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Approach to the patient with suspected iron overload

Approach to the patient with suspected iron overload
Authors:
Bruce R Bacon, MD
Janet L Kwiatkowski, MD, MSCE
Section Editor:
Robert T Means, Jr, MD, MACP
Deputy Editors:
Jennifer S Tirnauer, MD
Jane Givens, MD, MSCE
Literature review current through: Dec 2022. | This topic last updated: Jun 09, 2022.

INTRODUCTION — Iron overload is a potentially serious problem that is often overlooked because the symptoms are nonspecific and often develop gradually. A number of diagnostic tests are available, but their interpretation can be challenging. Once iron overload is diagnosed, the options for treatment are relatively straightforward in the majority of individuals. However, untreated individuals can develop life-threatening organ toxicity. Thus, it is important to identify iron overload before organ damage occurs.

An approach to evaluating individuals with suspected iron overload is presented here.

Separate topic reviews discuss the regulation of iron balance, the diagnosis of and treatment of hereditary hemochromatosis (HH), and the management of iron overload.

Iron balance – (See "Regulation of iron balance".)

HH population screening – (See "HFE and other hemochromatosis genes", section on 'Role of population screening'.)

HH diagnosis – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

HH treatment – (See "Management and prognosis of hereditary hemochromatosis".)

HH genetics – (See "HFE and other hemochromatosis genes".)

Chelation therapy – (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

Therapeutic phlebotomy – (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores' and "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

NORMAL IRON STORES — The normal iron content of the body is 3 to 4 grams. It exists in the following forms:

Hemoglobin in circulating red cells – Approximately 2.5 grams

Iron-containing proteins other than hemoglobin (eg, myoglobin, cytochromes, catalase) – 400 mg

Iron bound to transferrin in plasma – 3 to 7 mg

Storage iron in the form of ferritin or hemosiderin

Adult men have approximately 1 g of storage iron (mostly in liver, spleen, and bone marrow). Adult women have less storage iron, depending upon the extent of menses, pregnancies, deliveries, lactation, and iron intake, and some may have no stores [1].

Total body iron content is determined by the balance between dietary iron intake (or other sources such as transfusion) and iron loss from bleeding or shedding of iron-containing cells; there are no physiologic mechanisms to eliminate iron from the body when it is present in excess:

Intake – A typical Western diet in resource-rich settings contains approximately 10 to 20 mg of iron; approximately 10 percent of this is absorbed in the upper gastrointestinal tract. Heme iron (eg, iron in meats) is better absorbed than non-heme iron (eg, iron from vegetable sources). Other factors that influence the efficiency of iron absorption are discussed in detail separately. (See "Regulation of iron balance", section on 'Intestinal iron absorption'.)

Loss – Iron is normally lost in sweat, shed skin cells, and gastrointestinal loss at a rate of approximately 1 mg/day. Menstruating females lose additional iron, equivalent to 0.5 to 1.0 mg/day.

Recycling – Iron is recycled from the breakdown of senescent red blood cells in the macrophages of the reticuloendothelial system in the liver, spleen, and bone marrow.

While removal of iron from the body is not regulated, the absorption of iron from intestinal cells and the release of storage iron from macrophages is highly controlled, in a process involving a number of transport proteins and their regulators. (See "Regulation of iron balance", section on 'Role of specific proteins'.)

In hereditary hemochromatosis (HH), genetic variants in one of these regulators (typically, homozygous C282Y mutation in the HFE gene or compound heterozygosity for C282Y/H63D) leads to excessive intestinal iron absorption; other causes of increased iron stores include ineffective erythropoiesis (eg, in thalassemia), and a large number of red blood cell transfusions for indications other than blood loss (eg, hemoglobinopathies, hematologic neoplasms). (See 'Causes of iron overload' below.)

CAUSES OF IRON OVERLOAD

Overview of causes — Iron overload can occur because iron intake is increased or iron absorption is increased in the setting of normal intake (table 1).

The major cause of increased iron intake is from multiple red blood cell (RBC) transfusions for chronic anemia (eg, thalassemia, sickle cell disease, hemolytic anemias such as pyruvate kinase deficiency, inherited bone marrow failure syndrome, myelodysplastic syndrome). Less common causes include the excessive use of iron supplements or therapeutic infusions of iron-containing products such as hemin, used to treat certain porphyrias.

The major causes of increased iron absorption include hereditary hemochromatosis (HH) due to mutations in HFE; ineffective erythropoiesis that occurs in thalassemia, sideroblastic anemias, and certain other inherited anemias; and liver disease, especially alcoholic liver disease and chronic hepatitis. Less common causes include gestational alloimmune liver disease (GALD) and rare mutations affecting iron absorption or iron distribution.

Importantly, patients often have more than one cause of iron overload. A classic example is transfusional iron overload in an individual with beta thalassemia major. Other examples include genetic factors in individuals with excessive use of iron supplements, ingestion of alcohol stored in iron-containing barrels, or alcoholic liver disease.

Elevated serum ferritin levels (ferritin >300 ng/mL in males and >200 ng/mL in females) may also occur in some conditions in the absence of excess iron accumulation, as summarized in the table (table 2). This most commonly occurs in the setting of inflammation, including malignancies, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, renal failure, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and metabolic syndrome [2]. It is important to distinguish these causes, as treatment is directed towards the underlying condition and does not involve iron reduction methods. (See 'Differential diagnosis' below.)

Transfusional iron overload — Transfusional iron overload occurs when transfusions are given for anemia not caused by iron deficiency. Examples include thalassemias, in which iron overload is compounded by increased absorption due to ineffective erythropoiesis, as well as sickle cell disease, other inherited anemias, aplastic anemia, myelodysplastic syndromes, other hematologic malignancies, and hematopoietic cell transplantation. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

For individuals without iron deficiency, it is generally accepted that transfusion of more than 15 to 20 units of RBCs (>10 units in smaller children) can cause clinically significant iron overload. This is based on the approximation that each unit of RBCs has about 250 mg of iron. However, some individuals with ineffective erythropoiesis who also have increased iron absorption may develop iron overload earlier. The correlation between the total volume of transfusions and clinical manifestations of iron overload is not exact, and clinical judgment is required in determining when to assess for iron overload.

Individuals receiving chronic RBC transfusions are typically monitored using serum ferritin levels and liver and cardiac MRI (algorithm 1). (See 'Sequence and interpretation of testing' below and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

Hereditary hemochromatosis — Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by increased absorption of intestinal iron, which in some cases can lead to excessive iron stores. HH is caused by mutations in the HFE gene, typically homozygous C282Y/C282Y or compound heterozygous C282Y/H63D. Other HFE mutations and mutations in other iron regulatory genes have also been reported (eg, ferroportin, hemojuvelin, hepcidin, ceruloplasmin). (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Individuals with HH can absorb as much as 2 to 4 mg of dietary iron per day (twice the rate of individuals without HH). If the typical iron requirements to compensate for normal physiological iron losses is in the range of 1 to 2 mg per day, this increased absorption can result in as much as an additional 3 mg per day in excess of needs. (See 'Normal iron stores' above.)

Over time, iron accumulation can thus occur in the range of 1 gram per year (10 grams per decade). This explains the typical presentation of adult males with signs and symptoms of hemochromatosis in the fourth to fifth decades, and the slightly later presentation of females, often because they lose iron from menstruation and/or pregnancy. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Individuals with a family history of HH should be screened for HFE mutations (or in rare cases, other familial mutations), based on the rationale that if HH is present, therapy is straightforward and well-tolerated and can prevent permanent end-organ damage. In the Hemochromatosis and Iron Overload Screening (HEIRS) study, self-reported information about the family history had a sensitivity of 81 percent and a specificity of 97 percent for an accurate report, supporting the use of family history as a good screening tool [3]. If the individual has homozygosity for HFE C282Y or compound heterozygosity (C282Y/H63D), then iron studies and liver function tests should be obtained. (See 'Sequence and interpretation of testing' below.)

