Ferritin - Kresser Institute Membership Site

Marker Name: Ferritin

REFERENCE RANGES FOR SERUM FERRITIN:

Laboratory reference ranges:
Male: 30–400 ng/mL
Female: 15–150 ng/mL

Functional reference ranges:
Male: 30–200 ng/mL
Female: 30–100 ng/mL

DESCRIPTION:

Ferritin is the storage protein for iron. Each large ferritin protein has a spherical cavity that can hold up to 4,500 iron atoms as a crystalline solid.^1,2Ferritin stores and slowly releases iron in a non-toxic and controlled way, which helps protect against iron deficiency and iron overload.² Much of the iron in ferritin can be readily released for metabolic use. For example, in red cell precursors, ferritin plays a key role in providing iron for heme synthesis.¹

Biosynthesis of ferritin is partially controlled by the concentration of iron in the cell. Specifically, iron regulatory proteins 1 and 2 (IRP1, IRP2) sense cytoplasmic iron concentration and regulate translation of ferritin mRNA accordingly.^3,4 Iron is stored in its ferric form (Fe³⁺) and released in its ferrous form (Fe²⁺), but mechanistic details of iron uptake and release from ferritin remain unclear.⁴

Ferritin is also an acute-phase reactant that may help protect against oxidative stress and inflammation.¹ A wide variety of acute and chronic inflammatory conditions involve the production of cytokines that upregulate ferritin synthesis.⁵ Endotoxin, a toxic molecule found in gram-negative bacteria, stimulates a particularly strong increase in ferritin production.⁶

Ferritin is found in most tissues; the vast majority is inside cells as an iron storage protein, and a small amount is in plasma as an iron carrier.⁷ Circulating ferritin is most often in the form of apoferritin, which does not contain iron.¹ A separate form of ferritin, m-ferritin, is found in mitochondria and likely protects against oxidative damage.¹

In an otherwise healthy individual, serum ferritin is an excellent indirect marker of total body iron stores. This is no longer true in states of inflammation, as ferritin plays the dual roles of iron storage protein and acute-phase reactant. Therefore, normal serum ferritin may either indicate a healthy iron level or a state of simultaneous iron deficiency and inflammation. High ferritin may indicate iron overload, inflammation, or both. Many conditions involving blood loss are also inflammatory, in which case ferritin may be low, normal, or high. As a general rule, inflammation elevates ferritin concentration approximately threefold.⁸ Conditions causing relatively consistent ferritin changes are reviewed here.

High serum ferritin concentration (hyperferritinemia) can be caused by conditions of iron overload or inflammation (acute or chronic). A list of specific conditions that can cause hyperferritinemia is provided below.

Low serum ferritin concentration (hypoferritinemia) is exclusively caused by iron deficiency, which can in turn be caused by various conditions and drugs listed below.

For a full evaluation of iron status, serum ferritin should be considered with related markers, including a complete blood count (CBC), serum iron, TIBC, UIBC, and iron saturation. If etiology of high ferritin is unclear from patient history, tests for relevant genetic mutations and other acute-phase reactants, such as C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); and plasma fibrinogen can help distinguish between iron overload and underlying inflammation.^8,9

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^9,10

Multiple infusions of iron-containing agents
- Red cell transfusion
- Multiple infusions of intravenous iron
- Intravenous hemin/hematin
Massive increase in oral iron intake
- High-dose iron supplementation
- Medications containing iron
Hereditary hemochromatosis (HH)^11,12
- 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)
- Other genetic conditions, including:¹²
  - Hereditary hyperferritinemia-cataract syndrome
  - Benign hyperferritinemia
  - Wilson’s disease (aceruloplasminemia)
  - Neuroferritinopathy (dominant adult-onset basal ganglia disease)
  - Mutations in the iron transporter gene DMT1
- Ineffective erythropoiesis
  - Hereditary sideroblastic anemias
  - Severe alpha and beta thalassemia¹³
  - Myelodysplastic syndrome (MDS) variants, such as refractory anemia with ringed sideroblasts (RARS)
- Hemolytic anemia (e.g., autoimmune hemolytic anemia, sickle cell anemia)
- Hemosiderosis
  - Pulmonary hemosiderosis (as seen in anti-glomerular basement membrane antibody disease)
  - Chronic hemolysis
- Hyperthyroidism (thyrotoxicosis)^14,15
- 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
- States of acute inflammation (e.g., surgery, major trauma, myocardial infarction, sepsis)¹⁶
- Chronic inflammatory conditions, including:¹⁶
  - Infection (e.g., active pulmonary tuberculosis)
  - Malignancy (e.g., hematologic malignancy, papilla of Vater carcinoma, esophageal carcinoma)
  - HIV infection, especially with concurrent opportunistic infection
  - Hemophagocytic lymphohistiocytosis
  - Rheumatologic disorders (e.g., rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, adult-onset Still’s disease, macrophage activation syndrome)
  - Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)¹⁷
  - Certain gastrointestinal conditions (e.g., stomach polyposis, intra-abdominal abscess, cholecystectomy, colonic diverticulitis, perforated peptic ulcer, colonic polyposis, benign esophageal tumors)¹⁸
  - Castleman’s disease
  - Heart failure
  - Chronic kidney disease^19,20
  - Chronic obstructive pulmonary disease (COPD)
  - Hematopoietic stem cell transplantation (HSCT)
  - Metabolic syndrome
- Insulin resistance²¹

Low in:^8,22

Pregnancy
- Direct iron loss to fetus during pregnancy
- Blood loss during delivery
- Lactation
Inadequate dietary intake
- Diet low in meat
Gastrointestinal malabsorption
- Achlorhydria or hypochlorhydria
- Gastritis (e.g., atrophic gastritis, autoimmune metaplastic atrophic gastritis, Helicobacter pylori gastritis)²³
- Celiac disease²⁴
- Post-gastric bypass surgery²⁵
Blood loss (depending on level of associated inflammation, ferritin can also be high or normal in these conditions)²⁶
- Obvious bleeding (e.g., 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)^18,27
- Lasthénie de Ferjol syndrome
Treatment with erythropoietin (EPO)²⁸
Drugs²⁹
- 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 and metabolic dysfunction

Low in:

Functional iron deficiency
Malabsorption
Blood loss
Pregnancy

References: