occurs in the ribs, sternum, pelvis, and iliac crest. Unlike other cells, RBCs do not have a nucleus or other organelles. See RBC life cycle below.
- Reticulocyte - reticulocytes are immature RBCs that form in the bone marrow and are released into the circulation. Reticulocytes circulate for 1 day before they become mature RBCs. Histologically, reticulocytes are distinguishable from mature RBCs by the persistence of a small amount of basophilic material consisting of cytoplasmic organelles. Under normal conditions, the percent of RBCs that are reticulocytes in adults is 0.5 - 2.5%. The absolute reticulocyte count is found by taking the percentage of reticulocytes and multiplying by the RBC count. (reticulocyte illustration)
- Reticulocyte hemoglobin content (CHr) - the reticulocyte hemoglobin content (also called content of hemoglobin in reticulocytes (CHr)) is the amount of hemoglobin observed in circulating reticulocytes. It is reported in picograms and normal ranges vary by age. In adults, levels > 28 pg typically reflect adequate iron available for erythropoiesis. Since reticulocytes represent the newest RBCs in the circulation with a lifespan of 1 - 2 days, CHr is considered a more acute measure of hematopoietic-available iron than ferritin and TSAT. CHr can also be used to predict responses to IV iron therapy and has been shown to be more accurate than ferritin and TSAT in some studies. [34]
- Reticulocyte index - the reticulocyte index is the ratio of the observed absolute reticulocyte count to the normal reticulocyte count. Reticulocyte index = [observed reticulocyte count] / [normal absolute reticulocyte count] (online calculator). A reticulocyte index ≥ 2 is considered an appropriate marrow response to anemia. An index < 2 is considered inappropriate and suggests conditions suppressing erythropoiesis.
- Reticulocyte production index (RPI) - the RPI is a measure of reticulocyte production that adjusts for the level of anemia. When erythropoietin stimulates RBC production, it causes the early release of reticulocytes from the bone marrow into the circulation. Under normal conditions, reticulocytes in the circulation mature into erythrocytes in 1 day. When erythropoietin-stimulated early release occurs, reticulocyte maturation can last up to 2.5 days. Prolonged maturation increases the number of circulating reticulocytes, but this does not reflect a true increase in erythropoiesis. The RPI corrects for the shift in maturation and provides a more accurate measure of marrow response. An RPI > 3 is considered an appropriate marrow response to anemia and an RPI < 2 is considered inappropriate. The RPI can be calculated with one of the two following formulas: RPI = [Reticulocyte %] X [Hg (observed) / Hg(normal)] X 0.5 or RPI = [reticulocyte index] / [expected maturation rate in days] using the following:
- Hg 10 - 13 g/dl: 1.5 days
- Hg 7 - 10 g/dl: 2 days
- Hg 3 - 7 g/dl: 2.5 days
- Schistocytes - schistocytes are fragments of RBCs formed when the cells are damaged or destroyed. Conditions where schistocytes are seen include DIC and TTP (microvascular fibrin strands shear RBCs), hemolytic anemia, and mechanical heart valves.
- Serum - serum is plasma minus the clotting factors. Serum contains electrolytes, proteins, immunoglobulins, hormones, and anything else not involved in coagulation.
- Sideroblasts - sideroblasts are erythroid precursor cells that have a ring of iron-laden mitochondria around at least one-third of the cellular nucleus. Iron-laden mitochondria form secondary to abnormalities in heme synthesis. See sideroblastic anemia. (sideroblast illustration) [32]
- Spherocytes - spherocytes are RBCs with defective membranes that allow sodium and water to enter the cell. This causes the RBC to assume the shape of a sphere as opposed to the typical round, biconcave shape. Spherocytes are caused by hereditary disorders of RBC membrane formation (hereditary spherocytosis), and they are also seen in hemolytic anemia when complement fixation creates holes in the membrane. (spherocyte illustration)
- Target cells - target cells are RBCs that have a central concentration of hemoglobin surrounded by a pale ring. Target cells form when there is a disproportionate increase in the ratio of cell membrane area to cell contents. The increased ratio can occur from a decrease in hemoglobin (e.g. iron deficiency anemia) or from an increase in cell membrane surface area (e.g. liver disease, splenectomy). In liver disease, cholesterol and phospholipids deposit in the surface of RBCs causing their surface area to increase. The spleen typically removes lipids from the maturing RBC membrane, so its absence (e.g. splenectomy) can lead to increased surface area as well.
- Transferrin - transferrin is formed when iron binds to the protein apotransferrin. Transferrin transports iron through the blood to various tissues in the body. Iron is loosely bound to transferrin so it is easily released to cells that need iron. Excess iron is primarily stored in liver cells. See iron homeostasis below.
- Urobilinogen - urobilinogen is formed in the intestine from the bacterial metabolism of bilirubin. Some urobilinogen is excreted in the feces and some is reabsorbed and excreted by the kidneys. Elevated urinary urobilinogen can occur under conditions of increased hemoglobin metabolism (e.g. hemolytic anemia, clot reabsorption) and liver inflammation (e.g. cirrhosis, hepatitis). Low levels of urinary urobilinogen may occur with hepatic or biliary obstruction. See iron homeostasis below.
- Vitamin B12 - vitamin B12 is essential for the production of DNA. Vitamin B12 deficiency causes RBCs to develop abnormally leading to enlarged RBCs called macrocytes. Macrocytes carry oxygen normally, but they are not as pliable as normal RBCs and their lifespan is decreased by 30 - 50%. The stomach produces a glycoprotein called intrinsic factor that binds and protects Vitamin B12 and makes it available for absorption in the ileum. Stomach conditions that affect intrinsic factor production (e.g. gastritis, gastric surgery) can lead to decreased Vitamin B12 absorption. Only 1 - 3 micrograms/day of Vitamin B12 are required to maintain normal RBC production, so it can take 3 - 4 years of deficient absorption to affect RBC production. Vitamin B12 is found in animal products (meat, eggs, dairy) so vegetarians are at risk of deficiency. See vitamin B12 deficiency for more.

- EVALUATING ANEMIA
- Overview
- The cause of anemia is obvious in many cases but can be challenging to identify in others, especially when it is multifactorial. There are no professional guidelines that provide a straightforward diagnostic approach to anemia. The steps below are derived from review articles and offer a starting point that can be tailored to the individual. It's important to keep in mind that even after an extensive workup, the etiology of anemia will remain unknown in a significant number of cases.
Evaluating anemia |
---|
WHO definition of anemia
|
MCV is low (< 80 fL)
|
MCV is normal (80 - 100 fL)
|
MCV is elevated (> 100 fL)
|
- HEMOGLOBIN
- Overview
- Hemoglobin is a RBC protein that binds oxygen in the lungs for transport to tissues. Hemoglobin molecules contain 4 chains, and each chain is comprised of a heme molecule (iron + protoporphyrin IX) and a polypeptide called a globulin. Under normal conditions, there are four main types of chains - alpha chains, beta chains, gamma chains, and delta chains.
- Normal hemoglobin types
- Hemoglobin A (Adult hemoglobin) - Hemoglobin A is the most common form of hemoglobin in adults. It is made up of 2 alpha chains and 2 beta chains.
- Hemoglobin A2 - Hemoglobin A2 is a variant of hemoglobin A that comprises 1.5 - 3% of hemoglobin in adults. It is made up of 2 alpha chains and 2 delta chains.
- Hemoglobin F (fetal hemoglobin) - Hemoglobin F replaces embryonic hemoglobin and is the main hemoglobin during the last 7 months of gestation. It is made up of 2 alpha chains and 2 gamma chains. After birth, hemoglobin F is almost completely replaced by hemoglobin A. After 6 months of age, hemoglobin F makes up about 0.5% of hemoglobin. Hemoglobin F binds oxygen more tightly than adult hemoglobin to ensure proper intrauterine oxygen delivery.
- Hemoglobin E (embryonic hemoglobin) - Hemoglobin E is present during gestation from week 3 to 3 months. It is made up of 2 alpha chains and 2 epsilon chains. Hemoglobin E binds oxygen more tightly than adult hemoglobin to ensure proper intrauterine oxygen delivery.
- Abnormal hemoglobin types
- Bart's hemoglobin - Bart's hemoglobin is an abnormal form of hemoglobin that is composed of 4 gamma chains. Bart's hemoglobin occurs in homozygous alpha thalassemia. See alpha thalassemia below.
- Hemoglobin C - Hemoglobin C is hemoglobin A with a lysine substituted for glutamic acid at position 6 of each beta chain. See hemoglobin C disease below.
- Hemoglobin H - Hemoglobin H is a tetramer of 4 beta chains that forms in heterozygous types of alpha thalassemia. See alpha thalassemia below.
- Hemoglobin S - Hemoglobin S is hemoglobin A with a valine substituted for a glutamic acid at position 6 of each beta chain. Hemoglobin S causes sickle cell disease. See sickle cell disease below.