For those with a positive family history of HH, the ideal age to perform genetic testing and/or liver iron assessment has not been determined. Deferring screening until adulthood is reasonable because this permits the individual to give informed consent for testing, and iron stores are not expected to be high until later. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Pathophysiology'.)

The appropriate screening tests include genetic testing to determine whether one (or both) of the familial mutations have been inherited, and iron studies to determine the severity of iron overload in those who have inherited the familial mutation(s). These can be done sequentially with mutation testing followed by iron studies only in those with the implicated mutations; in some cases it may be cost effective to order the testing simultaneously. If the individual is known to lack the familial mutations or to have inherited only one mutation, iron studies are unnecessary unless indicated for another reason.

Screening family members of an individual with HH, interpretation of the results, and appropriate testing for those who have inherited the familial mutations are discussed in more detail separately. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)

Ineffective erythropoiesis — Ineffective erythropoiesis refers to a process in which RBC precursors are destroyed (eg, by apoptosis) before they differentiate into mature RBCs; this is manifested by intense erythroid hyperplasia in the bone marrow with a low peripheral blood reticulocyte count. This process is most commonly seen in thalassemia; ineffective erythropoiesis also may occur in pyruvate kinase (PK) deficiency, congenital dyserythropoietic anemia, and in some sideroblastic anemias. As noted above, the associated iron overload may be compounded by frequent RBC transfusions for anemia. (See "Pathophysiology of thalassemia", section on 'Ineffective erythropoiesis'.)

Ineffective erythropoiesis is also seen in megaloblastic anemias such as anemia due to vitamin B12 or folate deficiency; however, the underlying condition is usually treated before significant iron accumulation can occur. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Hematopoiesis'.)

In contrast, sickle cell disease and autoimmune hemolytic anemias are not associated with ineffective erythropoiesis; in these anemias, hemolysis primarily affects mature RBCs in the peripheral circulation rather than RBC precursors in the bone marrow. Individuals with these disorders can develop transfusional iron overload, but they are not at increased risk of iron overload attributable to their hemolytic anemia.

Ineffective erythropoiesis leads to increased intestinal iron absorption by an incompletely understood mechanism [4-9]. Elevated erythroferrone, produced by RBC precursors, suppresses hepcidin production, although the exact mechanism is poorly understood [4-10]. The functions of these proteins are discussed in more detail separately. (See "Regulation of iron balance" and "Regulation of erythropoiesis".)

Liver disease — A number of acute and chronic liver disorders are associated with inflammation and a subsequent increase in acute phase reactants, including ferritin. In addition, the liver is a major site for iron storage in the body, and any process that damages liver cells has the potential to release storage iron into the circulation, leading to an increase in ferritin [2,11]. In some cases, there is also increased iron absorption and increased iron deposition in the liver, although typically not to the extent seen in individuals with HH. Examples include neonatal hemochromatosis due to maternal alloantibodies and a number of chronic liver diseases in adults:

GALD – Gestational alloimmune liver disease (GALD; also called neonatal hemochromatosis or neonatal iron storage disease) is a rare disorder that occurs when maternal alloantibodies cross the placenta and cause injury to the fetal liver, leading to severe liver failure and/or cirrhosis in the newborn. Hepatic and extrahepatic iron deposition is often seen, but this deposition is a consequence of liver injury, not a cause. This condition is discussed separately. (See "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)'.)

Alcoholic liver disease – Alcoholic liver disease may be associated with increased stainable iron in the liver. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

Chronic liver diseases – Other chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD), chronic viral hepatitis, porphyria cutanea tarda (PCT), or chronic hepatitis from other causes may also lead to increased liver iron. In patients with chronic liver diseases including alcoholic liver disease, viral hepatitis, or PCT, phlebotomy improves the iron deposition. In PCT, phlebotomy also improves the underlying pathogenesis of the disease related to impaired heme biosynthesis. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Central importance of iron in PCT'.)

The mechanism of increased iron absorption in liver disease is incompletely understood but is likely caused by decreased hepcidin production in the diseased liver [12,13].

As noted above, some individuals with iron overload secondary to liver disease may also have a genetic component such as an HFE mutation(s) that contributes to increased iron absorption, sometimes exacerbating the liver injury. In other cases, it may not be clear which came first, liver disease or iron overload. In others, the severity of the initial liver injury may be challenging to determine (eg, unclear amount or duration of excess alcohol intake). These issues provide the rationale for performing genetic testing for HH in some cases. (See 'Post-diagnostic testing' below.)

Rare causes — Less common causes of iron overload include the following:

Increased intake due to an iron-loaded diet such as in African iron overload (also called Bantu syndrome or Bantu siderosis), in which homemade beer contains excess iron leached from iron barrels. In addition, there are rare occurrences of presumed genetic iron overload in African and African American populations [14].

Increased intake due to administration of hemin to treat certain porphyrias.

Increased intake due to multiple infusions of intravenous iron in patients with renal failure [15].

Increased accidental intake, as in unintentional childhood intake of the mother's prenatal vitamin with iron, or intentional excessive ingestion in attempted suicide.

Increased absorption due to ineffective erythropoiesis in rare inherited anemias such as congenital dyserythropoietic anemia.

Increased absorption caused by rare mutations in iron-regulatory proteins such as ferroportin, hemojuvelin, hepcidin, ceruloplasmin, or transferrin receptor 2.

CONSEQUENCES OF EXCESS IRON STORES

Organ damage from reactive oxygen species — As the body content of iron (iron burden) increases beyond that needed for normal production of red blood cells, muscle cells, and iron-containing enzymes, the plasma iron-binding protein transferrin becomes saturated, eventually exceeding its capacity and resulting in binding of iron to other proteins and molecules, including albumin, citrate, acetate, and others. This iron is referred to as non-transferrin-bound iron (NTBI); it begins to appear once the transferrin saturation exceeds 35 percent and rises significantly with transferrin saturation above 70 percent [16,17]. NTBI is taken up by cells that have active uptake mechanisms such as the L-type calcium channel. This includes parenchymal cells of the liver, heart, and endocrine organs.

In these affected organs, excess iron can chemically interact with hydrogen peroxide, acting as a Fenton reagent and catalyzing the Haber-Weiss reactions [18]:

          H2O2  +  Fe(2+)   —>   OH-  +  Fe(3+)  +  OH● (hydroxyl radical)
          O2- (superoxide anion)  +  Fe (3+)   —>   O2  +  Fe(2+)

           SUM: H2O2  +  O2-   —>   O2  +  OH-  +  OH●

These reactive oxygen species in turn can cause tissue damage, inflammation, and fibrosis [18,19]. The liver, heart, joints, and endocrine organs appear to be especially susceptible. By the time clinical findings have developed (hepatic fibrosis, heart failure, cardiac conduction defect), it is likely that significant iron deposition and tissue injury has occurred. (See 'Typical clinical findings' below.)

Some of the toxicity of iron may be abrogated by the body's antioxidant defenses such as glutathione-S-transferase (GST) [20]. Genetic variants in the GST system that modulate the clinical manifestations of iron toxicity in individuals with iron overload are under investigation [21,22].

