TIBC - Kresser Institute Membership Site

Marker Name: TIBC

REFERENCE RANGES FOR TIBC:

Laboratory reference range: 250–450 µg/dL

Functional reference range: 275–425 µg/dL

DESCRIPTION:

Total iron-binding capacity (TIBC), also known as transferrin iron-binding capacity, measures the blood’s capacity to carry iron. Since transferrin (Trf) binds and transports the majority of plasma iron, TIBC is used as an approximate indirect marker of transferrin concentration. However, proteins other than transferrin do contribute to TIBC.^1-3

Transferrin-bound iron only constitutes approximately 0.1 percent of total body iron, but it is a vital and dynamic iron pool.⁴ The main biological function of transferrin is to bind one or two ferric iron ions (Fe³⁺) and transport them from macrophages and absorption sites in the small intestine to all tissues, especially bone marrow, where red blood cell production occurs.^3-5 The vast majority of iron in the body is bound to proteins such as transferrin, which minimizes circulation of reactive free iron that could otherwise produce harmful free radicals.^3-5 Iron deficiency significantly upregulates transferrin production by unknown mechanisms, making TIBC an indirect marker for iron status.^3,6

Transferrin is also a negative acute-phase reactant, meaning that its production decreases in states of inflammation.⁷ This transferrin downregulation serves to decrease iron available to pathogens that need iron to survive and contributes to anemia of chronic inflammation.^7,8 Similarly, transferrin sequesters iron in intestinal mucosa to impede bacterial survival as part of the innate immune system.⁹

Transferrin synthesis occurs throughout the body but is particularly prevalent in the liver.¹⁰ Because of this, TIBC can reflect liver function. Overall, TIBC can reflect iron status, inflammation, liver function, or a combination of the three; this complicates interpretation of TIBC level.

High TIBC can be caused by iron deficiency, pregnancy, states of increased red blood cell production, certain acute liver conditions, and certain drugs (e.g., oral contraceptives).^6,11-21 A list of specific conditions and drugs that can cause high TIBC is provided below.

Low TIBC can be caused by hereditary hemochromatosis, hereditary atransferrinemia, multiple infusions of iron-containing agents, massive increase in oral iron intake, pernicious anemia, hypoproteinemia, chronic liver disease, chronic inflammatory conditions, and some cases of ineffective erythropoiesis, hemolytic anemia, and hemosiderosis.^{8,11-15,22-25} A list of specific conditions that can cause low TIBC is below.

TIBC is a useful marker for iron status but is less sensitive than serum ferritin and inconclusive on its own. Related markers should be considered, including a complete blood count (CBC), serum iron, ferritin, UIBC, and iron saturation.¹¹ To determine if low TIBC is due to an underlying inflammatory condition, measuring other acute-phase reactants such as C-reactive protein, erythrocyte sedimentation rate, and plasma fibrinogen can be helpful.⁶

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^6,16

Iron deficiency
- Inadequate dietary intake
  - Diet low in meat
- Gastrointestinal malabsorption
  - Achlorhydria or hypochlorhydria
  - Gastritis
    - Atrophic gastritis
    - Autoimmune metaplastic atrophic gastritis
    - Helicobacter pylori gastritis¹⁷
  - Celiac disease
  - Post-gastric bypass surgery¹⁸
- Chronic blood loss (if associated inflammation is high, TIBC can also be low or normal in these conditions)¹⁹
  - Obvious bleeding
    - External wound
    - Melena
    - Hematemesis
    - Hemoptysis
    - Gross hematuria
  - Heavy menstrual bleeding
  - Gastrointestinal bleeding (e.g., hemorrhoids, fissures)
  - Repeated blood donations
  - Intraluminal neoplasms (e.g., malignancies of the gastrointestinal tract)²⁰
  - Lasthénie de Ferjol syndrome
- Normal pregnancy (in the absence of iron deficiency)⁶
- States of increased red blood cell production
  - Treatment with erythropoietin (EPO)
  - Polycythemia vera
- Certain acute liver conditions, including:
  - Acute viral hepatitis
  - Acute hepatic necrosis
- Drugs²¹
  - Oral contraceptives⁶
  - Proton pump inhibitors
  - H₂ receptor blockers
  - Certain antibiotics (e.g., quinolones, tetracycline)
  - Excessive calcium supplementation

Low in:^11-15

Hereditary hemochromatosis (HH)^22,23
- Human hemochromatosis protein (HFE)-related
  - C282Y homozygosity
  - C282Y/H63D compound heterozygosity
  - Other mutations of HFE
- Other genetic mutation
  - Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
  - Ferroportin mutations
  - Transferrin receptor 2 mutation (rare)
- Hereditary atransferrinemia
- Multiple infusions of iron-containing agents
  - Red cell transfusion
  - Multiple infusions of intravenous iron
  - Intravenous hemin/hematin
- Massive long-term increase in oral iron intake
  - High-dose iron supplementation
  - Medications containing iron
  - Diet
- Pernicious anemia
- Hypoproteinemia, as seen in:
  - Malnutrition (e.g., kwashiorkor)
  - Nephrotic syndrome
- Chronic liver disease
  - Hepatitis B or C
  - Alcohol-induced liver disease
  - Porphyria cutanea tarda
  - Steatohepatitis (fatty liver disease)
  - Neonatal or perinatal iron overload, due to gestational alloimmune liver disease²⁴
- Chronic inflammation^8,25
  - Multiple causes (e.g., chronic infection, malignancy, rheumatologic disorders, inflammatory bowel disease, acute and chronic immune activation, etc.)
- Ineffective erythropoiesis (can be mildly decreased, but often normal)
  - Hereditary sideroblastic anemias
  - Severe alpha and beta thalassemia
  - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)
- Hemolytic anemia (can be mildly decreased, but often normal), such as:
  - Autoimmune hemolytic anemia
  - Sickle cell anemia
- Hemosiderosis (can be mildly decreased, but sometimes normal)
  - Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  - Chronic hemolysis

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional iron deficiency
Pregnancy

Low in:

Functional iron overload
Functional liver problems
Chronic inflammation

References: