Ferritin

Ferritin is a crucial biomarker; understanding its implications is vital for maintaining optimal health and well-being.

Ferritin is a protein complex that serves as the primary intracellular storage unit for iron in the body. It plays a fundamental role in iron metabolism, acting as a reservoir for iron while also regulating its availability to cells and tissues.

The main function of ferritin is to store iron in a non-toxic form, preventing iron from causing oxidative damage to cells and tissues. 

Additionally, ferritin helps maintain iron homeostasis by releasing stored iron when needed, such as during periods of increased demand or in response to low dietary intake. 

This dynamic regulation ensures that cells receive an adequate supply of iron for essential metabolic processes while preventing iron overload, which can lead to harmful effects.

This article will provide an in-depth exploration of ferritin, including its functions and its role in iron homeostasis, implications for disease with elevated ferritin levels, in addition to testing options for ferritin and other important aspects of ferritin in health and wellness.

Definition and Function of Ferritin

Definition of Ferritin: What is Ferritin?  [1., 6.]

Ferritin is a protein complex that functions as the primary intracellular storage unit for iron in the body. It plays a vital role in iron metabolism by storing iron in a non-toxic form and regulating its availability to cells and tissues. 

Structurally, ferritin consists of an apoferritin shell enclosing iron molecules, with 24 subunits comprising H and L types at its shell. It operates as a ferroxidase, converting available Fe(II) to Fe(III).  Fe(III) is then sequestered within its mineral core, safeguarding cells from the damaging effects of reactive iron species.

Ferritin helps maintain iron homeostasis by releasing stored iron when needed, such as during periods of increased demand or low dietary intake, ensuring cells receive adequate iron for essential metabolic processes while preventing iron overload.

Functions of Ferritin: What Does Ferritin Do in the Body?  [6.]

Ferritin plays a crucial role in maintaining iron balance within the body. Iron is vital for various physiological functions, including oxygen transport, energy production, and DNA replication. However, excess iron can be toxic due to its ability to generate reactive species.  Ferritin is an essential molecule to help regulate and conserve iron levels in the body. 

Ferritin acts as a ferroxidase, converting ferrous iron (Fe2+) to ferric iron (Fe3+), which is then stored in its mineral core, preventing damage to DNA and proteins caused by reactive iron species. 

Specific functions of ferritin include:

Iron Sequestration: ferritin serves as a ferroxidase, converting ferrous iron (Fe2+) to ferric iron (Fe3+), allowing it to be stored safely in its mineral core.

‍Prevention of Iron Toxicity: by storing iron within its core, ferritin prevents the formation of reactive iron species that can damage DNA and proteins.

Regulation of Systemic Iron Balance: ferritin plays a crucial role in regulating iron balance by sequestering iron within cells, particularly in the small intestine, where iron absorption primarily occurs.

Involvement in Iron Recycling: ferritin facilitates the recycling of iron from red blood cells within macrophages.

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Tight Regulation by Molecules like Hepcidin: ferritin levels are tightly regulated by molecules such as hepcidin, which helps maintain proper iron homeostasis.

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Clinical Utility as a Marker of Iron Status: ferritin levels are used clinically to assess iron status, aiding in the diagnosis and management of iron deficiency and overload conditions.

Differentiation between Iron Deficiency Anemia and Anemia of Chronic Disease: ferritin is valuable in distinguishing between these two types of anemia.

‍Monitoring in Iron Overload Conditions: ferritin levels are monitored in conditions such as hereditary hemochromatosis and transfusional iron overload to guide therapeutic interventions.

Guiding Therapeutic Interventions: ferritin levels help in determining appropriate therapeutic interventions such as phlebotomy or iron chelation therapy.

Ferritin’s Role in Maintaining a Healthy Iron Balance in the Body

Maintaining a healthy balance of iron in the body is essential for overall health and well-being. Iron plays a crucial role in various physiological processes, primarily as a component of hemoglobin, the protein responsible for transporting oxygen from the lungs to tissues throughout the body. 

Additionally, iron is involved in cellular metabolism, energy production, DNA synthesis, and immune function. Adequate iron levels are necessary to support optimal cognitive function, physical performance, and immune response.

However, an imbalance in iron levels, either through deficiency or overload, can lead to significant health issues. 

Iron deficiency can result in fatigue, weakness, impaired cognitive function, and compromised immune function, ultimately leading to conditions such as iron deficiency anemia. 

On the other hand, iron overload often resulting from hereditary conditions like hemochromatosis or chronic transfusion therapy, can lead to oxidative stress, tissue damage, and organ dysfunction. 

Excess iron accumulation in organs such as the liver, heart, and pancreas can cause serious complications including liver cirrhosis, heart failure, and diabetes, collectively known as iron overload disorders. Thus, maintaining a healthy balance of iron is critical for overall health and disease prevention.

Ferritin protects against the health issues associated with both iron excess and deficiency by acting as an iron-specific storage molecule.  

‍To learn more about iron’s role in the body, click here.