Typical clinical findings — Iron overload may be suspected in the following settings (see 'Overview of causes' above):

Family history of hereditary hemochromatosis (HH)

Multiple red blood cell transfusions for anemia other than iron deficiency

Unexplained organ damage such as liver disease, cardiac disease, endocrine disease

Incidental finding of increased serum ferritin or increased transferrin saturation (TSAT)

Excess total body iron (several grams or more) will cause organ damage. Typical manifestations include one or more of the following:

Hepatic involvement with biochemical abnormalities in liver function, inflammation, fibrosis, and eventually cirrhosis

Cardiac involvement with cardiomyopathy, heart failure, and/or arrhythmias

Pancreatic involvement with diabetes mellitus

Pituitary and gonadal involvement with hypogonadism, decreased libido, and impotence

Skin involvement with hyperpigmentation (the bronze color in "bronze diabetes")

Joint involvement with arthropathy, especially involving the second and third metacarpophalangeal joints, and often with chondrocalcinosis

Evaluation for iron overload is often part of the evaluation for individuals with unexplained organ dysfunction, especially liver, heart, gonadal dysfunction (see 'Differential diagnosis' below). The relative likelihood of iron overload versus other causes of organ dysfunction depends on a number of factors that affect the likelihood of possible diagnoses, including patient age, family history, other symptoms, and other comorbidities. As examples, iron overload is more likely to be a cause of organ damage in middle aged males or postmenopausal females, those with a family history of hemochromatosis, and those with a history of transfusions, and less likely in younger individuals or those with a personal or family history that suggests another etiology.

When testing for iron overload in these settings, iron studies are the most appropriate initial test, since genetic testing is only indicated if the iron studies are consistent with iron overload. If iron studies suggest or confirm iron overload, then genetic testing for HFE mutation(s) is indicated. (See 'Sequence and interpretation of testing' below and 'Post-diagnostic testing' below.)

SEQUENCE AND INTERPRETATION OF TESTING

Overview of approach — The evaluation for suspected iron overload differs depending on the clinical setting, as discussed in the following sections (algorithm 1) [2,23]. In addition to a thorough clinical evaluation, all patients with suspected iron overload should have the following laboratory tests (see 'CBC, LFTs, and iron studies' below):

Complete blood count (CBC) with red blood cell (RBC) indices

Iron studies including serum ferritin and transferrin saturation

Metabolic panel including hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST])

Testing for the common hereditary hemochromatosis (HH) mutations (HFE C282Y and H63D) is an appropriate initial step in individuals with a family history of HH. HFE mutation testing is also appropriate in most individuals with documented iron overload as a means of determining the genetic contribution. This is true even in individuals with an acquired cause of iron overload such as liver disease, because there may also be a genetic component in addition to the acquired condition. (See 'Post-diagnostic testing' below.)

Other testing such as magnetic resonance imaging (MRI) or liver biopsy with iron staining are generally limited to individuals with laboratory evidence of iron overload, in order to estimate total body iron stores, or in those for whom there is diagnostic confusion, in order to definitively establish or exclude the presence of increased tissue iron. (See 'Noninvasive imaging (MRI)' below and 'Other tests for selected individuals' below.)

Our approach is consistent with clinical guidelines published by a number of groups [24-28].

Of note, some of the studies used to diagnose iron overload are also extremely useful for monitoring the progress of phlebotomy or iron chelation to treat iron overload; these uses are discussed in separate topic reviews. (See "Management and prognosis of hereditary hemochromatosis" and "Iron chelators: Choice of agent, dosing, and adverse effects" and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

CBC, LFTs, and iron studies — The CBC and iron studies are interpreted together, because the presence of anemia (and type) influences the evaluation:

A normal CBC with increased ferritin and transferrin saturation is suggestive of hemochromatosis (eg, HH). If anemia is present, the diagnosis cannot be HH in isolation (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Microcytic anemia with increased ferritin and transferrin saturation is strongly suggestive of thalassemia. Transfusion-dependent thalassemia (TDT, also known as thalassemia major) or non-transfusion-dependent thalassemia (NTDT, also known as thalassemia intermedia) may be associated with substantial iron overload, which may be greater in those with a history of transfusions but may also be present in the absence of transfusions due to ineffective erythropoiesis leading to increased iron absorption. (See 'Ineffective erythropoiesis' above and "Diagnosis of thalassemia (adults and children)".)

Normocytic anemia with increased ferritin suggests anemia of chronic inflammation (also called anemia of chronic disease), which may have increased ferritin without increased total body iron stores or rarely may be associated with iron overload from other causes. (See "Anemia of chronic disease/anemia of inflammation".)

Macrocytic anemia with increased ferritin and/or transferrin saturation suggests that there is an underlying cause of anemia such as hemolysis or megaloblastic anemia (eg, due to vitamin B12 deficiency). (See "Macrocytosis/Macrocytic anemia".)

Polycythemia with increased ferritin and/or transferrin saturation suggests a primary or secondary process leading to increased production of RBCs. Secondary erythrocytosis may be caused by hypoxia (eg, lung or heart disease) or increased erythropoietin production (eg, liver or kidney disease). Primary erythrocytosis is caused by increased proliferation of erythroid cells in the bone marrow (eg, polycythemia vera or other myeloproliferative neoplasm [MPN]). MPNs are often associated with increased ferritin levels in the setting of transfusional iron overload, but MPNs are not associated with total body iron overload in the absence of transfusions. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

Liver function tests (LFTs) are often helpful, because iron studies are more likely to be abnormal in individuals with liver disease regardless of the total body iron burden, and the absence of liver disease eliminates this as a possible cause of abnormal iron studies. This has been illustrated in studies that show a poor correlation between iron studies and total body iron burden in individuals with liver disease of various causes [29].

Routine iron studies include serum iron, transferrin (also reported as total iron binding capacity [TIBC]), and ferritin; the transferrin saturation (TSAT) is calculated as the ratio of serum iron to TIBC and expressed as a percentage (TSAT = iron ÷ TIBC x 100). The results most useful for evaluating iron overload are the ferritin and TSAT, both of which are elevated in iron overload [26]:

Ferritin – The normal range for ferritin in plasma or serum is approximately 40 to 200 ng/mL (40 to 200 mcg/L; 89.9 to 449.4 picomoles/L). A ferritin level ≥200 to 300 ng/mL (≥200 to 300 mcg/L) in a man or ≥150 to 200 ng/mL (≥150 to 200 mcg/L) in a woman is consistent with iron overload, and a level below these values is good evidence that the patient does not have iron overload. Typically, ferritin levels in iron overload are in the range of up to 2000 to 3000 ng/mL (mcg/L) but may be even higher if iron overload is causing severe liver disease or cardiomyopathy; if the individual has received a large number of transfusions, ferritin may also be higher.

Elevated serum ferritin is a sensitive test for iron overload, but it is not very specific, because numerous conditions other than iron overload can lead to elevations in serum ferritin [2]. Ferritin is an acute phase reactant that increases in the setting of infection or inflammation. Ferritin can also be elevated in patients with liver disease. It is important to distinguish these other causes of abnormally high ferritin in order to avoid unnecessary invasive testing and/or delays in treatment. (See 'Differential diagnosis' below.)

In individuals with transfusional iron overload, there is some correlation between the ferritin level and the total body iron burden (eg, individuals with a ferritin in the range of 500 to 1000 ng/mL are unlikely to have severe iron overload; those with ferritin in the range of 3000 to 4000 ng/mL may have substantial iron burden), but there is a relatively high discordance between individuals and between measurements for the same individual [11]. It is the author's observation (BB) that the correlation between iron stores and ferritin levels is only reliable up to a ferritin level of 3000 to 4000 ng/mL [30]. Observational studies have generally found some weak correlations between ferritin and iron burden assessed by other measures (eg, liver biopsy, therapeutic phlebotomy), but results are mixed, and sensitivity and specificity are in the range of 60 to 80 percent [31-38].

The correlation of ferritin level and liver iron concentration does not correlate as linearly in individuals with a component of non-transfusional iron overload (eg, ineffective erythropoiesis). In addition, the correlation is generally worse in regularly transfused patients with sickle cell disease (SCD) compared with thalassemia, though high ferritin levels (above 3000 ng/mL) and low ferritin levels (below 1000 ng/mL) generally correlate with high and low liver iron concentration, respectively.