HEMOGLOBIN TYPE BY CONDITION | |||||||
---|---|---|---|---|---|---|---|
Condition | Hg A | Hg A2 | Hg F | Hg S/C/H/Bart | Clinical | Prevalence | |
Normal | 95 - 98% | 1.5 - 3.0% | 0.5% | 0 | - | - | |
Alpha (α) Thalassemias✝ | |||||||
Condition | Hg A | Hg A2 | Hg F | Hg H | Hg Bart | Clinical | Affected populations |
α-thalassemia carrier (1/4 genes affected) |
95 - 98% | 1.5 - 3.0% | 0.5% | 0 | 0 | Asymptomatic | Southeast Asian, Mediterranean, Indian, Middle Easten, African |
α-thalassemia trait (minor) (2/4 genes affected) |
95 - 98% | 1.5 - 3.0% | 0.5% | 0 | 0 | Causes low MCV Possible mild anemia Typically asymptomatic |
Southeast Asian, Mediterranean, Indian, Middle Easten, African |
α-thalassemia intermedia (α+) (3/4 genes affected) |
60 - 90% | < 2% | < 1% | 0.8 - 40% | 2 - 5% | Varies by severity See alpha thalassemia |
Southeast Asian, Mediterranean, Indian, Middle Easten, African |
α-thalassemia major (αO) (4/4 genes affected) |
0 | 0 | 0 | 0 | 85 - 90% | Typically fatal in utero (hydrops fetalis) | Very rare in the U.S. (< 20 cases/year) |
Beta (β) Thalassemias✝ | |||||||
Condition | Hg A | Hg A2 | Hg F | Hg S/C/H/Bart | Clinical | Affected populations | |
β-thalassemia trait (minor) (1/2 genes affected) |
92 - 95% | > 3.5% | 0.5 - 4% | 0 | Typically asymptomatic | Mediterranean, Middle Easten, African, Central Asia, Indian, Far East | |
β-thalassemia intermedia (β+) (2/2 genes affected) |
10 - 30% | 2 - 5% | 70 - 90% | 0 | Varies depending on severity See beta thalassemia |
Mediterranean, Middle Easten, African, Central Asia, Indian, Far East | |
β-thalassemia major (βO) (2/2 genes severely affected) |
0 | 2 - 5% | 95 - 98% | 0 | Severe See beta thalassemia |
Mediterranean, Middle Easten, African, Central Asia, Indian, Far East | |
Hemoglobin C disease | |||||||
Condition | Hg A | Hg A2 | Hg F | Hg S | Hg C | Clinical | U.S. prevalence |
Hg C trait (Hg A + Hg C) |
55 - 65% | < 3.5% | < 1% | 0 | 30 - 40% | Typically asymptomatic | 1 - 3% among blacks |
Hg C disease (Hg C + Hg C) |
0 | 0 | > 0.5% | 0 | > 90% | Typically asymptomatic See Hg C disease |
< 0.10% among blacks |
Sickle cell disease | |||||||
Condition | Hg A | Hg A2 | Hg F | Hg S | Hg C | Clinical | U.S. prevalence |
Sickle cell trait (Hb S + Hb A) |
55 - 65% | 1.5 - 3.0% | 0.5% | 35 - 45% | 0 | Typically asymptomatic See sickle cell trait |
8% among blacks |
Sickle cell disease (Hb S + Hb S) |
0 | 1.5 - 3.0% | 5 - 15% | 80 - 95% | 0 | Severe See sickle cell disease |
0.3% among blacks |
Hg S + β thalassemia major (βO) |
0 | > 3.5% | 5 - 15% | 80 - 90% | 0 | Similar to sickle cell disease | 1 - 3% among patients with sickle cell disease |
Hg S + Hg C | 0 | < 3.5% | < 3% | 50 - 55% | 40 - 45 | Midler than sickle cell disease | 25 - 30% among patients with sickle cell disease |
Hg S + β thalassemia intermedia (β+) |
10 - 25% | > 3.5% | < 3% | 70 - 80% | 0 | Midler than sickle cell disease | 5 - 10% among patients with sickle cell disease |
- Alpha thalassemia
- Normal adult hemoglobin is composed of 2 alpha chains and 2 beta chains
- Alpha thalassemia is an inherited condition where genetic defects decrease the production of alpha chains. Alpha chains are encoded in two regions on each chromosome 16 giving them a total of 4 genes. Deletions or mutations of these genes can inhibit alpha chain production. When inadequate amounts of alpha chains are present, beta chains will combine with themselves to form tetramers called hemoglobin H. Hemoglobin H cannot transport oxygen and it will form inclusion bodies in RBCs that can lead to hemolysis. If no alpha chains are produced, hemoglobin Bart's (4 gamma chains) will form and in utero death will occur secondary to hydrops fetalis, a condition marked by diffuse tissue edema (see abnormal hemoglobin types and hemoglobin table above).
- The clinical course of alpha thalassemia is dependent on the number of genes affected and the amount of hemoglobin H produced (see table below). Long-term effects of alpha thalassemia include anemia from chronic hemolysis, hypersplenism, extramedullary hematopoiesis, iron overload with organ deposition and damage, hypercoagulability, and cholelithiasis.
- When necessary, transfusions are used to treat alpha thalassemia. Transfusions provide normal erythrocytes which suppress the drivers of abnormal hemoglobin production and help to prevent disease sequelae.
- In general, most patients who have α-thalassemia intermedia and produce hemoglobin H are clinically well and do not require transfusions
Alpha thalassemia characteristics | |
---|---|
α-thalassemia carrier (1/4 genes affected) |
|
α-thalassemia trait (minor) (2/4 genes affected) |
|
α-thalassemia intermedia (α+) (3/4 genes affected) |
|
α-thalassemia major (αO) (4/4 genes affected) |
|
- Beta thalassemia
- Pathology
- Normal adult hemoglobin is composed of 2 alpha chains and 2 beta chains. Beta thalassemia is an inherited condition where genetic defects decrease the production of beta chains. Beta chains are encoded in one region on each chromosome 11 giving them a total of 2 genes. Deletions or mutations of these genes can inhibit beta chain production. When inadequate amounts of beta chains are present, alpha chains form tetramers that accumulate in RBCs and lead to premature cell death and ineffective erythropoiesis. Hemoglobin A is decreased, hemoglobin F is increased, and chronic anemia develops (see abnormal hemoglobin types and hemoglobin table above).
- Clinical course
- The clinical course of beta thalassemia is dependent on the severity of beta chain loss (see table below). Long-term effects of beta thalassemia include chronic transfusion-dependent anemia, hypersplenism, extramedullary hematopoiesis, iron overload from chronic transfusions causing organ deposition and damage, hypercoagulability, and cholelithiasis.
- Treatment
- Transfusions are used to treat significant beta thalassemia. Transfusions provide normal erythrocytes, which suppress the drivers of abnormal hemoglobin production and help to prevent disease sequelae.
- Stem cell transplant is an option in some patients and is potentially curative. Best outcomes are seen in patients younger than 14 years with an HLA-identical donor.
- A study published in 2022 described the use of gene therapy to treat 23 patients with transfusion-dependent beta thalassemia and a non–βo/βo genotype. Autologous stem cells were transduced with a virus that changed the beta globulin gene so that the cell produced functional beta globulin. After a median follow-up of 29.5 months, transfusion independence occurred in 91% of patients. [PMID 34891223] In 2022, the treatment received FDA approval under the trade name Zynteglo.
- In 2019, the FDA approved the first therapy to treat beta thalassemia, an injectable protein called Reblozyl® (luspatercept–aamt). In beta thalassemia, certain ligands inhibit the late stages of erythropoiesis. Reblozyl® binds these ligands and indirectly promotes RBC maturation. In a placebo-controlled trial, Luspatercept significantly reduced transfusion burden in patients with transfusion-dependent beta thalassemia. [PMID 32212518] In another study, it raised the average hemoglobin level in non–transfusion-dependent beta thalassemia. [PMID 36007538]
- In 2020, a report was published in the NEJM that described a case where a patient with transfusion-dependent beta-thalassemia was successfully treated with clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. BCL11A is a transcription factor that represses gamma globin and fetal hemoglobin production in erythroid cells. CRISPR editing was used to knockout the gene that codes for BCL11A, and fetal hemoglobin levels increased. [PMID 33283989]
Beta thalassemia characteristics | |
---|---|
β-thalassemia trait (minor) (1/2 genes affected) |
|
β-thalassemia intermedia (β+) (2/2 genes affected) |
|
β-thalassemia major (βO) (2/2 genes severely affected) |
|
- Hemoglobin C disease
- Hemoglobin C disease is a genetically inherited hemoglobinopathy that occurs when glutamic acid is replaced with a lysine at position six on the beta chain (see abnormal hemoglobin types)
- If only one beta globin gene is affected, the patient will have hemoglobin C trait. Patients with hemoglobin C trait produce 55 - 65% hemoglobin A with 30 - 40% hemoglobin C and are typically asymptomatic. Peripheral blood smears may show target cells and intracellular crystals.
- If both beta globin genes are affected, hemoglobin C disease will occur. Patients with hemoglobin C disease produce no hemoglobin A and > 90% hemoglobin C (see hemoglobin table above). Hemoglobin C may crystallize causing increased RBC rigidity and shortened RBC lifespan, but it does not polymerize and cause sickling like hemoglobin S. Most patients with hemoglobin C disease are asymptomatic but they may have mild chronic hemolysis, splenomegaly, and anemia. Peripheral blood smears will show microcytosis, target cells, spherocytes, and crystallized hemoglobin.
- Hemoglobin C is often inherited with other hemoglobinopathies and it can affect the pathology of these conditions. For example, coinheritance of hemoglobin S and hemoglobin C tends to have a milder course than homozygous hemoglobin S (sickle cell disease).
- Hemoglobin C appears to protect against malaria, and therefore, it is primarily found in people of African descent. In the U.S., 1- 3% of blacks have hemoglobin C trait and <0.10% have hemoglobin C disease. Hemoglobin C detection is part of the standard newborn screening test.
- Treatment of hemoglobin C disease is generally not needed. If chronic hemolytic anemia is present, folic acid supplementation of 1 mg/day may be recommended to support high RBC turnover. Gallstones may also develop. No physical activity restrictions are required. [17]
- SICKLE CELL DISEASE
- Epidemiology
- It's estimated that 300,000 newborns are born with sickle cell disease each year, with Sub-Saharan Africa, particularly Nigeria and the Congo, and India having the highest prevalence. In the U.S., about 100,000 people have the disease.
- In developed countries, treatment has improved substantially, with childhood mortality now similar to the general population and overall life expectancy reaching into the sixties. In poorer countries with limited resources, most children with sickle cell disease die before the age of five.
- Pathology
- Sickle cell disease is caused by hemoglobin S, an abnormal variant marked by the substitution of glutamic acid with valine at the sixth position of the hemoglobin A beta chain. When hemoglobin S is exposed to hypoxia, it elongates, causing the RBC to take on the shape of a sickle. Sickled RBCs do not pass freely through capillaries, leading to clumping and vessel occlusion with subsequent tissue hypoxia and pain (sickle cell crisis). Sickled cells are also fragile and prone to rupture, causing anemia.
- Sickle cell trait (SCT)
- Patients with two hemoglobin S genes will have sickle cell disease, while those with one hemoglobin S gene and one normal gene will have sickle cell trait. SCT is highly protective against severe malaria, and its prevalence ranges from 10 - 40% in certain parts of Africa and India. In the U.S., around 8% of African Americans are affected.
- Patients with sickle cell trait produce 35 - 45% hemoglobin S, and the rest is normal. The normal hemoglobin prevents the cells from sickling, so vaso-occlusive crises are not seen in SCT.
- The health consequences of sickle cell trait are the subject of much debate. Data from observational studies and case reports have suggested an increased risk for certain conditions (see below), and a high-profile lawsuit over a student-athlete death led the NCAA to enact universal sickle cell trait screening among all athletes. Possible risks of sickle cell trait include the following:
- Exercise-induced injuries - in observational studies, sickle cell trait has been associated with sudden death, exertional rhabdomyolysis, and other heat-related conditions. The incidence of these events is very low, and causality is unknown.
- Kidney disease - in observational studies, the prevalence of hematuria and chronic kidney disease has been higher in SCT patients
- Venous thromboembolism - observational studies have found an increased risk of venous thromboembolism among SCT patients
- Pregnancy complications - a small number of observational studies have found an increased risk of adverse pregnancy outcomes in SCT patients
- Renal medullary carcinoma - patients with SCT are at increased risk of renal medullary carcinoma, a rare cancer with an incidence of 1/20,000 to 1/39,000 among SCT patients [12,13,14,61]
- Effect of other hemoglobinopathies on severity of sickle cell disease
- Patients who are homozygous for hemoglobin S will only produce beta chains with the sickle cell defect. Other inherited hemoglobinopathies often occur with sickle cell disease, and these abnormalities can affect the severity of sickle cell disease.
- Alpha thalassemia reduces the amount of alpha chains produced. Coinheritance of alpha thalassemia and sickle cell disease tends to produce less severe disease because the thalassemia reduces the amount of hemoglobin in RBCs and this makes them less prone to sickling.
- Genetic variants that increase levels of hemoglobin F also reduce the severity of sickle cell disease because the hemoglobin F helps to prevent sickling
- Coinheritance of hemoglobin C disease leads to a milder disease course because hemoglobin C does not cause sickling
- Coinheritance of β-thalassemia intermedia allows for the production of some hemoglobin A and the disease can be milder. β-thalassemia major does not allow for the production of hemoglobin A and the disease course is similar to sickle cell disease
- See hemoglobin table for more [12,13,14]
- Sequelae of sickle cell disease
- The intermittent vaso-occlusive crises that occur in sickle cell disease lead to a number of long-term clinical sequelae
- Some of the more clinically relevant complications are listed below
- Functional asplenia - patients with sickle cell disease develop functional asplenia around the age of one year. Asplenia increases the risk for infections particularly from encapsulated bacteria like pneumococcus and haemophilus. In undeveloped nations, infections are a major cause of mortality in children with sickle cell disease. In developed nations, access to vaccines and prophylactic antibiotic therapy have greatly reduced the risk of death from childhood infections. See asplenic / hyposplenic patient care for more.
- Acute chest syndrome - acute chest syndrome is defined as a new pulmonary infiltrate accompanied by fever, chest pain, and shortness of breath. It is a leading cause of death among adults with sickle cell disease. Treatment includes antibiotics, respiratory support, and transfusions.
- Stroke - children with sickle cell disease are at a much greater risk for stroke with 11% of untreated patients experiencing a stroke by the age of 20 years. Transcranial doppler ultrasounds (TCD) are recommended from the ages of 2 to 16 years to help identify children at high risk. TCDs measure flow velocities in cranial arteries with higher velocities indicating stenosis and greater stroke risk. Velocities > 200 cm/sec are associated with an annual stroke risk of 10% and treatment is indicated. Velocities of 170 - 200 cm/sec are considered conditional and shorter follow-up is recommended. Normal scans are repeated annually. Treatment involves transfusions to maintain the hemoglobin S level at < 30% and has been shown to decrease stroke risk by > 90%.
- End-organ damage - over time, the repeated cycles of infarction and reperfusion begin to take their toll on bodily organs. Organ dysfunction and failure typically start to appear after the age of thirty, and any organ system can be affected. The table below gives some commonly affected organs and their sequelae
End-organ damage in sickle cell disease | |
---|---|
Organ | Comments |
Blood and lymphatic system |
|
Bones |
|
Brain |
|
Cardiopulmonary |
|
Eyes |
|
Gastrointestinal |
|
Skin |
|
Urogenital |
|
- Treatment
- Transfusions - transfusions are the primary treatment for sickle cell disease. They are used acutely to treat acute chest syndrome, stroke, and anemia. Preventively, transfusions are primarily used preoperatively and for stroke prevention (see stroke above). In general, the goal of transfusion therapy is a hemoglobin level that does not exceed 10 g/dl and a hemoglobin S level of < 30%. Chronic transfusions can have adverse effects including alloimmunization leading to hemolytic reactions, iron overload, and transmission of blood-borne pathogens.
- Hydroxyurea - hydroxyurea is an antineoplastic agent that inhibits ribonucleotide reductase. In sickle cell anemia, hydroxyurea increases the production of hemoglobin F by shifting RBC production from rapidly dividing precursor cells to progenitor cells that contain more hemoglobin F. This effect has made it a mainstay in the treatment of sickle cell disease for many years. Hydroxyurea is typically started at a dose of 15 mg/kg/day. It can then be titrated to a maximum dose of 35 mg/kg/day. After 6 months of use, hemoglobin F levels typically double. Hydroxyurea is myelosuppressive and blood counts must be monitored closely during therapy. Hydroxyurea (Hydrea®) has been around for a long time, and it has a cheap generic. Two newer versions of hydroxyurea, Siklos® and Droxia®, are also available, but they are more expensive. See the Droxia PI for hydroxyurea dosing information in sickle cell disease. [23]
- Infection prevention - functional asplenia and a number of other factors greatly increase the risk of infection in patients with sickle cell disease. All patients with sickle cell disease should have recommended immunizations for asplenic patients (see immunizations in asplenia). Antibiotic prophylaxis with a penicillin is recommended in all children until the age of five years (see antibiotic prophylaxis in asplenia).
- Stem cell transplantation - stem cell transplantation is the only curative treatment for sickle cell disease with a success rate approaching 90% when marrow or cord blood stem cells from HLA-matched siblings are used. Unfortunately, only 10 - 20% of sickle cell patients have unaffected matched sibling donors. [12,13]
- Gene therapy - gene therapy is a rapidly evolving field of medicine, and it is being studied in sickle cell disease as a possible treatment. A study published in 2022 described the use of gene therapy to treat 35 patients with sickle cell disease and at least 4 severe vaso-occlusive events in the prior 24 months. Autologous stem cells were transduced with a virus that changed the beta globulin gene so that the cell produced an antisickling hemoglobin. After a median follow-up of 17.3 months, median hemoglobin levels increased from 8.5 g/dl to 11 g/dl, and there were no severe vaso-occlusive events. [PMID 34898139] Another paper published in 2021 described the use of gene therapy to alter the BCL11A gene. BCL11A is a transcription factor that represses gamma globin and fetal hemoglobin production in erythroid cells. Using gene therapy, BCL11A production was suppressed in 6 patients with sickle cell disease, and fetal hemoglobin levels increased. [PMID 33283990]
- CRISPR gene editing - In 2020, a report was published in the NEJM that described a case where a patient with sickle cell disease was successfully treated with clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. CRISPR gene editing was used to knock out the gene that codes for BCL11A, a transcription factor that represses gamma globin and fetal hemoglobin production in erythroid cells. After treatment, the patient's fetal hemoglobin levels increased. [PMID 33283989]
- Adakveo® (crizanlizumab-tmca) - in 2019, the FDA approved Adakveo® for the prevention of vaso-occlusive crises in patients with sickle cell disease. In vaso-occlusive crises, a molecule called P-selectin is expressed on the surface of endothelial cells. P-selectin promotes erythrocyte adhesion which helps propagate vaso-occlusion. Adakveo® is an antibody to P-selectin that blocks the interaction between P-selectin and erythrocytes. In a study involving 198 patients, Adakveo® was shown to almost half the number of pain crises per year. [PMID 27959701] [Adakveo PI]
- Oxbryta® (voxelotor) - Oxbryta® (voxelotor) has been approved by the FDA to treat sickle cell disease in patients ≥ 4 years old. Voxelotor is an oral hemoglobin S polymerization inhibitor that reversibly binds to hemoglobin and increases its affinity for oxygen, thus preventing the sickled state. In a study involving 274 patients, hemoglobin levels increased by > 1 g/dl over 24 weeks in 51% of voxelotor-treated patients compared to 7% of placebo-treated patients. [PMID 27959701] [Oxbryta PI]
- MICROCYTIC ANEMIA | Iron-deficiency anemia
- Overview
- Iron-deficiency anemia is the number one cause of anemia worldwide affecting about 2 billion people
- Pathology
- Iron homeostasis is tightly controlled in humans. Total body iron amounts to about 4 - 5 grams with 65% of iron found in hemoglobin, 15 - 30% as ferritin, 4% in myoglobin, and 0.1% as transferrin. Under normal conditions, the majority of body iron is recycled from dying RBCs by macrophages and about 1 - 2 mg per day is absorbed from food in the intestine. Men lose an average of 0.6 mg/day of iron in the feces and women lose an average of 1.3 mg/day due to fecal loss and menses.
