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Iron overload

Iron overload, also known as hemochromatosis in its hereditary form or hemosiderosis in secondary cases, is a disorder in which the body accumulates excessive amounts of iron, primarily in organs such as the liver, heart, and pancreas, potentially leading to severe tissue damage, organ dysfunction, and life-threatening complications if not managed.^[1] This condition arises when iron absorption from the diet exceeds the body's needs or when iron is retained from repeated blood transfusions, resulting in total body iron stores that can surpass 20 grams in advanced cases, far above the normal range of 3-4 grams in men and 2-3 grams in women.^[1] Chronic iron overload promotes the generation of reactive oxygen species through the Fenton reaction, causing oxidative stress, fibrosis, and cellular injury in affected tissues.^[2] Iron overload can be classified into primary and secondary types based on etiology. Primary iron overload, most commonly hereditary hemochromatosis (HH), stems from genetic mutations—predominantly in the HFE gene (e.g., C282Y homozygosity)—that impair the hormone hepcidin's regulation of intestinal iron absorption, leading to unchecked uptake of dietary iron.^[3] HH is the most prevalent genetic disorder among individuals of Northern European descent, affecting about 1 in 200 to 300 people, though penetrance varies and not all carriers develop clinical disease.^[4] Secondary iron overload, in contrast, results from acquired factors such as frequent blood transfusions in patients with thalassemia, sickle cell disease, or myelodysplastic syndromes; excessive oral iron supplementation; or chronic liver conditions like alcoholic liver disease and nonalcoholic fatty liver disease that disrupt normal iron homeostasis.^[1] Rare causes include juvenile hemochromatosis due to mutations in HJV or HAMP genes, or ferroportin disease from SLC40A1 variants, which affect iron export from cells.^[5] Symptoms of iron overload often manifest gradually and nonspecifically, particularly in early stages, with many individuals remaining asymptomatic until significant organ involvement occurs. Common early signs include chronic fatigue, arthralgia (especially in the metacarpophalangeal joints), abdominal pain, and loss of libido or erectile dysfunction in men.^[6] As iron deposits accumulate, characteristic features emerge such as bronze hyperpigmentation of the skin, hepatomegaly, and cardiac arrhythmias.^[5] Complications are primarily driven by end-organ damage and include cirrhosis and hepatocellular carcinoma (increasing liver cancer risk up to 200-fold in advanced HH), diabetes mellitus (bronze diabetes), congestive heart failure, hypogonadism, and arthropathy; without intervention, mortality rates can exceed 50% by age 50 in symptomatic cases.^[7] Women are often protected until post-menopause due to menstrual blood loss, explaining a later age of onset compared to men.^[4] Diagnosis of iron overload relies on a combination of clinical evaluation, biochemical testing, imaging, and genetic analysis to confirm excess iron and identify the underlying cause. Initial screening involves measuring serum transferrin saturation (typically >45% in HH) and serum ferritin levels (>300 μg/L in men or >200 μg/L in women indicating overload), with elevated values prompting further investigation. Genetic testing for HFE mutations confirms hereditary forms, while liver biopsy or MRI for hepatic iron quantification assesses severity and fibrosis in ambiguous cases; non-invasive options like superconducting quantum interference device (SQUID) magnetometry provide precise total body iron measurements.^[1] Early detection through family screening or population programs, such as those targeting high-risk groups, is crucial to prevent progression.^[4] Treatment strategies aim to reduce iron burden, alleviate symptoms, and prevent complications, with approaches tailored to the type and severity of overload. For primary iron overload, therapeutic phlebotomy—weekly removal of 500 mL of blood to deplete 200-250 mg of iron per session—is the cornerstone, continuing until ferritin normalizes and then as maintenance therapy every 2-3 months. Iron chelators like deferoxamine, deferasirox, or deferiprone are preferred for secondary overload in transfusion-dependent patients, as they bind and excrete excess iron via urine or feces, though they carry risks of renal toxicity and gastrointestinal side effects.^[1] Supportive measures include avoiding iron-rich foods, vitamin C supplements (which enhance absorption), and alcohol; in advanced cases, organ-specific interventions like chelation for cardiomyopathy or hormone replacement for hypogonadism may be necessary.^[8] With timely treatment, life expectancy approaches normal, underscoring the importance of screening and adherence.^[3]

Clinical features

While clinical features are similar across iron overload disorders, secondary forms often show earlier cardiac and endocrine involvement compared to the gradual hepatic and joint predominance in primary forms such as hereditary hemochromatosis.^[9]

