Biomarkers of Iron Status: Serum Iron

Optimal Takeaways

Iron is an essential mineral found primarily in red blood cell hemoglobin, though some circulates bound to transferrin or is stored in ferritin and hemosiderin. Iron binds oxygen in the hemoglobin molecule, so a deficit of iron can cause a deficit of oxygen in tissues throughout the body. An iron deficit is characterized by anemia, weakness, and fatigue. Iron must be safely bound in the blood to prevent free iron from damaging tissues and organs.

Low serum iron is associated with insufficient intake and absorption, increased requirements, blood loss, anemia, and cognitive and behavioral dysfunction. Elevated levels are associated with iron overload, lead toxicity, hemolytic anemia, oxidative stress, and liver disease. Certain medications may increase or decrease serum iron.

Standard Range: 40.00 - 190.00 ug/dL (7.16 - 34.01 umol/L)

The ODX Range: 85.00 - 130.00 ug/dL (15.22 - 23.27 umol/L)

Low serum iron can be seen with decreased intake or absorption, increased requirements, iron deficiency anemia, blood loss, pregnancy, heavy menstruation, chronic hematuria, and neoplasia. Drugs that decrease iron include ACTH, cholestyramine, colchicine, chloramphenicol, deferoxamine, methicillin, testosterone (Pagana 2022), and gastric acid-suppressing drugs. Frequent blood donations, gastrointestinal bleeding, and parasitic infection also contribute to iron deficiency. Iron malabsorption can be due to celiac disease, H. pylori infection, bariatric surgery, atrophic gastritis, or interference from tannins, phytates, oxalates, phosphates, and calcium (Hanif 2022).

Iron insufficiency can also impair energy generation, neurotransmitter changes, and cognitive and behavioral dysfunction (Kim 2014).

High serum iron can be seen with iron toxicity, lead toxicity, hemolytic anemia, hemochromatosis, hemosiderosis, hepatitis, hepatic necrosis, iron supplementation, and blood transfusions, which can cause a transient increase. Hemolysis of the blood sample will cause iron to be released from red blood cells and artificially increase serum levels. Drugs that increase serum iron include estrogen, oral contraceptives, ethanol, dextran, and methyldopa (Pagana 2022). Excess iron contributes to oxidative stress (DePalma 2021), neurodegenerative disease (Hare 2013), colon cancer risk, cirrhosis, and hepatocellular carcinoma (Kotze 2009).

Overview

Iron is an essential trace mineral required for hemoglobin, myoglobin, and DNA synthesis; cell regulation and proliferation; and electron transfer in the mitochondria (Hanif 2022).

Approximately 70% of the iron in the body is found in hemoglobin bound to oxygen, with the remainder stored in ferritin and hemosiderin. Iron is transported in the blood bound to transferrin, and serum iron reflects this circulating iron. Iron deficiency anemia occurs when iron availability decreases, a phenomenon caused by insufficient intake or absorption, increased iron requirements, or blood loss. Lack of sufficient iron reduces hemoglobin production, resulting in the microcytic, hypochromic RBCs characteristic of iron deficiency anemia (IDA). Low transferrin saturation and elevated total iron binding capacity are also observed in IDA. However, an iron overload can exceed iron binding capacity and cause it to be deposited in the heart, brain, and liver, which can severely impair function (Pagana 2022).

Ordinarily, iron can be efficiently recycled following the breakdown of hemoglobin and ferritin in the liver, spleen, and bone marrow (Gropper 2021).

Iron deficiency is the most common nutrient deficiency worldwide and a common cause of anemia. Metabolic dysfunction due to iron insufficiency can manifest as weakness, irritability, poor concentration, headaches, systolic murmur, brittle spoon-shaped nails, hair loss, restless leg syndrome, atrophic glossitis, cheilosis, pica, and pagophagia, a craving for ice that is specific to iron deficiency (Hanif 2022).

Symptoms of iron deficiency may also include shortness of breath, decreased work performance, and worsening of congestive heart failure. As iron deficiency advances, serum iron, ferritin, and transferrin saturation decrease while total iron-binding capacity increases. Complications from IDA may include infection, cardiovascular issues, depression, pregnancy complications, and developmental delay (Warner 2021).

If indicated, iron supplementation should be provided judiciously, preferably through food, to avoid iron overload and promotion of bacterial growth. Iron absorption is highly regulated by the protein hepcidin, decreasing absorption as hepcidin increases and vice versa. Hepcidin levels increase with iron overload or inflammation and decrease in IDA (Prentice 2017).