- Because high iron levels are toxic to the body, the hormone hepcidin helps to control iron levels by suppressing iron release from the liver and inhibiting iron absorption from the intestines. High iron levels in the blood and liver stimulate hepcidin release while low iron levels and tissue hypoxia suppress hepcidin release. Hepcidin release is also stimulated by inflammatory mediators, and prolonged inflammation can lead to decreased iron levels and anemia of chronic inflammation.
- Iron-deficiency anemia occurs when iron stores are unable to maintain normal erythropoiesis. The iron deficient state typically occurs through excessive blood loss (e.g. menses, gastrointestinal bleeding), inadequate intake or increased demand (e.g. vegetarian diet, pregnancy) or impaired absorption (e.g. celiac disease, bariatric surgery).
RISK FACTORS FOR IRON-DEFICIENCY ANEMIA | |
---|---|
Pathology | Risk factors |
Increased demand |
|
Insufficient intake |
|
Impaired absorption |
|
Blood loss |
|
Chronic hemolysis |
|
- Diagnosis
- Iron-deficiency anemia is diagnosed with iron studies. The best tests for assessing iron status are the serum ferritin and the transferrin saturation.
- A serum ferritin < 30 mcg/L and/or a transferrin saturation < 16% is inadequate to support erythropoiesis, and these findings are highly suggestive of iron-deficiency anemia
- Ferritin is also an acute phase reactant and may be elevated in chronic inflammatory states. The total iron binding capacity (TIBC) may be helpful in distinguishing iron-deficiency anemia from anemia of chronic inflammation. A high TIBC is consistent with iron deficiency, and a low TIBC is consistent with anemia of inflammation. If iron-deficiency anemia and anemia of inflammation are both present, the TIBC is not helpful.
- Treatment
- The underlying cause of iron deficiency (see risk factors) should be addressed. Oral iron replacement is preferred in most cases, while intravenous iron may be appropriate in others (e.g. impaired absorption, rapid correction desired).
- Screening infants and children
- The CDC recommends screening the following infants and children for iron deficiency at age 9 -12 month and 6 months later:
- Preterm or low-birthweight infants
- Infants fed a diet of non-iron-fortified infant formula for greater than 2 months
- Infants introduced to cow's milk before age 12 months
- Breast-fed infants who do not consume a diet adequate in iron after age 6 months (i.e., who receive insufficient iron from supplementary foods)
- Children who consume greater than 24 oz daily of cow's milk
- Children who have special healthcare needs (e.g., children who use medications that interfere with iron absorption and children who have chronic infection, inflammatory disorders, restricted diets, or extensive blood loss from a wound, an accident, or surgery) [4]
- USPSTF
- The USPSTF states that the current evidence is insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in children ages 6 to 24 months [8]
- Preventing iron deficiency in pregnancy
- CDC recommendations
- The CDC recommends 30 mg a day of supplemental elemental iron in order to prevent iron deficiency in pregnancy
- Women should start supplementation as soon as they find out they are pregnant [4]
- USPSTF
- The USPSTF states that the current evidence is insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in pregnant women to prevent adverse maternal health and birth outcomes
- The USPSTF states that the current evidence is insufficient to assess the balance of benefits and harms of routine iron supplementation for pregnant women to prevent adverse maternal health and birth outcomes [8]
- MICROCYTIC ANEMIA
- Lead poisoning
- Lead poisoning is an important cause of microcytic anemia, particularly in children. Lead induces microcytosis and anemia through several mechanisms, including inhibition of heme synthesis by blocking the insertion of iron into protoporphyrin, decreased RBC lifespan, and suppression of erythropoietin production by the kidneys. Chronic exposure to lead can lead to developmental delay in children and cardiovascular disease in adults.
- The average lead level in U.S. adults is 0.92 mcg/dl. Levels > 3.5 mcg/dl are considered elevated in children, while levels > 5 mcg/dl are elevated in adults. Levels ≥ 10 mcg/dl require monitoring and investigation. Chelation therapy is recommended for levels > 45 mcg/dl in children and > 80 mcg/dl in adults. Lead-induced anemia is seen at levels > 50 mcg/dl.
- Lead is absorbed in the digestive tract or lungs when ingested or inhaled. Children absorb about 50% of the lead they ingest, whereas adults only absorb about 10%. Concomitant iron deficiency increases absorption. Once absorbed, lead is distributed between the soft tissues, bones, and teeth. In adults, 80 - 95% of lead is stored in the bones, whereas in children, only about 70% stays in the bones, making them more susceptible to its toxic effects. Lead is slowly eliminated from the body through the urine and bile.
- If lead poisoning is confirmed, a search for the source should ensue. See sources of lead from the CDC for more. After removal of the offending agent, lead levels begin to decline slowly. A study that measured the amount of time it took for toxic levels to decline in children < 6 years of age is detailed in the table below. [27,28,59]
Time for lead levels to fall below 10 mcg/dl in children < 6 years of age | |
---|---|
Initial lead level (mcg/dl) |
Median days to fall below 10 mcg/dl |
10 - 14 (N=452) |
237 |
15 - 19 (N=315) |
424 |
20 - 24 (N=112) |
659 |
25 - 29 (N=59) |
954 |
≥ 30 (N=59) |
1083 |
- Thalassemias
- Worldwide, the thalassemias are a common cause of microcytic anemia. See alpha thalassemia and beta thalassemia above.
- Rare causes of microcytic anemia
- Hypotransferrinemia - Hypotransferrinemia is caused by defects in the gene that codes for transferrin which lead to transferrin deficiency and inadequate iron availability. It presents as microcytic and hypochromic anemia early in life with low serum iron and high ferritin levels. Transferrin levels are undetectable or below normal and fully saturated. It can be treated with apotransferrin transfusions. [31]
- Iron-refractory iron deficiency anemia (IRIDA) - IRIDA is caused by defects in the TMPRSS6 gene that codes for matriptase-2, a protein that senses iron deficiency and blocks hepcidin transcription. In IRIDA, hepcidin levels are inappropriately elevated and iron absorption is inhibited. IRIDA presents with microcytic anemia, low TSAT, and normal or reduced ferritin that does not have an expected response to oral or IV iron. [31]
- Sideroblastic anemia - sideroblastic anemia is a microcytic anemia that is caused by abnormalities in heme synthesis which can be inherited through genetic defects or acquired. Abnormal heme synthesis leads to the deposition of iron in the mitochondria of erythroid precursor cells. Iron-laden mitochondria form a ring around the nucleus of the cell giving it the characteristic "ringed sideroblast" appearance which can be seen in the bone marrow (sideroblast illustration). Inherited forms of sideroblastic anemia arise from defects in the genes that code for enzymes involved in heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial metabolism. Acquired forms of sideroblastic anemia can arise from drugs (e.g. isoniazid, chemotherapy), toxins (e.g. lead), copper deficiency, and chronic myelodysplastic diseases. [32]
- NORMOCYTIC ANEMIA | Anemia of inflammation
- Overview
- Anemia of inflammation (AI), also called anemia of chronic disease, is the second most common cause of anemia. It is estimated that 40% of all anemias are due to AI or have a component of AI which means it affects more than 1 billion people worldwide.
- AI by itself is a normocytic normochromic anemia, but it often occurs with iron-deficiency anemia, so microcytosis and hypochromia can also be present
- Unlike iron-deficiency anemia where there is an inadequate supply of body iron, iron stores in AI are typically sufficient, but the iron is unable to distribute appropriately to maintain normal erythropoiesis. The reason for this is multifactorial and not completely understood.
- Since AI and iron-deficiency anemia can coexist, and there is no definitive test for AI, differentiating between the two can be diagnostically challenging [24,25]
- Pathological processes through which AI is thought to occur
- Disruption of iron homeostasis - in AI, inflammatory mediators (e.g.interleukin-6) alter iron homeostasis by stimulating hepcidin production which in turn causes a decrease in the intestinal absorption of iron and inhibits the release of iron from macrophages. Iron retention by macrophages is particularly disruptive since macrophages supply > 90% of the iron needed for erythropoiesis.
- Suppression of erythropoiesis - in the bone marrow, inflammatory mediators (e.g. tumor necrosis factor alpha, interferon-γ) promote myelopoiesis and lymphopoiesis which in turn suppresses erythropoiesis. Inflammation also reduces the production of erythropoietin and blunts the response of marrow to its effects.
- Decrease in RBC lifespan - in the inflammatory state, RBC lifespan is decreased from an average of 120 days to around 90. This is thought to occur secondary to macrophage stimulation and "bystander" damage to erythrocytes from surrounding inflammatory processes (e.g. inadvertent complement and antibody deposition on RBCs). [24,25]
- Diseases associated with AI
- Cancer and hematological malignancies
- Infections
- Immune-mediated diseases (e.g. rheumatoid arthritis, lupus)
- Inflammatory diseases
- Chronic kidney disease
- Congestive heart failure
- Chronic pulmonary disease
- Obesity
- Anemia of the elderly
- Anemia of critical illness (accelerated course) [25]
- Diagnosis
- AI by itself presents is a normochromic, normocytic anemia with normal to high ferritin levels, reduced transferrin saturation, and reduced transferrin. Depending on the study, 20 - 85% of patients with AI also have a true iron deficiency. When both coexist, iron studies and RBC indices are less definitive, and further evaluation may be necessary.
- The table below details how different iron studies are affected by AI and iron-deficiency anemia
Findings in AI and iron-deficiency anemia |
---|
Ferritin
|
Serum iron
|
TIBC
|
Transferrin saturation
|
Soluble transferrin receptor
|
- Treatment
- When treating AI, it's important to consider that in some cases, the pathology behind AI plays an important role in the body's defense mechanism, particularly with infections and certain cancers. Circulating pathogens need iron to proliferate and certain solid tumors and hematologic malignancies express transferrin receptors. Suppressing iron levels can help to contain these conditions. Low iron levels also promote myelopoiesis and lymphopoiesis which provide the cells needed to combat these ailments.
- Curing the underlying disorder is the only way to resolve AI, but this is not always possible. When anemia becomes significant and treatment is required, iron supplementation and/or erythropoiesis-stimulating agents are the two main options. There are no good clinical trials to guide the use of these therapies in AI. In general, hemoglobin targets similar to those used in chronic kidney disease (11 - 12 g/dl) appear to be safe. See treatment of anemia in chronic kidney disease for more. [24,25,26]
- NORMOCYTIC ANEMIA | Chronic kidney disease (CKD)
- Pathology
- The kidneys release erythropoietin in response to tissue hypoxia. Erythropoietin stimulates RBC production in the bone marrow. In CKD, erythropoietin release is reduced and RBC production is diminished. It's important to note that erythropoietin levels are often normal or slightly elevated in patients with CKD, but they are inappropriate for the anemia that is present with similarly anemic patients without CKD having erythropoietin levels 10 - 100 times that of patients with CKD. Because of this, erythropoietin levels are not recommended in the workup of CKD-induced anemia.
- Other factors that play a role in the anemia of CKD include shortened RBC lifespan, anemia of chronic inflammation, vitamin deficiencies, and retained toxins from uremia that suppress erythropoiesis
- Anemia from CKD can start to appear when the GFR falls below 60 ml/min. The table below gives the prevalence of anemia and average Hg stratified by GFR in a sample of 15,419 U.S. adults. [35,36,37]
Anemia in CKD | ||
---|---|---|
GFR (ml/min) | % or patients with anemia | Average Hg (g/dl) |
≥ 90 | 1.8% | 14.2 |
60 - 89 | 1.3% | 14.2 |
30 - 59 | 5.2% | 13.6 |
15 - 29 | 44.1% | 11.8 |
- Diagnosis
- There is no single measure that can definitively diagnose anemia of CKD. Measuring an erythropoietin level seems intuitive, but levels are often normal or slightly elevated in CKD and are noninformative. Further complicating matters is the fact that patients with CKD often have some degree of anemia of chronic inflammation which presents similarly. The table below gives the recommended testing from the National Kidney Foundation along with associated findings in CKD. [34,35]
Findings in Anemia of CKD |
---|
RBC indices
|
Reticulocyte indices
|
Iron studies
|
- Treatment
- Anemia of CKD is treated with erythropoietin-stimulating agents (ESA) along with careful monitoring of iron indices to ensure that there is sufficient functional iron available for erythropoiesis. While ferritin levels > 100 ng/ml typically indicate adequate iron stores, studies have consistently found that iron supplementation at ferritin levels up to 1200 ng/ml will produce an increase in hemoglobin in CKD patients
- The table below gives the recommendations for treating anemia of CKD from the International Society of Nephrology and the American Kidney Foundation
Treatment Recommendations for Anemia of CKD in Adults |
---|
Hemoglobin
|
Iron therapy
|
ESA therapy targets
|
Erythropoietin-stimulating agents
|
- Hemolytic anemia
- Hemolytic anemia is often normocytic (e.g. autoimmune hemolytic anemia, mechanical hemolysis) but can also be microcytic (e.g. thalassemia, sickle cell disease). See hemolytic anemia for more.
- Hemorrhagic anemia
- Anemia may occur through blood loss. After an acute hemorrhage that is stopped, it typically takes 3 - 6 weeks for RBC concentrations to return to normal. In chronic blood loss, the absorption of iron often cannot meet the demands of RBC production and microcytic anemia may occur.
- Aplastic anemia
- Aplastic anemia occurs when bone marrow damage or destruction leads to decreased RBC production. Causes of aplastic anemia include chemotherapy, toxic chemicals (e.g. benzene), and autoimmune disorders (e.g. lupus). In half the cases of aplastic anemia, an etiology is never found.
- HEMOLYTIC ANEMIA
- Epidemiology
- Hemolytic anemia accounts for about 5% of all anemias
- Acute autoimmune hemolytic anemia (AHA) is a rare condition with an incidence of only 1 - 3 cases per 100,000 people/year. Patients with certain underlying conditions are at much greater risk for AHA with up to 10% of systemic lupus erythematosus (SLE) patients, 5 - 10% of chronic lymphocytic leukemia patients, and 4.5% of hematopoietic stem cell transplant recipients being affected. [38]
- Types of hemolytic anemia
- There are 3 basic types of hemolytic anemia: autoimmune, mechanical hemolysis, and RBC abnormalities. All 3 types lead to the destruction of RBCs, but the underlying process is different for each type. It's also important to note that the pathology behind some causes of hemolytic anemia is not completely understood. RBC hemolysis can occur in the circulation (intravascular) or in tissues like the liver and spleen where macrophages reside (extravascular).
- The table below gives the underlying pathology and associated risk factors for each type of hemolytic anemia.
Autoimmune hemolytic anemia (AHA) |
---|
Pathology
Warm autoimmune hemolytic anemia (WAHA)
Cold autoimmune hemolytic anemia (CAHA)
Mixed autoimmune hemolytic anemia
Risk factors for AHA
|
Mechanical hemolysis |
Pathology
Artificial heart valves
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
|
RBC abnormalities |
Pathology
Paroxysmal nocturnal hemoglobinuria (PNH)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hereditary spherocytosis
Sickle cell anemia
Thalassemias
|
- Diagnosis
- Hemolytic anemia should be considered in any patient with risk factors for the condition
- The table below details the labs that are used to evaluate for hemolytic anemia, and their findings depending on the cause
Autoimmune hemolytic anemia treatment |
---|
Overview
WAHA treatment
CAHA treatment
|
Mechanical hemolysis treatment |
|
RBC abnormality treatment |
|
- MACROCYTOSIS
- Overview
- Macrocytosis, defined as MCV > 100 fL, is present in about 3% of the population. Macrocytosis can be divided into two subtypes: megaloblastic and nonmegaloblastic.
- Megaloblastic macrocytosis
- Megaloblastic macrocytosis occurs when there is insufficient folic acid and/or vitamin B12 during erythropoiesis. Folic acid and vitamin B12 are essential for the production of DNA, and their deficiency causes RBCs to develop abnormally and become enlarged. Hypersegmented neutrophils (neutrophils with six or more lobes or the presence of more than 3% of neutrophils with at least five lobes) are often seen in megaloblastic macrocytosis and their presence can be helpful in determining the subtype.
- Nonmegaloblastic macrocytosis
- The mechanisms behind nonmegaloblastic macrocytosis are varied and not completely understood. Common causes of nonmegaloblastic macrocytosis are alcohol abuse, medications, and hypothyroidism.
Megaloblastic causes |
---|
Vitamin B12 deficiency
|
Folate/folic acid deficiency (Vitamin B9)
|
Nonmegaloblastic causes |
Alcohol abuse
|
Hemolysis / Hemorrhage
|
Hypothyroidism
|
Medication side effects
|
Myelodysplasia
|
Liver disease
|
COPD
|
Splenectomy
|
Spurious causes |
Cold agglutinins
|
Hyperglycemia
|
Significant leukocytosis
|
Megaloblastic vs Nonmegaloblastic |
---|
Peripheral smear
|
Nonmegaloblastic labs |
|
- VITAMIN B12 DEFICIENCY
- Physiology
- Vitamin B12 is an essential cofactor in the synthesis of DNA. Rapidly dividing cells like RBCs require adequate amounts of vitamin B12 to carry out erythropoiesis. Insufficient vitamin B12 levels cause RBCs to develop abnormally resulting in enlarged cells (macrocytes) with flimsy membranes. Macrocytes carry oxygen normally, but their fragility shortens their lifespan by one-half to one-third.
- Daily requirements of vitamin B12 to support normal erythropoiesis are about 1 - 3 mcg. The liver stores about 1000 times this amount so it takes about 3 - 4 years of deficient absorption before macrocytosis and anemia develop.
- Vitamin B12 absorption occurs through a series of steps. First, parietal cells in the gastric mucosa secrete a glycoprotein called intrinsic factor that binds vitamin B12 in food and protects it from digestion. The B12-intrinsic factor complex then travels to the terminal ileum where it is absorbed and transported to the liver for storage.
- Causes
- Atrophic gastritis (pernicious anemia) - atrophic gastritis results from autoimmune antibodies that destroy gastric parietal cells and lead to the loss of intrinsic factor. Pernicious anemia typically affects older patients with a median age of diagnosis between 70 - 80 years.
- Medications - see drugs that decrease B12 absorption for more
- Bowel surgery - bowel surgeries that affect the stomach (e.g. gastric bypass) and terminal ileum can lead to decreased B12 absorption
- Intestinal diseases - diseases that affect the lining of intestine (e.g. celiac disease, Crohn's, helminth infections) can reduce the absorption of vitamin B12
- Vegetarian diet - vitamin B12 is mainly found in animal products (fish, meat, chicken, eggs, dairy). Strict vegetarians who do not take supplements are at risk for deficiency.
- Chronic pancreatitis - pancreatic enzymes are necessary for the proper processing of vitamin B12 in the duodenum and their deficiency can lead to decreased absorption
- H pylori infection - in rare cases, H pylori infection may cause gastritis that leads to decreased intrinsic factor
- Symptoms
- Because vitamin B12 is necessary for DNA synthesis, vitamin B12 deficiency affects rapidly dividing cells like RBCs, skin cells, and cells of the mucous membranes. Vitamin B12 is also essential for the maintenance of the myelin sheaths that surround nerve cells. Symptoms of vitamin B12 deficiency include anemia, paresthesias, inflammation of the lips and gums, difficulty walking, and loss of position and vibration sense.
- Diagnosis
- Vitamin B12 level
- Levels > 400 pg/ml are consistent with sufficient vitamin B12 for erythropoiesis
- Levels 100 - 400 pg/ml are borderline low and may require further evaluation with methylmalonic acid and homocysteine
- Methylmalonic acid (MMA) levels - Methylmalonic acid (MMA) is a byproduct of protein metabolism that is converted to succinyl-coenzyme A. Vitamin B12 is a cofactor in MMA conversion, and if vitamin B12 levels are low, conversion is decreased and MMA levels rise. Elevated MMA levels are an early predictor of vitamin B12 deficiency. Elevated MMA levels with elevated homocysteine is indicative of vitamin B12 deficiency whereas normal MMA levels and elevated homocysteine levels is suggestive of folic acid deficiency.
- Homocysteine levels - Homocysteine is an intermediary amino acid that is converted to methionine through a reaction that requires folic acid and vitamin B12. Homocysteine levels will rise in the setting of deficient folic acid and/or vitamin B12. Elevated MMA levels with elevated homocysteine is indicative of vitamin B12 deficiency whereas normal MMA levels and elevated homocysteine levels is suggestive of folic acid deficiency.
- Peripheral smear - the presence of hypersegmented neutrophils (neutrophils with six or more lobes or the presence of ≥ 3% of neutrophils with at least five lobes) is suggestive of megaloblastic macrocytosis. Macroovalocytes are also suggestive of megaloblastic macrocytosis.
- Intrinsic factor antibodies - intrinsic factor antibodies are seen in pernicious anemia. There are 2 types of antibodies. Type 1 antibodies block the binding or vitamin B12 to intrinsic factor. Type 2 antibodies block ileal intrinsic factor binding sites. Type 1 antibodies are present in 50% of patients with pernicious anemia and Type 2 antibodies are seen in 35%. Intrinsic factor antibodies have a sensitivity of 50% and specificity of 100% for pernicious anemia.
- Gastric parietal cell antibodies - parietal cell antibodies are present in 90% of patients with pernicious anemia. They are also found in up to 60% of patients with chronic atrophic gastritis who do not have vitamin B12 malabsorption, 30% of patients with Sjogren's syndrome, 20% of patients with gastric ulcers, and 7% of healthy adults. Parietal antibodies have a sensitivity of 90% for pernicious anemia but their specificity varies widely depending on the population tested.
- Treatment
- The treatment for vitamin B12 deficiency is replacement. Vitamin B12 is available in oral forms, a prescription nasal spray, and intramuscular injections. If absorption is still intact or only mildly affected, then oral supplementation is usually sufficient. If absorption is significantly impaired, then the intramuscular route is preferred. Trials have shown that even in patients with pernicious anemia or ileal resection, oral supplementation is often effective.
- Megaloblastic anemia typically responds after 6 - 8 weeks of treatment. Resolution of neurologic symptoms depends upon the severity and can take weeks to months.
- Vitamin B12 for injection is called cyanocobalamin in the U.S. and hydroxocobalamin in Europe. Oral forms of vitamin B12 (cyanocobalamin and methylcobalamin) are available from a number of supplement manufacturers. An intranasal product called Nascobal® is also available by prescription but is very expensive and rarely prescribed. Common treatment regimens are presented below.
- Cyanocobalamin injection - administer 1000 mcg intramuscularly once daily or every other day for 1 week, then once weekly for 4 - 8 weeks, then once monthly from then on
- Oral vitamin B12 (cyanocobalamin) 500 - 2000 mcg once daily
- Dosing to prevent deficiency in vegans - supplement containing ≥ 2 mcg of vitamin B12 once daily [49, 53, 54, 55]
- ANEMIA IN THE ELDERLY
- Overview
- Anemia is more common in older populations with a prevalence of 10% in community dwelling adults ≥ 65 years old. In patients ≥ 85 years old, the prevalence jumps to more than 20%. Anemia also varies by race. In a cross-sectional study of persons ≥ 65 years old, the prevalence of anemia was as follows: Blacks - 28%, Mexican-Americans - 10.4%, Whites - 9%, Other races - 14%. The racial disparity probably reflects the higher prevalence of anemia-causing conditions (e.g. thalassemia) that affect certain races more than others.
- The etiology of anemia in older patients is diverse, and in many cases, a cause is never found. The lack of a definitive diagnosis in a significant number of patients led to the creation of a entity called "unexplained anemia of the elderly" which is defined as a normocytic anemia that is not secondary to nutritional deficiency, kidney disease, or inflammatory disease and is characterized by a blunted response to erythropoietin. [50,52]
- The results below are from a study where 174 anemic elderly adults (median age 76 years) underwent an extensive workup to determine a cause
Cause of anemia in 174 elderly patients | |
---|---|
Cause | % of patients |
Unexplained anemia of the elderly | 44% |
Iron-deficiency anemia | 25% |
Anemia of inflammation | 9.8% |
Hematologic malignancy | 7.5% |
Other causes✝ | 5.7% |
Thalassemia | 4.6% |
Chronic kidney disease | 3.4% |
- Diagnosis
- The workup for anemia in elderly patients is the same as younger patients with the understanding that a significant number of patients (up to 44%) will have no identifiable cause
- Iron-deficiency anemia is the most common identifiable cause, and in some studies, up to 22% of patients without laboratory findings consistent with iron-deficiency anemia responded to oral iron therapy. If iron deficiency is present, a gastrointestinal workup should be performed, keeping in mind that up to 66% of these patients will have a negative workup. IV iron may be necessary in patients where decreased iron absorption is thought to be the underlying cause.
- If the GFR is < 60 ml/min, chronic kidney disease should be considered, but it is not a common cause until the GFR falls below 30 ml/min
- When an extensive workup yields no identifiable cause, undetermined anemia of the elderly should be considered [52]
- IRON REPLACEMENT
- Adult oral iron replacement
- Adults with iron deficiency are typically treated with 65 - 195 mg of elemental iron a day (Ferrous sulfate 325 mg one to three times a day)
- Several recent studies have found that less frequent iron dosing leads to greater absorption. In one study, lower iron doses (40 - 80 mg elemental iron) given once daily as opposed to twice daily resulted in better absorption. [PMID 26289639]. Another study found that iron absorption was significantly greater with every other day dosing when compared to daily dosing. [PMID 29032957]
- It is sometimes recommended that a vitamin C supplement be taken with iron to enhance its absorption. A study published in 2020 found that taking vitamin C with iron did not improve hemoglobin or ferritin levels when compared to iron alone. [PMID 33136134]
- Hemoglobin levels should rise by about 2 g/dL every 3 weeks
- Once hemoglobin levels are normal, iron replacement should continue for 3 - 6 months to replenish iron stores [5,9]
- Pediatric oral iron replacement
- Treat iron deficiency with iron drops at a dose of 3 mg/kg/day of elemental iron. Dose is given in 1 - 2 divided doses a day.
- Repeat hemoglobin testing in 4 weeks. An increase in hemoglobin concentration of ≥ 1 g/dL or in hematocrit of ≥ 3% confirms the diagnosis of iron-deficiency anemia.