Symptoms

Iron overload, particularly in hereditary forms such as hemochromatosis, often presents with an insidious onset of symptoms that develop gradually over decades due to progressive iron accumulation in tissues.^[5] For hereditary hemochromatosis, symptoms typically emerge in men during their 40s and in women after age 60 or post-menopause, as menstrual iron loss delays manifestation in premenopausal women.^[6] Early symptoms are nonspecific and commonly include chronic fatigue, generalized weakness, and arthralgia, with joint pain frequently affecting the hands (particularly the second and third metacarpophalangeal joints) and knees.^[5]^[10] Abdominal pain is another frequent early complaint, often vague and related to hepatic involvement.^[6] As the condition advances, symptoms become more pronounced and organ-specific. Patients may report impotence and loss of libido in men, while women can experience amenorrhea alongside diminished sexual interest.^[5]^[6] Pancreatic involvement may lead to diabetes mellitus, presenting with symptoms such as increased thirst, frequent urination, and unexplained weight loss.^[5] Unintentional weight loss often accompanies these reproductive complaints, reflecting systemic metabolic disruptions.^[4] Complaints of skin hyperpigmentation, such as a darkening or bronze appearance, may also arise in advanced stages, though these are subjective reports of perceived changes.^[5] In severe cases involving cardiac deposition, patients describe palpitations or irregular heartbeats attributable to cardiomyopathy.^[11]

Signs

In iron overload disorders such as hereditary hemochromatosis, dermatological signs often include bronze or gray hyperpigmentation of the skin, resulting from deposition of iron (hemosiderin) and increased melanin production in dermal macrophages and basal keratinocytes.^[12]^[13] This pigmentation is typically most prominent in sun-exposed areas, such as the face, neck, and dorsal hands, though it may also appear in non-exposed regions like the oral mucosa or genitalia in advanced cases.^[7]^[14] Advanced hepatic involvement in iron overload can manifest as palpable hepatomegaly due to iron accumulation and fibrosis in the liver parenchyma, with splenomegaly occasionally present secondary to portal hypertension in cirrhotic patients.^[7] These abdominal findings are detectable on physical examination as firm, enlarged organs below the costal margins, particularly in untreated or longstanding disease.^[15] Arthropathy in hereditary hemochromatosis frequently presents with objective joint swelling and tenderness, most characteristically affecting the second and third metacarpophalangeal joints, though the proximal interphalangeal joints, wrists, hips, and knees may also be involved.^[7]^[16] Physical examination may reveal boggy synovitis, reduced range of motion, and crepitus, often mimicking inflammatory arthritis without the systemic features of rheumatoid disease.^[17] Cardiac manifestations of iron overload cardiomyopathy include detectable arrhythmias, such as atrial fibrillation or conduction abnormalities, audible on auscultation or via pulse irregularity, particularly in patients with significant myocardial iron deposition.^[7]^[18] In advanced cases, signs of heart failure may be evident, including jugular venous distension, peripheral edema, and a third heart sound, reflecting dilated cardiomyopathy with systolic dysfunction.^[19]^[20] Endocrine signs related to iron-induced hypogonadism include gynecomastia in men, presenting as palpable breast tissue enlargement due to pituitary dysfunction and altered sex hormone metabolism. In women, signs of hypogonadism may include amenorrhea and atrophy of secondary sexual characteristics. Hypothyroidism may present with goiter or bradycardia.^[7]^[21] Other examinable features may encompass testicular atrophy and loss of secondary sexual hair in men, though these are less specific and often accompany chronic liver disease.^[21]

Etiology

Primary causes

Primary causes of iron overload encompass genetic disorders that disrupt normal iron absorption and regulation, leading to progressive accumulation in tissues without external influences such as transfusions. The most prevalent form is hereditary hemochromatosis (HH), an autosomal recessive disorder primarily caused by mutations in the HFE gene on chromosome 6, which normally helps regulate iron uptake in the intestines.^[22] The C282Y mutation, particularly in homozygous form, is the most common variant, resulting in unchecked intestinal iron absorption due to impaired signaling to reduce hepcidin, the key hormone that limits iron entry into the bloodstream.^[23] H63D is another frequent mutation, though it typically requires compound heterozygosity with C282Y to confer significant risk.^[5] HH type 1 (HFE-related) predominates in populations of Northern European descent, where the disorder has a prevalence of about 1 in 200-400 individuals, though clinical penetrance varies widely.^[24]^[25] Non-HFE forms of HH, classified as types 2 through 4, arise from mutations in genes directly involved in hepcidin regulation or iron export, often presenting with more severe or atypical phenotypes. Type 2 (juvenile hemochromatosis) results from biallelic mutations in HJV (hemojuvelin) or HAMP (hepcidin antimicrobial peptide), leading to profound hepcidin deficiency and rapid iron overload typically manifesting before age 30, with prominent cardiac and endocrine involvement.^[26] Type 3, caused by TFR2 (transferrin receptor 2) mutations, disrupts hepcidin sensing of iron levels, resulting in intermediate-severity overload similar to HFE-HH but with earlier onset in some cases.^[27] These rare variants collectively account for less than 5% of HH cases and are identified through genetic testing when HFE mutations are absent.^[28] African iron overload, also known as Bantu siderosis, represents a distinct genetic predisposition to excessive iron absorption, primarily observed in sub-Saharan African populations and differing from classical HH by lacking HFE mutations. It involves a polygenic susceptibility, potentially including variants in ferroportin (SLC40A1), combined with environmental factors like consumption of iron-rich fermented beverages, leading to hepatic and pancreatic deposition.^[29] This condition is not strictly monogenic but highlights how genetic backgrounds can amplify dietary iron uptake independently of HFE pathways.^[30]