One retrospective study investigated serum iron and survival in 253 individuals with hepatocellular carcinoma (HCC), a prominent cause of cancer death worldwide. Those with a pre-op serum iron above 94 ug/dL (16.83 umol/L) had significantly better overall survival rates and significantly lower recurrence than those with serum iron 94 ug/dL or below. Interestingly, lower serum iron was associated with higher inflammatory markers in the study. It is noted that excess iron can promote tissue damage and cancer, including HCC, and should be kept within optimal range (Li 2020). Unfortunately, the study did not examine ferritin or other iron status markers.

Another retrospective study of HCC found that HCC patients with hepatitis B and larger tumors had the lowest serum iron levels. A serum iron of 84.7 (15.1 umol/L) or below was significantly associated with worsening survival (Wei 2018). Higher serum iron was associated with increased overall survival in oral cancer patients. In one study of 747 patients, survival was greater in those with a serum iron above 85.5 ug/dL (15.3 umol/L), especially in those with squamous cell cancer (Lin 2021). Additional iron biomarkers should be assessed as well. For example, in HCC patients, a high serum ferritin of 244 ng/mL (244 ug/L), suggestive of increased hepatic inflammation from stored iron, was associated with faster recurrence and reduced survival (Facciorusso 2014).

Although iron is an essential nutrient, excess, unbound iron can be highly toxic due to its promotion of oxidative stress (DePalma 2021). Evaluation of 60 healthy individuals found that the mean serum iron in healthy men was 105.2 ug/dL (18.84 umol/L), and in healthy women, it was 99.2 ug/dL (17.77 umol/L) (Penkova 2019).

References  

Facciorusso, Antonio et al. “Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation.” Journal of gastroenterology and hepatology vol. 29,11 (2014): 1905-10. doi:10.1111/jgh.12618

Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8^th edition. Wadsworth Publishing Co Inc. 2021.

Hanif, Nazma. and Faiz Anwer. “Chronic Iron Deficiency.” StatPearls, StatPearls Publishing, 10 September 2022.

Hare, Dominic et al. “A delicate balance: Iron metabolism and diseases of the brain.” Frontiers in aging neuroscience vol. 5 34. 18 Jul. 2013, doi:10.3389/fnagi.2013.00034

Kim, Jonghan, and Marianne Wessling-Resnick. “Iron and mechanisms of emotional behavior.” The Journal of nutritional biochemistry vol. 25,11 (2014): 1101-1107. doi:10.1016/j.jnutbio.2014.07.003

Koenig, Gerald, and Stephanie Seneff. “Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk.” Disease markers vol. 2015 (2015): 818570. doi:10.1155/2015/818570

Kotze, M J et al. “Pathogenic Mechanisms Underlying Iron Deficiency and Iron Overload: New Insights for Clinical Application.” EJIFCC vol. 20,2 108-23. 25 Aug. 2009

Li, Yicheng et al. “Correlation Analysis Between Preoperative Serum Iron Level and Prognosis as Well as Recurrence of HCC After Radical Resection.” Cancer management and research vol. 12 31-41. 6 Jan. 2020, doi:10.2147/CMAR.S227418

Lin, Yilin et al. Wei sheng yan jiu = Journal of hygiene research vol. 50,5 (2021): 756-762. doi:10.19813/j.cnki.weishengyanjiu.2021.05.009

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Penkova, Mariana, and Nadezhda Ivanova. “Serum Iron Metabolism Variables in Clinically Healthy Persons.” Open access Macedonian journal of medical sciences vol. 7,3 318-321. 7 Feb. 2019, doi:10.3889/oamjms.2019.083

Prentice, Andrew M et al. “Dietary strategies for improving iron status: balancing safety and efficacy.” Nutrition reviews vol. 75,1 (2017): 49-60. doi:10.1093/nutrit/nuw055

Tako, Elad. “Dietary Trace Minerals.” Nutrients vol. 11,11 2823. 19 Nov. 2019, doi:10.3390/nu11112823

Warner, Matthew J. and Muhammad T. Kamran. “Iron Deficiency Anemia.” StatPearls, StatPearls Publishing, 11 August 2021.

Wei, Yanyan et al. “Serum Iron Levels Decreased in Patients with HBV-Related Hepatocellular Carcinoma, as a Risk Factor for the Prognosis of HBV-Related HCC.” Frontiers in physiology vol. 9 66. 6 Feb. 2018, doi:10.3389/fphys.2018.00066