Laboratory Assessment of Ferritin

Lab Test Information and Preparation 

Ferritin levels are typically measured through a blood test, which requires a venipuncture.  Fasting is not required.  

Interpreting Test Results

Reference Range for Ferritin

The reference ranges for ferritin are typically given as: [7.]

Adult males: 30-300 ng/mL (30-300 mcg/L) 

Adult females: 10-200 ng/mL (10-200 mcg/L) 

The reference ranges for children are as follows:  [11.]

Newborns: 25-200 ng/mL (25-200 mcg/L) 

Children, 1 month: 200-600 ng/mL (200-600 mcg/L) 

‍Children, 2-5 months: 50-200 ng/mL (50-200 mcg/L) 

‍Children, 6 months-15 years: 7-140 ng/mL (7-140 mcg/L)

Monitoring ferritin levels alongside other biomarkers provides comprehensive insights into iron status and related health conditions.  [1.]

Clinical Significance of High Levels of Ferritin

Elevated ferritin levels in clinical testing can indicate various health conditions including iron overload disorders such as hemochromatosis; chronic liver disease; inflammatory disorders; or malignancies. 

This hyperferritinemia is commonly regarded as indicative of macrophage activation and is often linked with heightened mortality rates. The state of hyperferritinemia triggers activation of the reticuloendothelial system alongside increased cytokine levels, potentially instigating inflammatory pathways that contribute to multiple organ dysfunction.

Clinically, high ferritin levels often prompt further investigation to determine the underlying cause and guide appropriate management strategies, which may include treatment of the underlying condition or therapeutic interventions to reduce iron levels.

Iron Overload Disorders

Iron overload, characterized by excessive iron stores in the body, can arise from inherited genetic mutations or secondary causes such as transfusion, hemolysis, or excessive iron intake.  Hereditary hemochromatosis is the leading cause of iron overload.  [8.] 

This excess iron deposition can lead to organ damage, particularly affecting the liver, heart, and endocrine glands. Symptoms may include fatigue, joint pain, abdominal discomfort, irregular heart rhythms, and hyperpigmentation, among others.

Undiagnosed iron overload can lead to serious health consequences if left untreated. Chronic iron deposition in organs such as the liver can progress to cirrhosis and hepatocellular carcinoma, while iron accumulation in the heart may result in heart failure and arrhythmias. 

Furthermore, untreated iron overload can exacerbate existing conditions such as diabetes, hypothyroidism, and joint disorders, significantly impacting the patient's overall health and quality of life. 

Early detection and intervention are crucial to prevent the progression of iron overload-related complications.

Chronic Liver Disease [10.]

Elevated ferritin levels are often observed in chronic liver disease, reflecting the complex interplay between iron metabolism, inflammation, and hepatic injury. 

In patients with advanced liver disease, elevated ferritin levels are attributed to disrupted iron metabolism and heightened inflammation, reflecting the severity of liver damage and subsequent complications. 

Studies have shown that serum ferritin serves as a prognostic marker in various liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, and viral-related liver diseases, aiding in predicting mortality and disease progression. Ferritin levels correlate with hepatic histological lesions and are associated with worse Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores, indicating advanced disease severity. 

Moreover, ferritin levels may reflect immune-mediated responses, infectious stimuli, and potential iron overload conditions, contributing to significant morbidity and early mortality. 

Alcoholism also drives elevated ferritin levels.  [4.]  

Understanding the role of ferritin in chronic liver disease can help clinicians assess disease severity and guide treatment strategies effectively.

Inflammatory Disorders

Excessive iron levels can lead to toxicity by promoting the formation of free radicals through the Fenton reaction. In this reaction, ferrous iron (Fe^2+) reacts with hydrogen peroxide, resulting in the generation of hydroxyl radicals and hydroxide ions, which can damage cellular components. 

To prevent oxidative stress and inflammation, cells tightly regulate iron metabolism, including sequestration by ferritin molecules.  While ferritin plays a protective role in iron homeostasis and redox biology, elevated serum ferritin levels are associated with inflammation. 

Inflammation is an important component of many disease processes, including rheumatological diseases.  While elevated ferritin does not specifically indicate the presence of a rheumatological condition, it is important to consider.  

Some conditions presenting with high serum ferritin include adult-onset Still's disease, systemic juvenile idiopathic arthritis, rheumatoid arthritis, vasculitis and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.  [9., 12.]

Malignancies  [2.]

Altered iron metabolism is a hallmark of cancer, with dysregulation occurring at various stages of iron metabolism. 

Serum ferritin levels serve as diagnostic and prognostic markers in several cancers, including neuroblastoma, Hodgkin's lymphoma, cervical, oral squamous cell, renal cell, T cell lymphoma, colorectal, and breast cancers. 

Tumor-associated macrophages (TAMs) are implicated as major contributors to elevated serum ferritin, promoting tumor proliferation, angiogenesis, and immunosuppression. Additionally, altered expression of iron-related proteins, such as transferrins, lipocalin 2 (LCN2), and heme scavenger receptors, contributes to tumorigenesis. 