TSAT – A high TSAT (≥45 percent in males or ≥40 percent in females; refer to the laboratory's reference range) may be seen in patients with iron overload [2]; a TSAT below these levels is good evidence that the patient does not have iron overload, even if the ferritin is elevated. If TSAT is not provided by the laboratory, it can be calculated (calculator 1).

An increased TSAT may precede an increased ferritin, and rarely, a person may have an isolated increased TSAT without overt iron overload or organ damage, especially in a younger adult. An elevated TSAT with a normal ferritin suggests that the individual is at risk for, or in the early stages of, iron overload. Such individuals are likely to benefit from further monitoring to determine whether the TSAT normalizes or the ferritin increases. (See 'Organ damage from reactive oxygen species' above.)

There are several factors that may confound ferritin and TSAT measurements, including diet and comorbidities, especially liver disease [23,39]. Ferritin and TSAT can be elevated in liver disease because dying hepatocytes release storage iron into the circulation and alcohol may suppress hepcidin synthesis, leading to increased intestinal iron absorption. TSAT may be increased in liver disease caused by excess alcohol because alcohol suppresses liver transferrin synthesis. As noted above, ferritin is also an acute phase reactant. Thus, it is ideal to obtain at least two independent measurements. There is no simple algorithm to follow when the ferritin and TSAT are discordant; the clinical context determines the likely interpretation and the subsequent approach. Hematology consultation may be appropriate in these cases.

If the patient is in the midst of an acute infection or inflammation, it may be prudent to delay iron studies testing until the acute event has resolved, or if the studies have already been performed, to repeat them after the acute event has resolved, rather than pursuing more aggressive testing for iron overload such as MRI. An exception is suspected hemophagocytic lymphohistiocytosis, for which elevated ferritin is one of the diagnostic criteria. If it is not clear whether the patient has an acute infection or inflammatory process, then the C-reactive protein (CRP) can be checked. A normal CRP is inconsistent with inflammation or infection and in most cases eliminates these as an explanation for the increased ferritin.

Some clinicians prefer to use fasting samples for iron studies. This is not supported by data from clinical studies, but it is not unreasonable to use at least one fasting sample, especially in individuals with a borderline result or discordance between clinical and laboratory findings [26]. For an individual with increased ferritin in the setting of an ongoing inflammatory process such as malignancy, diabetes, or connective tissue disease, other testing is likely to be needed to determine whether there is total body iron overload (eg, MRI, course of phlebotomy, biopsy).

Additional information about iron studies including iron studies measurements used to evaluate iron deficiency are discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

Noninvasive imaging (MRI) — Noninvasive imaging studies such as magnetic resonance imaging (MRI) using T2*, R2, and R2* measurements have become increasingly accurate for determining both hepatic as well as cardiac iron deposition and have generally supplanted direct tissue biopsy for assessing the presence of iron overload and quantifying its severity (image 1).

We routinely use combined liver and cardiac MRI to confirm iron overload and measure its extent in individuals with increased serum ferritin and transferrin saturation (algorithm 1). This is especially true for those with thalassemia and other severe, transfusion-dependent anemias such as Diamond-Blackfan anemia. Imaging of both the liver and heart is important because iron accumulation is not uniform. If the clinical history strongly suggests a cause of iron overload such as implicated HFE mutations, multiple RBC transfusions (eg, more than 20 to 30 units, for any indication), or non-transfusion-dependent thalassemia in the absence of transfusions, then a ferritin value above the upper limit of normal with a transferrin saturation above 45 percent is an appropriate threshold for performing MRI.

Liver MRI – A liver iron concentration (LIC) estimated by MRI >3 mg Fe/g dry weight (equivalent to approximately 53 to 125 micromol/g dry weight) indicates the presence of hepatic iron overload. Generally a LIC of over 5 to 7 is used to indicate the need for treatment. Estimation of LIC and details of the methods are presented separately. (See "Methods to determine hepatic iron content", section on 'Magnetic resonance imaging'.)

Cardiac MRI – A cardiac T2* by MRI <20 milliseconds (normal: >20 milliseconds) indicates the presence of cardiac iron overload [40]. Values <10 milliseconds have been associated with severe myocardial iron loading and high risk of the development of cardiac failure and/or arrhythmias. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

Other tissues – MRI of other tissues (eg, pancreas, pituitary gland) has been reported in individuals with known iron overload but is not routinely used to diagnose iron overload [23,41].

MRI assessment of liver and cardiac iron is very useful for transfusional iron overload. The usefulness of MRI for other disorders is mixed, and results must be interpreted in the clinical context. A 2015 systematic review and meta-analysis of liver MRI to determine iron overload in individuals with hereditary hemochromatosis (20 studies; 819 patients) found substantial heterogeneity of studies, with significant risk of bias and variable sensitivity and specificity; the authors concluded that a negative liver MRI was sufficient to exclude iron overload [42]. The threshold value for the presence of iron overload was also inconsistent, ranging from 2 to 15 mg of iron by gram of liver dry weight. The authors considered a value of 7 mg of iron per gram of liver dry weight (equivalent to approximately 125 micromol/gram of dry weight) to indicate iron overload. However, as noted above, other experts including UpToDate authors use a lower threshold, especially in individuals with known HFE gene mutation or transfusional iron overload. When following changes in liver iron concentration over time with MRI, the same technique should be used (eg, R2 or R2*), as systematic differences between the two techniques exist [43].

High diagnostic accuracy has been reported using a superconducting quantum interference device (SQUID) [23,44-46]. However, this test is not routinely used because it requires a specialized instrument not available in most institutions.

Computed tomography (CT) scanning has also been used to assess liver iron content (image 2). However, CT involves radiation exposure, and dual-energy scans are required to compensate for background attenuation [11]. CT is thus reserved for individuals who require an imaging study but do not have access to MRI [47].

The degrees of hepatic and myocardial iron overload may be discordant in an individual patient; this subject is discussed in depth separately. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

Other tests for selected individuals

Liver biopsy — Liver biopsy is considered by some experts to be the gold standard for determining increased total body iron stores. Others consider the response to phlebotomy to be a better measure, although this cannot be done in all patients. (See 'Response to phlebotomy' below.)

Liver biopsy may be especially useful for those who do not have access to MRI, those with evidence of liver injury, those with concomitant viral hepatitis, in the pre-hematopoietic stem cell transplant (pre-HSCT) setting, and in any cases where it is important to assess liver histology. The majority of patients do not require a liver (or other) biopsy since noninvasive MRI estimation of iron stores is highly effective for estimating iron burden. Occasionally, liver or endomyocardial biopsy done for histologic diagnosis will reveal iron overload.

We generally reserve liver biopsy for individuals who require precise estimation of liver iron burden and/or concurrent assessment of liver histology. Examples include individuals with elevated hepatic enzymes and a very high ferritin (eg, >1000 ng/mL [>1000 mcg/L]) in whom it is not clear which came first, individuals with thalassemia prior to HSCT with concern for hepatic fibrosis, or those with other causes of liver injury for whom the severity of iron overload and extent of liver injury are unclear from other testing. This practice is consistent with a 2011 guideline from the American Association for the Study of Liver Diseases (AASLD) [26]. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis", section on 'Liver biopsy' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Estimation of iron stores'.)

Liver tissue can be analyzed for hepatic iron content (HIC; also called liver iron content [LIC]). The upper limit of normal for HIC has been variously given as 25 to 32 micromol of iron per gram (equivalent to approximately 1.4 to 1.8 mg/g) of liver dry weight, with any value >2 mg/g being considered abnormal. This procedure is discussed separately. (See "Methods to determine hepatic iron content", section on 'Hepatic iron concentration'.)

In a series of patients with transfusion-dependent beta thalassemia who had undergone hematopoietic cell transplantation followed by phlebotomy to remove excess iron, there was a strong linear correlation between HIC measured from liver biopsy and total body iron overload based on phlebotomy [48]. The authors were able to determine that total body iron stores (in mg of iron per kg of body weight) equaled approximately 10.6 times the HIC (in mg of iron per gram of dry liver weight) (figure 1). Thus, a 70 kg individual with a HIC of 7 mg/gram of liver weight would have a total body iron burden of approximately 5 grams. (See "Methods to determine hepatic iron content".)

Liver iron can also be estimated semi-quantitatively using a histologic stain for iron (Perls' Prussian blue staining) (picture 1A-B). For individuals who undergo liver biopsy, the specimen can also be evaluated for the degree of liver injury, inflammation, and fibrosis/cirrhosis [48].

There is a potential for sampling variability with any biopsy-based testing, which is especially likely in individuals with cirrhosis or patchy liver injury. (See "Interpretation of nontargeted liver biopsy findings in adults" and "Histologic scoring systems for chronic liver disease".)

Response to phlebotomy — Response to therapeutic phlebotomy is considered by some experts to be the gold standard for determining total body iron stores [48]. Phlebotomy is only possible in individuals who do not have significant anemia at baseline. Information about the response to phlebotomy can also be highly useful in individuals for whom the presence or degree of iron overload is unclear or those who do not have access to MRI. In iron overload, the ferritin level will decline as iron is removed. Others use liver biopsy with quantitation of liver iron content. (See 'Liver biopsy' above.)

Phlebotomy can only be safely performed in individuals who do not have significant anemia or other comorbidities that would prevent them from tolerating the procedure. Typical settings for phlebotomy are individuals with hereditary hemochromatosis or individuals with transfusional iron overload who undergo treatments to correct their anemia and thus can tolerate phlebotomy (eg, people with SCD treated with exchange transfusion; or people with thalassemia, SCD, aplastic anemia, or myelodysplastic syndrome who have undergone hematopoietic stem cell transplantation [HSCT] and are no longer severely anemic). In these individuals, we generally use noninvasive methods to assess iron stores (eg, ferritin, TSAT, liver MRI) and correlate these results with the number of phlebotomies that can be performed before the patient becomes iron deficient. However, if there is no access to these noninvasive tests, serial phlebotomies with assessment of the number of units of blood removed is a reasonable alternative for determining the total body iron burden.

Each phlebotomy of 500 mL of whole blood will remove approximately 200 to 250 mg of elemental iron. Thus, an individual with total body iron stores of 5 grams (corresponding to a liver iron content of 7 mg/g dry weight) would require approximately 20 phlebotomies to reach an iron deficient state. We typically perform phlebotomy of 500 mL of blood one to two times per week until the patient's hemoglobin has fallen to approximately 12 g/dL, the red blood cells have become slightly microcytic (mean corpuscular volume [MCV] approximately 75 to 80 fL), and the transferrin saturation and ferritin are below normal (<15 percent and <20 ng/mL, respectively), and then calculate the iron burden from the number of phlebotomies [49]. The schedule and monitoring of therapeutic phlebotomy is discussed in more detail separately. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores' and "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

Endomyocardial biopsy — Endomyocardial biopsy may be appropriate in individuals with heart failure or conduction defects in an individual with elevated cardiac iron on MRI or those who do not have access to cardiac MRI. In rare cases, cardiac biopsy done for other indications may reveal iron overload that was not expected. (See "Endomyocardial biopsy".)

For all other patients, cardiac MRI is the preferred method for assessing cardiac iron deposition. (See 'Noninvasive imaging (MRI)' above.)

DIAGNOSIS — The diagnosis of iron overload may be made by one or more of the following findings [11,23,40,41,47,50-56]:

Increased serum or plasma ferritin (≥200 to 300 ng/mL [≥200 to 300 mcg/L] in a man; ≥150 to 200 ng/mL [≥150 to 200 mcg/L] in a woman) in a patient without significant inflammation or infection and with increased transferrin saturation (TSAT; ≥45 percent). Of note, ferritin and TSAT typically are repeated, although there are no data regarding whether repeat values are needed, and the diagnosis is typically confirmed by imaging studies (to quantify the degree of overload) and/or response to phlebotomy or chelation therapy. (See 'CBC, LFTs, and iron studies' above and 'Post-diagnostic testing' below.)

Evidence of iron overload by MRI of the liver or heart. A liver iron concentration (LIC) estimated by MRI >3 mg iron per gram of dry liver weight is consistent with hepatic iron overload. A cardiac T2* by MRI <20 milliseconds (normal: >20 milliseconds) is consistent with cardiac iron overload. (See 'Noninvasive imaging (MRI)' above.)

Evidence of iron overload on tissue biopsy (requires iron stain). Levels of hepatic iron >2 mg/g dry weight is consistent with hepatic iron overload. (See 'Liver biopsy' above.)

Removal of iron with a course of therapeutic phlebotomy, typically in the range of ≥1.5 to 2 grams (at least five to six phlebotomies) with normalization of the ferritin level. (See 'Response to phlebotomy' above.)

As noted below, MRI, biopsy, or a course of phlebotomy are generally required to provide an estimate of the extent of the total body iron burden. There are not good data comparing findings from MRI with those from liver biopsy in the same patient [53,57,58]. Additional testing (eg, genetic testing for HFE mutations) is needed to determine the underlying cause in individuals who do not have known transfusional iron overload or known ineffective erythropoiesis. (See 'Post-diagnostic testing' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of iron overload includes other causes of elevated serum ferritin levels and other causes of liver, cardiac, or endocrine dysfunction.

Other causes of high ferritin

Acute illnesses with hemophagocytosis – Certain acute illnesses can cause very high ferritin levels due to hemophagocytosis (table 2). Examples include hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), HIV infection, and certain cancers. Unlike iron overload, these conditions cause a rapid, acute, and extremely high ferritin level along with other manifestations of disease including fevers, cytopenias, and other worrisome findings.

HLH – Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening inflammatory condition in which excessive immune activation leads to tissue destruction and acute systemic illness; it can occur in children and adults. In HLH and the related macrophage activation syndrome (MAS; associated with underlying rheumatologic/connective tissue disease), the ferritin is often extremely high, in the range of 5000 to 20,000 ng/mL (or even higher) and the presentation is often acute severe illness with fever, hepatosplenomegaly, rash, neurologic findings, and pancytopenia. Like iron overload, there may be liver and cardiac involvement. Unlike iron overload, patients with HLH are acutely ill with fever, cytopenias, neurologic findings, and abnormal coagulation studies. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)

HIV infection – Infection with human immunodeficiency virus (HIV) can cause high ferritin levels independent of iron status, especially if there is advanced disease, low CD4 count, and opportunistic infection such as histoplasmosis or tuberculosis [59-63]. Like iron overload, there may be liver involvement. Unlike iron overload, these individuals are often acutely ill with fever, cytopenias, and evidence of infection. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

Chronic inflammatory conditions – In inflammatory conditions (eg, metabolic syndrome, diabetes, Still's disease), ferritin may be increased as an acute phase reactant [39,64,65]. Like iron overload, the ferritin is above normal and the patient may have nonspecific symptoms such as fatigue. Unlike iron overload, in most inflammatory states the degree of ferritin elevation does not exceed two to three times normal, the transferrin saturation (TSAT) typically does not exceed 45 percent, and there are other features of the clinical picture or signs of inflammation such as increased C-reactive protein (CRP) and other acute phase reactants. This was illustrated in a 2012 population-based case-control study of 766 middle-aged adult outpatients in which 329 met criteria for metabolic syndrome [66]. Compared with controls, the individuals with metabolic syndrome had higher ferritin levels and higher CRP, but similar transferrin receptor (reflective of similar TSAT values). (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)" and "Acute phase reactants".)