- If iron-deficiency anemia is confirmed, reinforce dietary counseling, continue iron treatment for 2 more months, then recheck hemoglobin concentration or hematocrit
- Reassess hemoglobin concentration or hematocrit approximately 6 months after successful treatment is completed [4]
- A study published in 2017 found that ferrous sulfate was superior to iron polysaccharide complex in treating nutritional iron-deficiency anemia in children aged 9 - 48 months. [PMID 28609534]
- Oral iron products
- There are three basic forms of iron that are available in supplements
- Each form of iron contains a different percentage of elemental iron
- Modified release products are not recommended because they likely decrease iron absorption
Iron form | % elemental iron | Other |
---|---|---|
Ferrous gluconate | 12% |
|
Ferrous sulfate | 20% |
|
Ferrous fumarate | 33% |
|
- Side Effects
- Common side effects of iron supplements are listed below
- Taking iron after a meal may lessen side effects. Gradually increasing the dose may also help to minimize side effects.
- Iron supplements do NOT affect guaiac (Hemoccult II® and Sensa®) stool testing [3, 6]
- Common side effects of iron supplements include:
- Constipation
- Nausea
- Stomach upset
- diarrhea
- Dark-colored stools
- IV iron replacement
- IV iron replacement may be necessary in some patients, particularly when impaired absorption is an issue or when rapid correction is desired. IV iron also enhances the effects of erythropoietin agents.
- Hypersensitivity infusion reactions have traditionally limited the use of IV iron, but newer formulations are better tolerated and have led to expanded use, although the high cost of IV iron is still an issue
- The amount of iron that can be infused during a single treatment depends on the product and ranges from 250 - 1000 mg
- Side effects of IV iron include itching, nausea and vomiting, muscle cramping, chest pain, headache, and flushing. Serious hypersensitivity reactions are rare. [9]
- Dosing for IV iron is calculated with the following formula:
- Body weight(kg) X 2.3 X hemoglobin deficiency + 500 to 1000 mg iron (for the repletion of iron stores)
- Where hemoglobin deficiency = target hemoglobin level - patient hemoglobin level
- Indications for IV iron
- Failure of oral iron therapy
- Impaired absorption of oral iron (see risk factors for iron deficiency above)
- Need for rapid correction (e.g. pregnancy)
- Individual objection to blood transfusion (e.g. Jehovah's Witness)
- Use of erythropoietin agents in chronic kidney disease [9]
- Recommended dietary iron intake
- An adult male contains about 50 mg/kg of iron. An adult menstruating female has about 40 mg/kg of iron.
- Median dietary intake of iron is about 16 - 18 mg/day in men and 12 mg/day in women. Healthy adults absorb about 10 - 15% of dietary iron
- Adult men need to absorb about 1 mg/day of iron to maintain iron balance. Adult menstruating females need to absorb about 1.5 mg/day to maintain iron balance. There is high individual variation in daily iron requirements. In the absence of bleeding, only a small amount of iron is lost from the body each day (0.90 - 1.02 mg/day).
- In food sources, iron is found in two forms - heme iron and nonheme iron
- Nonheme iron is the primary source of iron absorbed from food. A small amount of heme iron is absorbed. [1]
U.S. recommended dietary iron intake | ||
---|---|---|
Age | Male (mg/day) | Female (mg/day) |
0 - 6 months | 0.27* | 0.27* |
7 - 12 months | 11 | 11 |
1 - 3 years | 7 | 7 |
4 - 8 years | 10 | 10 |
9 - 13 years | 8 | 8 |
14 - 18 years | 11 | 15 |
19 - 30 years | 8 | 18 |
31 - 50 years | 8 | 18 |
≥ 51 years | 8 | 8 |
Pregnancy | - | 27 |
- Heme iron
- Heme iron is found in animal products that contain hemoglobin such as red meat, fish, and poultry products. It is absorbed more easily than nonheme iron. About 15 - 35% of heme iron is absorbed from food. Heme iron is not typically affected by other dietary components.
- The iron content of a large number of foods can be found here - USDA food database
Food sources of heme iron | |
---|---|
Food | Iron content per 1 serving (3 ounces) |
Chicken liver | 11 mg |
Canned oysters | 5.7 mg |
Beef liver | 5.2 mg |
Beef chuck | 3.1 mg |
Turkey, dark meat | 2.0 mg |
Beef, ground | 2.2 mg |
Beef, top sirloin | 1.6 mg |
Tuna, light | 1.3 mg |
Turkey, light meat | 1.1 mg |
Chicken, dark meat | 1.1 mg |
Chicken, light meat | 0.9 mg |
Pork, loin chop | 0.7 mg |
Halibut | 0.2 mg |
- Nonheme iron
- Nonheme iron is found in fruits and vegetables. It is also in many grain and cereal products which are iron-fortified. About 2 - 20% of nonheme iron is absorbed. Nonheme iron absorption is affected by other dietary components. Nonheme iron is the most abundant source of iron in most diets. [1,6]
- The iron content of a large number of foods can be found here - USDA food database
Food sources of nonheme iron | |
---|---|
Food (serving size) |
Iron content per 1 serving |
Iron-fortified cereal (3/4 cup) |
18 mg |
Oatmeal, instant (1 packet) |
11 mg |
Soybeans (1 cup) |
8.8 mg |
Beans, kidney (1 cup) |
5.2 mg |
Beans, lima (1 cup) |
4.5 mg |
Black eyed peas (1 cup) |
4.3 mg |
Beans, navy (1 cup) |
4.3 mg |
Beans, black (1 cup) |
3.6 mg |
Beans, pinto (1 cup) |
3.6 mg |
Tofu (1/2 cup) |
3.4 mg |
Spinach, fresh (1/2 cup) |
3.2 mg |
Raisins (1/2 cup) |
1.6 mg |
Bread, white (1 slice) |
0.9 mg |
Bread, whole-wheat (1 slice) |
0.7 mg |
- IRON LABS
- Ferritin
- Ferritin is the major storage form of iron in the body (see RBC and iron homeostasis for more). The liver, spleen, and bone marrow are the primary sites of iron storage.
- Ferritin is mostly found in cells while a small amount circulates in the blood. Ferritin concentrations in the blood are proportional to cellular concentrations which makes serum ferritin levels a good measure of body iron stores. Serum ferritin is the most sensitive and specific test for detecting iron deficiency.
- In adults, 1 ng/ml of serum ferritin represents about 8 mg of storage iron. Total body iron stores normally range from 600 mg - 1500 mg in non-menstruating adults.
- Ferritin levels < 30 ng/ml are considered iron deficient regardless of hemoglobin status. When serum ferritin concentrations fall below 12 ng/ml, iron stores are totally depleted.
- Ferritin is also an "acute phase reactant" which means inflammatory states (ex. infections, cancer, liver disease) may cause an increase in serum concentrations. In anemia of inflammation, ferritin levels may be normal when an iron-deficient state is actually present. [1,9]
- For adults living in the U.S., the median serum ferritin concentrations are 36 - 40 ng/ml for menstruating females, and 112 - 156 ng/ml for men [1]
- Normal ranges
- Adult male: 30 - 400 ng/ml
- Adult female: 15 - 150 ng/ml
- Reference: LabCorp®
- Factors which may cause a spuriously high ferritin level (normal ferritin when iron stores are low)
- Infections
- Cancer
- Liver disease
- Increased alcohol consumption
- Obesity
- Diabetes
- Serum iron
- The serum iron level is the amount of iron that is present in the blood
- Iron levels are used with the TIBC to calculate the transferrin saturation which is a more useful indicator of iron status
- Ferritin is a more useful measure of total body iron stores.
- Normal ranges:
- Adult male: 45 - 170 μg/dL
- Adult female: 40 - 160 μg/dL
- Reference: Quest Diagnostics®
- Abnormal values:
- Low serum iron
- Low iron levels are typically seen in iron deficiency. They may also be seen in chronic disease states.
- High serum iron
- Hemochromatosis
- Hemolytic anemia
- Sideroblastic anemia
- Iron poisoning
- Soluble transferrin receptor
- Transferrin receptor is a transmembrane protein that regulates iron uptake by cells. Cellular expression of transferrin receptor is increased when a cell needs iron. Soluble transferrin receptor is a cleavage product of transferrin receptor that can be measured in the blood.
- Erythroid progenitor cells are the primary cells that need iron, and 80% of soluble transferrin receptor in the blood comes from these cells. Inflammation does not affect soluble transferrin receptor levels, so this makes it a specific marker for iron deficiency. This lab is not widely available.
- Anemia of inflammation
- Levels are typically normal
- Iron-deficiency anemia
- Levels are increased
- Total Iron Binding Capacity (TIBC)
- When iron is transported in the blood between cells, it is mostly bound to transferrin (see RBC and iron homeostasis for more)
- Transferrin can be measured directly, but it is commonly measured indirectly with the Total Iron Binding Capacity. To measure TIBC, iron is added to a sample of blood so that all the transferrin is saturated with iron. The TIBC is then calculated.
- The TIBC test is used in conjunction with the total serum iron level to calculate the transferrin saturation or "% saturation" which represents the amount of transferrin that is saturated with iron
- Normal ranges
- Adult male: 250 - 425 μg/dL
- Adult female: 250 - 450 μg/dL
- Reference: Quest Diagnostics®
- Abnormal values
- High TIBC
- A high TIBC usually indicates iron deficiency. It can also be increased in pregnancy and with oral contraceptive use.
- Low TIBC
- Hemochromatosis
- Malnutrition
- Chronic disease
- Inflammation
- Liver disease
- Nephrotic syndrome [2]
- Transferrin saturation (TSAT)
- The transferrin saturation is the proportion of transferrin (expressed as a percentage) that is saturated with iron
- Transferrin saturation below 16% indicate that the rate of delivery of iron is insufficient to maintain the normal rate of hemoglobin synthesis
- For adults living in the U.S., the median transferrin saturations are 26 - 30% for men, and 21 - 24% for women [1]
- Transferrin saturation is calculated with the following formula:
- Transferrin saturation (%) = (Serum iron level / TIBC) X 100
- Normal ranges
- Adult male: 20 - 50%
- Adult female: 15 - 50%
- Reference: Quest Diagnostics®
- Abnormal values
- Low saturation
- A low transferrin saturation is typically seen in iron deficiency. It may also be seen in chronic disease states.
- High saturation
- Hemochromatosis
- Hemolytic anemia
- Sideroblastic anemia
- Iron poisoning
- Unbound Iron Binding Capacity (UIBC)
- The UIBC is the amount of transferrin that is not bound by iron
- It is measured with the following formula:
- UIBC(μg/dL) = TIBC(μg/dL) - Serum Iron(μg/dL)
Iron study values in certain conditions | ||||
---|---|---|---|---|
Condition | Ferritin | Iron level | Transferrin saturation | TIBC |
Iron-deficiency anemia | Low | Low | Low | High |
Anemia of chronic disease | > 100 | Low | Low / Normal | Low |
Anemia of chronic disease + Iron-deficiency anemia | < 100 | Low | Low / Normal | Low |
Hemochromatosis | High | High | High | Low |
Hemolytic anemia | High | High | High | Normal / Low |
Sideroblastic anemia | High | Normal / High | High | Normal / Low |
Iron poisoning | Normal | High | High | Normal |
- BLOOD DONATION
- Overview
- People who donate blood frequently may be at increased risk of iron deficiency
- A study published in 2015 looked at the effects of iron supplementation after blood donation on hemoglobin recovery. The study is detailed below.
- STUDY
- A study published in the JAMA in 2015 looked at the effects of iron supplementation after blood donation
- The study enrolled 215 patients who had not donated blood within the previous 4 months
- Patients were stratified by their baseline ferritin levels: low ferritin ≤ 26 ng/ml | higher ferritin > 26 ng/ml
- Every patient donated a unit of blood (500 ml) after which they were randomized to ferrous gluconate 325 mg (37.5 mg elemental iron) once daily or no iron (control)
- The primary outcome was hemoglobin recovery, defined as the time for restoration of 80% of the hemoglobin lost at donation
- During follow-up, the following was seen:
- After donation hemoglobin decline: low ferritin - 13.4 to 12 g/dl | higher ferritin - 14.2 to 12.9 g/dl
- Average time to primary outcome in the iron group: low ferritin - 32 days | higher ferritin - 31 days
- Average time to primary outcome in the control group: low ferritin - 158 days | higher ferritin - 78 days
- Median time to recover to baseline ferritin level in the iron group: low ferritin - 21 days | higher-ferritin - 107 days
- Median time to recover to baseline ferritin level in the control group: low ferritin >168 days | higher ferritin >168 days
- Summary
- In the U.S., individuals are allowed to donate blood every 8 weeks
- This study showed that on average, most people do not recover iron stores and hemoglobin levels in that time period
- Iron supplementation with 325 mg of ferrous gluconate once daily had a profound effect on hemoglobin and iron store recovery
- Patients at increased risk of anemia and frequent blood donors should consider taking an iron supplement for 2 - 4 months post-donation
- BIBLIOGRAPHY
- 1 - IOM Dietary Reference Intake for Iron
- 2 - AACC website
- 3 - PMID 2186616
- 4 - CDC website
- 5 - PMID 9040336 BMJ review
- 6 - NIH website
- 7 - Guyton and Hall Textbook of Medical Physiology, 13 ed. (2016)
- 8 - USPSTF website
- 9 - PMID 25946282 - Iron-deficiency Anemia, NEJM (2015)
- 10 - PMID 28774421 - Thalassemia, Lancet (2018)
- 11 - PMID 19678601 - Alpha and Beta Thalassemia, Am Fam Physician (2009)
- 12 - PMID 28159390 - Sickle cell disease, Lancet (2017)
- 13 - PMID 28423290 - Sickle cell disease, NEJM (2017)
- 14 - PMID 26637716 - Sickle cell trait diagnosis: clinical and social implications, Hematology Am Soc Hematol Educ Program (2015)
- 15 - Gene Reviews, Alpha-thalassemia, University of Washington, Seattle (1993-2019)
- 16 - Gene Reviews, Beta-thalassemia, University of Washington, Seattle (1993-2019)
- 17 - Hemoglobin C disease, Medscape, Milton et al, (2017)
- 18 - PMID 16162884 - Beta thalassemia, NEJM (2005)
- 19 - PMID 28774421 - Thalassemia, Lancet (2018)
- 20 - PMID 19678601 - Alpha and Beta Thalassemia, American Family Physician (2009)
- 21 - PMID 25390741 - The alpha thalassemias, NEJM (2014)
- 22 - PMID 25729487 - Transcranial Doppler screening in sickle cell disease: The implications of using peak systolic criteria, World J Radiol (2015)
- 23 - PMID 18367739 - Hydroxyurea for the treatment of sickle cell anemia, NEJM (2008)
- 24 - PMID 31532961 - Anemia of Inflammation, NEJM (2019)
- 25 - PMID 30401705 - Anemia of Inflammation, Blood (2019)
- 26 - PMID 27557596 - Iron deficiency or anemia of inflammation?, Wien Med Wochenschr (2016)
- 27 - PMID 31365805 - A Diagnosis to Chew On, NEJM (2019)
- 28 - PMID 31082141 - Halmo L, Nappe TM. Lead Toxicity. [Updated 2019 Nov 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-
- 29 - PMID 18629325 - Reduction of Elevated Blood Lead Levels in Children in North Carolina and Vermont, 1996-1999, Environ Health Perspect (2008)
- 30 - Histology, basophilic stippling, Sanchez JR, Lynch DT. Histology, Basophilic Stippling. [Updated 2019 Jul 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545259/
- 31 - PMID 24665134 - Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis, Blood 2014
- 32 - Sideroblastic anemia - Ashorobi D, Chhabra A. Sideroblastic Anemia. [Updated 2020 Jan 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538287/
- 33 - PMID 12076240 - Association of Kidney Function With Anemia: The Third National Health and Nutrition Examination Survey (1988-1994), Arch Intern Med (2002)
- 34 - PMID 18027835 - Reticulocyte Hemoglobin Content, Am J Hematol (2008)
- 35 - KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease, Volume 2:Issue 4 (2012)
- 36 - PMID 16678659 - KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease, Am J Kidney dis (2006)
- 37 - PMID 27887750 - Chronic Kidney Disease, Lancet (2017)
- 38 - PMID 31839434 - Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting, Blood Reviews (2019)
- 39 - Clinical Pathology Laboratories test directory
- 40 - Hemolytic Anemia, Medscape
- 41 - Paroxysmal Nocturnal Hemoglobinuria, Medscape
- 42 - PMID 31039274 - Cardiac prostheses-related hemolytic anemia, Clinical Cardiology, (2019)
- 43 - PMID 25119611 - Syndromes of Thrombotic Microangiopathy, NEJM (2014)
- 44 - Hemolytic-Uremic syndrome, Medscape
- 45 - Disseminated intravascular coagulation, Medscape
- 46 - G6PD deficiency, Medscape
- 47 - PMID 18940465 - Hereditary spherocytosis, Lancet (2008)
- 48 - PMID 26488695 - Drug-Induced Megaloblastic Anemia, NEJM (2015)
- 49 - PMID 19202968 - Evaluation of Macrocytosis, Am Fam Physician (2009)
- 50 - PMID 15238427 - Prevalence of Anemia in Persons 65 Years and Older in the United States: Evidence for a High Rate of Unexplained Anemia, Blood (2004)
- 51 - PMID 21659341 - Unexplained Anemia Predominates Despite an Intensive Evaluation in a Racially Diverse Cohort of Older Adults From a Referral Anemia Clinic, J Gerontol A Biol Sci Med Sci (2011)
- 52 - PMID 24122955 - Evaluation and management of anemia in the elderly, American Journal of Hematology (2014)
- 53 - Macrocytosis, Medscape
- 54 - Clinical Pathology Laboratories
- 55 - PMID 23301732 - Vitamin B12 Deficiency, NEJM (2013)
- 56 - PMID 33207098 - Case 36-2020: A 72-Year-Old Woman with Dark Urine and Weakness, NEJM (2020)
- 57 - PMID 33730455 - Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria, NEJM (2021)
- 58 - PMID 33826820 - Sutimlimab in Cold Agglutinin Disease, NEJM (2021)
- 59 - PMID 35749111 - Chronic Abdominal Pain and Anemia in a 59-Year-Old Man, JAMA (2022)
- 60 - PMID 36322848 - A Shear Decline, NEJM (2022)
- 61 - NORD rare disease website
- 62 - PMID 36920760 - Case 8-2023: A 71-Year-Old Woman with Refractory Hemolytic Anemia, NEJM (2023)