Moreover, ferritin subunit expression and localization determine its role in cancer biology and prognosis. Exceeding ferritin storage capacity leads to hemosiderin deposits, detectable by MRI, serving as a non-invasive marker of disease stage and treatment response. 

Ferroportin, the sole exporter of intracellular iron, is reduced in cancer cells, promoting iron accumulation and tumor growth, making the hepcidin-ferroportin axis a potential therapeutic target.

Other Conditions

Elevated ferritin can also be seen with a myocardial infarction, end-stage renal disease, non-iron deficiency anemias, and hyperthyroidism.  [4.]

Clinical Significance of Low Levels of Ferritin  [14.]

Low ferritin is most commonly seen in iron deficiency anemia, although it may also be seen with hemodialysis.  [4.] 

Iron deficiency anemia (IDA) holds significant clinical importance due to its widespread prevalence and profound impact on various physiological functions. IDA affects individuals across all age groups and demographics, making it a global public health concern. 

IDA arises when there is an insufficient supply of iron to meet the body's demands for hemoglobin synthesis, leading to reduced oxygen-carrying capacity in red blood cells. Consequently, patients with IDA often experience symptoms such as fatigue, weakness, palpitations, and shortness of breath, which can impair their quality of life and functional capacity. 

Furthermore, IDA can exacerbate existing health conditions and contribute to complications such as impaired cognitive function, compromised immune response, and increased susceptibility to infections.

Iron deficiency anemia poses particular challenges and implications for both maternal and fetal health. During pregnancy, the demand for iron escalates to support the expansion of maternal blood volume, placental development, and fetal growth and development. Consequently, pregnant individuals are at heightened risk of developing iron deficiency anemia, especially in the later stages of gestation. 

Untreated IDA during pregnancy can lead to adverse outcomes such as preterm birth, low birth weight, and maternal morbidity, highlighting the critical importance of early detection and management. 

Similarly, the postpartum period represents a vulnerable phase where women may experience ongoing iron depletion due to blood loss during childbirth and lactation-related demands.

Related Biomarkers

Clinicians may wish to provide a more comprehensive assessment of iron status for patients.  Testing these biomarkers in addition to ferritin can provide additional insight:

Transferrin saturation (TS): %TS measures the percentage of transferrin in the blood that is saturated with iron, providing insight into iron availability for cellular uptake.

Serum iron levels: this is a direct measurement of iron concentration in the blood, reflecting both dietary intake and iron metabolism.

Total iron-binding capacity (TIBC): TIBC measures the capacity of transferrin to bind iron, indicating the body's ability to transport iron to tissues.

Hemoglobin and hematocrit levels: these are indicators of overall blood oxygen-carrying capacity and erythropoiesis, affected by iron status.

C-reactive protein (CRP): CRP is a marker of inflammation that can affect ferritin levels, especially in the absence of iron overload.

Erythrocyte sedimentation rate (ESR): another indicator of inflammation, which can influence ferritin levels.

Liver function tests (e.g., AST, ALT, ALP, bilirubin): these are ordered to assess liver health with concern of elevated iron levels, as excess iron levels and hepatic iron deposition can cause liver dysfunction.  

Further assessment for the diagnosis of hemochromatosis includes:

Genetic testing for hemochromatosis mutations (e.g., HFE gene mutations): Identifies genetic predisposition to iron overload disorders, such as hereditary hemochromatosis.

HFE gene-associated hereditary hemochromatosis is diagnosed if the genotypic analysis shows C282Y homozygosity.  The patient should be assessed for secondary causes of iron overload in cases without C282Y homozygosity on HFE mutation analysis.  [DYNAMED>>>>

Imaging studies (e.g., liver MRI, abdominal ultrasound): these may be ordered to assess organ iron content and detect hemosiderin deposition, supporting the diagnosis of iron overload conditions.

Natural Ways to Support Healthy Ferritin Levels 

Because ferritin is a marker of iron status, supporting healthy ferritin levels requires a healthy iron balance.  Focusing on a healthy diet with iron-rich foods, along with plenty of vegetables, fruits, and fiber is foundational to promote a healthy iron balance.

• Mediterranean diet: Following a Mediterranean-style diet rich in fruits, vegetables, whole grains, fish, and healthy fats like olive oil provides ample dietary fiber and can help reduce inflammation.  

• Incorporate iron-rich foods into your diet, such as lean meats, poultry, fish, beans, lentils, tofu, spinach, kale, and fortified cereals.

• Pair iron-rich foods with sources of vitamin C, like citrus fruits, strawberries, bell peppers, and tomatoes, to enhance iron absorption.

• Avoid drinking tea or coffee with meals, as they contain compounds that can inhibit iron absorption.

• Cook in cast-iron pots and pans, as they can increase the iron content of food.

• Limit consumption of calcium-rich foods and supplements during meals, as calcium can interfere with iron absorption.

• Eat foods rich in folate, vitamin B12, and vitamin A, as they play crucial roles in red blood cell production and iron metabolism.

• Consider incorporating iron supplements under the guidance of a healthcare professional if dietary sources alone are insufficient to meet your iron needs.

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