Iron

Marker Name: Iron

REFERENCE RANGES FOR SERUM IRON:

Laboratory reference range: 40–155 µg/dL

Functional reference range: 40–135 µg/dL

DESCRIPTION:

Most of the body’s iron (Fe) is found in hemoglobin proteins of red blood cells, where it plays the crucial role of transporting oxygen to tissues throughout the body.¹ A small but important portion of iron is found in metalloenzymes needed for tyrosine, dopamine, serotonin, and noradrenaline synthesis and is used as a cofactor for enzymes involved in gluconeogenesis, energy production, and DNA and RNA synthesis.²

Iron homeostasis is achieved by a complex balance of intestinal absorption, iron recycling from red blood cells, release of iron stores from ferritin in the mononuclear phagocyte system, and iron loss through sweat, shed skin cells, minor gastrointestinal losses, and menstruation in women.^3,4 Research suggests that the protein hepcidin plays a major role in iron balance by adjusting the rate of iron absorption in the gastrointestinal tract and iron export from macrophages in response to many signals, such as body iron levels, inflammation, infection, endotoxin, p53, hypoxia, anemia, and erythropoiesis (red blood cell production) rate. Gastrointestinal absorption of iron is tightly regulated, since there is no innate way to upregulate iron excretion if too much is absorbed. Iron is primarily absorbed in the duodenum of the small intestine, though many mechanistic details remain unclear.³

When iron is absorbed from food, it is transported through plasma by the protein transferrin. Transferrin carries iron throughout the body and primarily delivers it to bone marrow, where red blood cell precursors incorporate the iron into hemoglobin during erythropoiesis. The many biological functions of iron involve its ability to readily change oxidation states, cycling between Fe²⁺ and Fe³⁺. However, this reactivity can also produce harmful free radicals, so the vast majority of iron in the body is bound to proteins. Most iron circulating in plasma is bound to transferrin; the remaining trace amount is usually chelated to amino acids or citrate and promptly taken up by the liver.²

The serum iron (SI) test effectively measures the concentration of iron in transit, bound to transferrin.⁵

For high serum iron, consider hereditary hemochromatosis, massive iron intake, liver disease, and ineffective erythropoiesis. A full list of conditions that can cause elevated iron concentration is below.^6,7

For low serum iron, consider blood loss, low dietary intake, gastrointestinal malabsorption, chronic inflammatory disease, pregnancy, certain genetic conditions, and certain drugs (e.g., proton pump inhibitors, certain antibiotics). A complete list of conditions and drugs that can cause low iron concentration is provided below.^1,8,9-15

Serum iron concentration is a useful measure of circulating iron, but it should be considered with other iron markers, including a complete blood count (CBC), ferritin, TIBC, UIBC, and iron saturation.¹⁶

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:⁶

• Increased iron absorption from a normal diet
  • Hereditary hemochromatosis (HH)
    • Human hemochromatosis protein (HFE)-related
      • C282Y homozygosity
      • C282Y/H63D compound heterozygosity
      • Other mutations of HFE
    • Other gene mutations
      • Juvenile hemochromatosis (mutations in hemojuvelin or hepcidin)
      • Ferroportin mutations
      • Transferrin receptor 2 mutation (rare)
    • Multiple infusions of iron-containing agents
      • Red cell transfusion
      • Multiple infusions of intravenous iron
      • Intravenous hemin/hematin
    • Massive increase in oral intake
      • High-dose iron supplementation
      • Medications containing iron
      • Diet
    • 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 disease
    • Wilson’s disease (aceruloplasminemia)
    • Ineffective erythropoiesis
      • Hereditary sideroblastic anemias
      • Severe alpha and beta thalassemia
      • Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)
    • Insulin resistance (considered once other causes are ruled out)⁷

Low in:^1,9

• Inadequate dietary intake
  • Diet low in meat
• Gastrointestinal malabsorption
  • Achlorhydria or hypochlorhydria
  • Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
  • Gastritis
    • Atrophic gastritis
    • Autoimmune metaplastic atrophic gastritis
    • Helicobacter pylori gastritis
  • Celiac disease
  • Post-gastric bypass surgery¹⁰
• Chronic inflammatory disease¹¹
  • Multiple causes (e.g., infections, malignancy, diabetes mellitus, acute and chronic immune activation, etc.)
• Pregnancy
  • Fluid expansion during pregnancy
  • Direct iron loss to fetus during pregnancy
  • Blood loss during delivery
  • Lactation
• Blood loss⁸
  • Obvious bleeding
    • Trauma
    • Melena
    • Hematemesis
    • Hemoptysis
    • Gross hematuria
  • Heavy menstrual bleeding
  • Gastrointestinal bleeding
    • Multiple causes (e.g., hemorrhoids, fissures, inflammatory bowel disease, infection, diverticulitis)¹²
  • Repeated blood donations
  • Surgery
  • Hemodialysis¹³
  • Intraluminal neoplasms (e.g., malignancies of the gastrointestinal or genitourinary tract)¹⁴
  • Intravascular hemolysis, with accompanying hemoglobinuria and hemosiderinuria
  • Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  • Lasthénie de Ferjol syndrome
• Treatment with erythropoietin (EPO)
• Congenital iron deficiencies
  • Iron-refractory iron deficiency anemia (IRIDA)
  • Mutations in the iron transporter gene DMT1
• Drugs¹⁵
  • Proton pump inhibitors
  • H₂ receptor blockers
  • Certain antibiotics (e.g., quinolones, tetracycline)
  • Excessive calcium supplementation

FUNCTIONAL RANGE INDICATIONS:

High in:

• Functional iron overload
• Functional liver problems
• Insulin resistance

Low in:

• Functional iron deficiency
• Celiac disease and other GI conditions that cause malabsorption
• Blood loss
• Pregnancy
• Chronic inflammatory conditions

References:

1. http://www.uptodate.com/contents/approach-to-the-adult-patient-with-anemia
2. http://www.uptodate.com/contents/overview-of-dietary-trace-minerals
3. http://www.uptodate.com/contents/regulation-of-iron-balance
4. Kong, Weina, Xianglin Duan, Zhenhua Shi, and Yanzhong Chang. “Iron Metabolism in the Mononuclear Phagocyte System.” Progress in Natural Science 18, no. 10 (October 10, 2008): 1197–1202. doi:10.1016/j.pnsc.2008.03.024.
5. http://www.irondisorders.org/iron-tests/
6. http://www.uptodate.com/contents/approach-to-the-patient-with-suspected-iron-overload
7. http://www.uptodate.com/contents/iron-overload-syndromes-other-than-hereditary-hemochromatosis?source=see_link
8. http://www.uptodate.com/contents/anemia-caused-by-low-iron-beyond-the-basics
9. http://www.uptodate.com/contents/causes-and-diagnosis-of-iron-deficiency-anemia-in-the-adult
10. https://www.nlm.nih.gov/medlineplus/ency/article/000584.htm
11. http://www.uptodate.com/contents/anemia-of-chronic-disease-inflammation
12. http://chemocare.com/chemotherapy/side-effects/iron-deficiency-anemia.aspx
13. http://www.uptodate.com/contents/diagnosis-of-iron-deficiency-in-chronic-kidney-disease
14. http://www.uptodate.com/contents/hematologic-complications-of-malignancy-anemia-and-bleeding
15. http://www.uptodate.com/contents/treatment-of-the-adult-with-iron-deficiency-anemia
16. http://unitedlabservice.com/comprehensive-lab-tests/iron-and-total-iron-binding-capacity-tibc/