Liver injury – In liver disease (eg, viral hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis), injury to hepatocytes may cause an increase in serum ferritin despite normal total body iron stores. Alcohol can be hepatotoxic at levels of consumption as low as one to two drinks per day. Like iron overload, there may be increased transaminases and jaundice. Unlike iron overload, in liver disease, total liver iron (as estimated by MRI or measured by liver biopsy) is not increased, and therapeutic phlebotomy would not improve the ferritin level. Importantly, iron overload can cause liver disease, and each can exacerbate the other. Thus, the presence of liver disease does not exclude the possibility of iron overload, and the presence of iron overload does not exclude the possibility of underlying liver disease. (See "Approach to the patient with abnormal liver biochemical and function tests" and "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis", section on 'When to consider alcohol-associated liver disease'.)

Malignancy – Malignancy can be associated with increased ferritin; in some cases ferritin levels can be extremely high. This was illustrated in a 2015 publication that evaluated the cause of a ferritin level >50,000 ng/mL (mcg/L) in a series of 113 adults at a single institution [30]. Of these, 36 (32 percent) had a hematologic malignancy and 5 (4 percent) had a solid tumor.

Rare genetic conditions – Several variants affecting the ferritin light chain (FTL) have been described that cause elevated serum ferritin without systemic iron overload, referred to as "benign hyperferritinemia" [67]. We generally do not test for this since it does not affect patient management, which includes assessment for tissue iron and attention to other causes of high ferritin such as alcoholic liver disease or non-alcoholic steatohepatitis. Testing might be used in the rare individual with no other cause of elevated ferritin who is concerned about the finding and/or who wishes to avoid additional testing in the future.

The hereditary hyperferritinemia-cataract syndrome can cause exceedingly high serum ferritin levels (often >1000 ng/mL) without tissue iron overload, in association with bilateral congenital cataracts. This disorder, which has been termed "hereditary hyperferritinemia-cataract syndrome" is inherited in an autosomal dominant manner and appears to involve a number of different mutations in the iron responsive element of FTL [68-71]. A direct relationship between the degree of hyperferritinemia and the severity of cataracts suggests that the latter is a consequence of excessive ferritin production within the lens fibers [72].

Other cause of organ dysfunction

Other causes of liver disease – Other causes of liver disease include a number of inherited and acquired conditions. Like liver disease secondary to iron overload, there may be increased transaminases, liver inflammation, or, in later stages, liver fibrosis/cirrhosis. As discussed above, these conditions are often associated with elevated ferritin, because the liver is the major site for iron storage and liver damage will cause ferritin to be released into the circulation. (See 'Other causes of high ferritin' above.)

Other causes of heart disease, diabetes, or hypogonadism – There are numerous other causes of heart disease, diabetes, hypogonadism, and other organ dysfunction. Like iron overload, these may occur gradually and present with nonspecific symptoms such as fatigue. Unlike iron overload, these conditions are not associated with evidence of increased iron stores on noninvasive imaging or biopsy. The need for this testing depends on the specific clinical scenario, as discussed in separate topic reviews. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Classification of diabetes mellitus and genetic diabetic syndromes" and "Causes of secondary hypogonadism in males".)

POST-DIAGNOSTIC TESTING — Two major issues that need to be addressed once iron overload is documented (or strongly suspected) are the extent of iron overload and severity of tissue damage, which determines the need for and urgency of therapeutic interventions; and diagnosing the underlying cause(s) of iron overload so that it can be addressed with a long-term treatment plan. (See 'Determining the extent and severity' below and 'Determining the cause(s)' below.)

This post-diagnostic testing to determine the severity and cause(s) of iron overload applies to patients with documented iron overload. Testing for HFE mutations in asymptomatic first-degree relatives of individuals with hereditary hemochromatosis is addressed separately. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)

Determining the extent and severity — The degree of iron overload can be determined from a combination of the serum ferritin level, noninvasive (MRI) imaging, and in some cases tissue biopsy and/or response to a course of therapeutic phlebotomy. As noted above, liver iron is not necessarily predictive of cardiac iron burden. Thus, cardiac MRI is appropriate in individuals with significant transfusional iron overload or significant iron overload from hereditary hemochromatosis, as well as those with heart failure or cardiac conduction abnormalities [27,73]. (See 'Sequence and interpretation of testing' above and 'Noninvasive imaging (MRI)' above.)

For individuals with transfusional iron overload, the number of transfusions should be tracked as this can also be incorporated into risk estimates. (See 'Transfusional iron overload' above.)

The degree of iron overload that causes organ damage varies among patients. However, as a general rule, total body iron stores above 5 grams and liver iron concentration >7 mg per gram of dry liver weight are associated with an increased risk of iron-induced complications such as hepatic fibrosis and diabetes. In individuals with transfusional iron overload, this corresponds to approximately 20 to 30 transfusions (fewer in those with thalassemia, who have abnormally high iron uptake as well). Liver iron concentrations >15 mg per gram of dry liver weight are associated with a substantial risk for hepatic fibrosis, cardiac disease, and increased mortality [11].

Additional testing to characterize organ damage is listed in the table (table 3).

Determining the cause(s) — Causes of iron overload are listed in the accompanying table (table 1). Many of these will have already been diagnosed and/or be obvious from a routine history and physical examination and basic laboratory studies such as a complete blood count and liver function studies.

Individuals with hereditary hemochromatosis (HH) may have a family history of the disorder, but the absence of a family history does not eliminate the possibility of HH, because HH almost always has a recessive mode of inheritance and many otherwise healthy carriers are unaware of their genetic status. Moreover, the common form of this genetic disorder has low clinical penetrance and therefore is likely to be underdiagnosed.

Regardless of whether an individual is initially diagnosed with an inherited or acquired cause of iron overload, the possibility of other causes of iron overload should also be addressed. As an example, a common scenario is an individual with increased ferritin and/or transferrin saturation in the setting of excess alcohol use and liver disease [74]. In such individuals, it may be difficult to assess the amount of alcohol intake, the degree of total body iron overload, and the contribution of other factors such as HFE status. If there is concomitant cirrhosis and/or gastrointestinal bleeding, these estimations may be even more difficult (cirrhosis may affect the distribution of hepatic iron deposition; bleeding may decrease total body iron stores).

These cases require an individualized approach. The following may be helpful:

Testing for HFE variants should be performed if there is any doubt about the possibility of a contribution of HH to excess iron stores. This includes all adults with iron overload not due to transfusions, and some individuals with transfusional iron overload, especially if the iron burden appears to be out of proportion to the number of transfusions administered. The importance of HFE mutation testing was examined in a study involving 132 individuals with liver disease who underwent HFE mutation testing; of these, 45 (34 percent) had HFE mutations and 6 (5 percent) were homozygous for C282Y, the classical form of HH, with the rest having mutations of lower or marginal significance [75].

Testing for the two common mutations (C282Y and H63D) is relatively inexpensive; homozygosity for C282Y strongly supports a component of iron overload; compound heterozygosity for C282Y/H63D confirms a likely contribution of iron overload in the appropriate setting (eg, middle aged adult); and negative results essentially eliminate the possibility of HH. The likelihood of iron overload with these and other genotypes is discussed separately. (See "HFE and other hemochromatosis genes".)

Treatment for HH with phlebotomy is low-risk and can greatly reduce the risk of life-threatening organ toxicity. Individuals who are heterozygous for a single HFE mutation or homozygous for H63D have a lower risk of iron overload but may require serial monitoring. (See "Management and prognosis of hereditary hemochromatosis".)

Repeating iron studies after an acute illness has resolved, especially infection or inflammatory condition, may give a more accurate result and may reduce the need for unnecessary additional testing. However, this may not be possible in cases of chronic inflammatory conditions such as diabetes or metabolic syndrome.

If there is doubt about the degree or cause of iron overload, therapeutic phlebotomy to estimate the total iron stores may be useful in establishing the cause, because significant iron overload in the absence of transfusion is strongly suggestive of a hereditary component. Most individuals with uncomplicated alcoholic liver disease have <4 grams of mobilizable iron, whereas individuals with symptomatic HH typically have ≥5 grams.

HFE mutation testing has become widely available. Listings of testing laboratories can be accessed online through the Genetic Testing Registry (www.ncbi.nlm.nih.gov/gtr/).

Interpretation of HFE genotypes, additional testing for rare HH mutations in those with a strong suspicion of HH who test negative for the common mutations, and appropriate management are listed in the table and discussed in detail separately. (See "Management and prognosis of hereditary hemochromatosis" and "HFE and other hemochromatosis genes", section on 'Rare HFE variants' and "HFE and other hemochromatosis genes", section on 'Non-HFE hemochromatosis'.)

TREATMENT — The majority of individuals with iron overload should be treated, to prevent end-organ damage. Rare exceptions may include those with only modest iron overload who would be unable or unwilling to tolerate therapy.

The major treatments for iron overload include phlebotomy for those without significant anemia, and chelation therapy for those with anemia. In some cases, chelation therapy may be deferred until the underlying anemia is treated (eg, after hematopoietic stem cell transplantation [HSCT] for aplastic anemia). These subjects are discussed in detail separately:

Phlebotomy – (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores' and "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

Exchange transfusions in sickle cell disease – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

Chelation therapy – (See "Iron chelators: Choice of agent, dosing, and adverse effects" and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

Individuals with iron overload should also be educated to avoid inadvertent iron intake (eg, from multivitamins containing iron) and to avoid hepatotoxic medications and alcohol. However, individuals with iron overload should follow a healthy diet and should not feel compelled to avoid red meat or other iron-containing foods. (See "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Addressing concerns about dietary iron'.)

Blood transfusions should be administered as needed; however, unnecessary transfusions should be avoided. (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)

In some cases it may be possible to reduce transfusions by using other methods to treat anemia. Examples include:

Erythropoiesis-stimulating agents in renal failure (see "Treatment of anemia in nondialysis chronic kidney disease")

Exchange transfusion in sickle cell disease (see "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion')

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemochromatosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hemochromatosis (The Basics)")

Beyond the Basics topics (see "Patient education: Hereditary hemochromatosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Mechanisms and causes – There are no physiologic mechanisms to eliminate iron from the body when it is present in excess. Major causes of iron overload include blood transfusion and increased uptake of dietary iron, which may be due to hereditary hemochromatosis (HH); syndromes of ineffective erythropoiesis such as beta thalassemia, sideroblastic anemia, or certain other inherited anemias; and liver disease, especially alcoholic liver disease and chronic hepatitis (table 1). (See 'Normal iron stores' above and 'Causes of iron overload' above.)

Clinical manifestations – Excess iron can lead to the product of reactive oxygen species that can cause tissue damage, inflammation, and fibrosis. The liver, heart, joints, skin, and endocrine organs appear to be especially susceptible. Individuals with clinically significant iron overload will have increased serum ferritin and transferrin saturation (TSAT). (See 'Consequences of excess iron stores' above.)

Evaluation – In addition to a thorough clinical evaluation, all patients with suspected iron overload should have a complete blood count (CBC) and iron studies including ferritin and TSAT. Liver function testing is often helpful. A low or normal serum ferritin or TSAT is helpful in eliminating the possibility of iron overload. Higher values are consistent with iron overload but are not particularly specific, and additional testing is often indicated (algorithm 1). (See 'Sequence and interpretation of testing' above.)

Diagnosis – The diagnosis of iron overload may be suspected by one or more of the following findings (see 'Diagnosis' above):

Increased serum ferritin (≥200 to 300 ng/mL [≥200 to 300 mcg/L] in males, ≥150 to 200 ng/mL [≥150 to 200 mcg/L] in females) in a patient without significant inflammation and increased TSAT (≥45 percent in males; ≥40 percent in females). Often we repeat these measurements. An increased TSAT may precede an increased ferritin, and rarely, a person may have an isolated increased TSAT without overt iron overload or organ damage, especially in a younger adult. This finding suggests increased risk for iron overload or early stages of iron overload and warrants close monitoring. (See 'CBC, LFTs, and iron studies' above.)

Evidence of iron overload by MRI of the liver (liver iron concentration >3 mg per gram of dry liver weight) or heart (cardiac T2* by MRI <20 milliseconds). (See 'Noninvasive imaging (MRI)' above.)

Evidence of iron overload on tissue iron stain. (See 'Liver biopsy' above.)

Removal of iron with a course of therapeutic phlebotomy (at least five to six phlebotomies) with normalization of the ferritin level. (See 'Response to phlebotomy' above.)

Differential diagnosis – The differential diagnosis of iron overload includes inflammatory conditions, liver disease, and malignancy (table 2). Other conditions that may be associated with an extremely high ferritin level include hemophagocytic lymphohistiocytosis (HLH); human immunodeficiency virus (HIV) infection, especially when the CD4 count is low and there is an opportunistic infection; and cancer, especially hematologic malignancies. (See 'Differential diagnosis' above.)

Post-diagnostic testing – Patients diagnosed with iron overload should have an assessment of the total body iron burden (by liver MRI or biopsy) and organ damage (table 3). The cause of iron overload should be determined, keeping in mind that there may be multiple causes. HFE mutation testing should be performed in all adults with iron overload not due to transfusions, and some individuals with transfusional iron overload, especially if the iron burden appears to be out of proportion to the number of transfusions administered. (See 'Post-diagnostic testing' above and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Testing family members – Testing for HFE mutations in asymptomatic first-degree relatives of individuals with HH is addressed separately. (See "Management and prognosis of hereditary hemochromatosis", section on 'Testing and counseling first-degree relatives'.)

Management – The major treatments for iron overload include phlebotomy for those without significant anemia, and chelation therapy for those with anemia. These are discussed in separate topic reviews. (See "Iron chelators: Choice of agent, dosing, and adverse effects" and "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores' and "Management and prognosis of hereditary hemochromatosis" and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

ACKNOWLEDGMENTS — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, and William C Mentzer, MD, to earlier version of this and many other topic reviews.

  1. Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003; 101:3359.
  2. Cullis JO, Fitzsimons EJ, Griffiths WJ, et al. Investigation and management of a raised serum ferritin. Br J Haematol 2018; 181:331.
  3. Acton RT, Barton JC, Passmore LV, et al. Accuracy of family history of hemochromatosis or iron overload: the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol 2008; 6:934.
  4. Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology Am Soc Hematol Educ Program 2013; 2013:1.
  5. Ginzburg Y, Rivella S. β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood 2011; 118:4321.
  6. Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med 2014; 20:398.
  7. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13:1096.
  8. Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood 2014; 124:479.
  9. Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014; 46:678.
  10. Gupta R, Musallam KM, Taher AT, Rivella S. Ineffective Erythropoiesis: Anemia and Iron Overload. Hematol Oncol Clin North Am 2018; 32:213.
  11. Wood JC. Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program 2014; 2014:210.
  12. Pietrangelo A. Iron and the liver. Liver Int 2016; 36 Suppl 1:116.
  13. Hörl WH, Schmidt A. Low hepcidin triggers hepatic iron accumulation in patients with hepatitis C. Nephrol Dial Transplant 2014; 29:1141.
  14. Gordeuk VR. African iron overload. Semin Hematol 2002; 39:263.
  15. Ghoti H, Rachmilewitz EA, Simon-Lopez R, et al. Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron. Eur J Haematol 2012; 89:87.
  16. Piga A, Longo F, Duca L, et al. High nontransferrin bound iron levels and heart disease in thalassemia major. Am J Hematol 2009; 84:29.
  17. Coates TD. Physiology and pathophysiology of iron in hemoglobin-associated diseases. Free Radic Biol Med 2014; 72:23.
  18. Hebbel RP. Auto-oxidation and a membrane-associated 'Fenton reagent': a possible explanation for development of membrane lesions in sickle erythrocytes. Clin Haematol 1985; 14:129.
  19. Le Lan C, Loréal O, Cohen T, et al. Redox active plasma iron in C282Y/C282Y hemochromatosis. Blood 2005; 105:4527.
  20. Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 1999; 31:273.
  21. Berhane K, Widersten M, Engström A, et al. Detoxication of base propenals and other alpha, beta-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases. Proc Natl Acad Sci U S A 1994; 91:1480.
  22. Stickel F, Osterreicher CH, Datz C, et al. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis. Arch Intern Med 2005; 165:1835.
  23. Jensen PD. Evaluation of iron overload. Br J Haematol 2004; 124:697.
  24. Wells RA, Leber B, Buckstein R, et al. Iron overload in myelodysplastic syndromes: a Canadian consensus guideline. Leuk Res 2008; 32:1338.
  25. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008; 93:741.
  26. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328.
  27. Ho PJ, Tay L, Lindeman R, et al. Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias. Intern Med J 2011; 41:516.
  28. Remacha A, Sanz C, Contreras E, et al. Guidelines on haemovigilance of post-transfusional iron overload. Blood Transfus 2013; 11:128.
  29. Chapman RW, Morgan MY, Laulicht M, et al. Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis. Dig Dis Sci 1982; 27:909.
  30. Schram AM, Campigotto F, Mullally A, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood 2015; 125:1548.
  31. Brittenham GM, Cohen AR, McLaren CE, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993; 42:81.
  32. Harmatz P, Butensky E, Quirolo K, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 2000; 96:76.
  33. Puliyel M, Sposto R, Berdoukas VA, et al. Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. Am J Hematol 2014; 89:391.
  34. Pakbaz Z, Fischer R, Fung E, et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer 2007; 49:329.
  35. Panch SR, Yau YY, West K, et al. Initial serum ferritin predicts number of therapeutic phlebotomies to iron depletion in secondary iron overload. Transfusion 2015; 55:611.
  36. Conte D, Manachino D, Colli A, et al. Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus. Ann Intern Med 1998; 128:370.
  37. Karam LB, Disco D, Jackson SM, et al. Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels. Pediatr Blood Cancer 2008; 50:62.
  38. Hamidieh AA, Moeininia F, Tayebi S, et al. Efficacy of hepatic T2* MRI values and serum ferritin concentration in predicting thalassemia major classification for hematopoietic stem cell transplantation. Pediatr Transplant 2015; 19:301.
  39. Goot K, Hazeldine S, Bentley P, et al. Elevated serum ferritin - what should GPs know? Aust Fam Physician 2012; 41:945.
  40. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001; 22:2171.
  41. Noetzli LJ, Coates TD, Wood JC. Pancreatic iron loading in chronically transfused sickle cell disease is lower than in thalassaemia major. Br J Haematol 2011; 152:229.
  42. Sarigianni M, Liakos A, Vlachaki E, et al. Accuracy of magnetic resonance imaging in diagnosis of liver iron overload: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015; 13:55.
  43. Wood JC, Pressel S, Rogers ZR, et al. Liver iron concentration measurements by MRI in chronically transfused children with sickle cell anemia: baseline results from the TWiTCH trial. Am J Hematol 2015; 90:806.
  44. Brittenham GM, Sheth S, Allen CJ, Farrell DE. Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease. Semin Hematol 2001; 38:37.
  45. Fischer R, Longo F, Nielsen P, et al. Monitoring long-term efficacy of iron chelation therapy by deferiprone and desferrioxamine in patients with beta-thalassaemia major: application of SQUID biomagnetic liver susceptometry. Br J Haematol 2003; 121:938.
  46. Busca A, Falda M, Manzini P, et al. Iron overload in patients receiving allogeneic hematopoietic stem cell transplantation: quantification of iron burden by a superconducting quantum interference device (SQUID) and therapeutic effectiveness of phlebotomy. Biol Blood Marrow Transplant 2010; 16:115.
  47. Wood JC, Mo A, Gera A, et al. Quantitative computed tomography assessment of transfusional iron overload. Br J Haematol 2011; 153:780.
  48. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000; 343:327.
  49. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med 1993; 328:1616.
  50. Ooi GC, Khong PL, Chan GC, et al. Magnetic resonance screening of iron status in transfusion-dependent beta-thalassaemia patients. Br J Haematol 2004; 124:385.
  51. Gandon Y, Olivié D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363:357.
  52. Alústiza JM, Artetxe J, Castiella A, et al. MR quantification of hepatic iron concentration. Radiology 2004; 230:479.
  53. St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105:855.
  54. Wood JC, Otto-Duessel M, Aguilar M, et al. Cardiac iron determines cardiac T2*, T2, and T1 in the gerbil model of iron cardiomyopathy. Circulation 2005; 112:535.
  55. Wood JC, Enriquez C, Ghugre N, et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 2005; 106:1460.
  56. Hankins JS, McCarville MB, Loeffler RB, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood 2009; 113:4853.
  57. St Pierre TG, Clark PR, Chua-Anusorn W. Measurement and mapping of liver iron concentrations using magnetic resonance imaging. Ann N Y Acad Sci 2005; 1054:379.
  58. St Pierre TG, El-Beshlawy A, Elalfy M, et al. Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration. Magn Reson Med 2014; 71:2215.
  59. Lee MH, Means RT Jr. Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance. Am J Med 1995; 98:566.
  60. Kirn DH, Fredericks D, McCutchan JA, et al. Serum ferritin levels correlate with disease activity in patients with AIDS and disseminated histoplasmosis. Clin Infect Dis 1995; 21:1048.
  61. Gupta S, Imam A, Licorish K. Serum ferritin in acquired immune deficiency syndrome. J Clin Lab Immunol 1986; 20:11.
  62. McKenzie SW, Means RT Jr. Extreme hyperferritinemia in patients infected with human immunodeficiency virus is not a highly specific marker for disseminated histoplasmosis. Clin Infect Dis 1997; 24:519.
  63. Visser A, van de Vyver A. Severe hyperferritinemia in Mycobacteria tuberculosis infection. Clin Infect Dis 2011; 52:273.
  64. Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145:657.
  65. Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117:1155.
  66. Hämäläinen P, Saltevo J, Kautiainen H, et al. Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study. Cardiovasc Diabetol 2012; 11:116.
  67. Kannengiesser C, Jouanolle AM, Hetet G, et al. A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload. Haematologica 2009; 94:335.
  68. Girelli D, Corrocher R, Bisceglia L, et al. Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene. Blood 1997; 90:2084.
  69. Arnold JD, Mumford AD, Lindsay JO, et al. Hyperferritinaemia in the absence of iron overload. Gut 1997; 41:408.
  70. Hetet G, Devaux I, Soufir N, et al. Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 2003; 102:1904.
  71. Cazzola M. Hereditary hyperferritinaemia/ cataract syndrome. Best Pract Res Clin Haematol 2002; 15:385.
  72. Cazzola M, Bergamaschi G, Tonon L, et al. Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA. Blood 1997; 90:814.
  73. Ware HM, Kwiatkowski JL. Evaluation and treatment of transfusional iron overload in children. Pediatr Clin North Am 2013; 60:1393.
  74. LeSage GD, Baldus WP, Fairbanks VF, et al. Hemochromatosis: genetic or alcohol-induced? Gastroenterology 1983; 84:1471.
  75. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999; 130:953.
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