Secondary causes

Secondary iron overload arises from acquired conditions that lead to excessive iron accumulation through increased absorption, frequent transfusions, or impaired regulatory mechanisms, in contrast to primary genetic forms driven by hereditary defects in iron handling.^[9]^[31] Disorders involving ineffective erythropoiesis, such as thalassemia major and sickle cell disease, often necessitate regular blood transfusions, which introduce substantial iron loads. Each unit of packed red blood cells, typically containing 200-300 mL of blood, delivers approximately 200-250 mg of iron that cannot be excreted by normal physiological means.^[32]^[33] In these patients, cumulative transfusions over time result in progressive iron deposition, particularly when therapy begins early in life.^[34] Chronic liver diseases, including alcoholic cirrhosis and viral hepatitis, contribute to secondary iron overload by disrupting hepcidin production, the key regulator that inhibits intestinal iron absorption and promotes export from cells. This impairment leads to reduced iron export from hepatocytes and increased uptake, exacerbating hepatic iron stores.^[35]^[31] Iatrogenic causes are prominent in conditions like aplastic anemia and myelodysplastic syndromes, where repeated blood transfusions are required to manage anemia, mirroring the iron burden seen in ineffective erythropoiesis disorders. Overuse of parenteral iron supplementation, such as intravenous iron formulations, can also precipitate overload in patients receiving excessive doses beyond therapeutic needs.^[33]^[36] Dietary excess remains a rare but notable cause, observed in regions of sub-Saharan Africa where traditional home-brewed beer, fermented in iron-rich steel containers, can contain up to 80 mg of iron per liter and lead to chronic high intake when consumed in large volumes. Abuse of oral iron supplements in otherwise healthy individuals can similarly result in overload, though this is uncommon without predisposing factors.^[29]^[37]^[9] Porphyria cutanea tarda is associated with mild to moderate iron overload, where elevated hepatic iron levels contribute to the disorder's pathogenesis, often requiring iron depletion as part of management.^[38]^[39]

Pathophysiology

Iron homeostasis disruption

Iron homeostasis maintains a delicate balance to meet physiological needs while preventing toxicity from excess accumulation. The liver-derived hormone hepcidin plays a central role by binding to ferroportin, the sole known iron exporter on the surface of enterocytes and macrophages, inducing its internalization and degradation.^[40] This interaction limits intestinal iron absorption to approximately 1-2 mg per day, matching daily losses through desquamation, minor bleeding, and, in premenopausal women, menstrual blood.^[41] Under normal conditions, dietary iron is reduced to ferrous form (Fe²⁺) by duodenal cytochrome b (Dcytb), taken up into enterocytes via the divalent metal transporter 1 (DMT1), and exported into circulation via ferroportin, where it binds to transferrin for transport.^[42] In primary iron overload disorders, such as hereditary hemochromatosis, hepcidin levels are inappropriately low due to disruptions involving HFE, leading to unchecked ferroportin activity.^[43] This results in unregulated duodenal iron uptake through DMT1 and excessive export via ferroportin, causing progressive iron accumulation.^[44] Consequently, transferrin becomes fully saturated, and non-transferrin-bound iron (NTBI) emerges in plasma, representing a highly reactive, redox-active form capable of catalyzing oxidative damage.^[45] Secondary iron overload, often from repeated transfusions or ineffective erythropoiesis, disrupts homeostasis differently, with altered macrophage handling of iron. Macrophages, which recycle iron from senescent red blood cells via phagocytosis, exhibit increased iron export due to suppressed hepcidin levels and preserved ferroportin activity in conditions like ineffective erythropoiesis, contributing to systemic iron overload when combined with transfusional iron load.^[46] Iron balance is governed by the equation: iron balance = absorption - losses, where chronic absorption exceeding 1 mg/day—unmitigated by factors like menstrual losses in women—leads to overload.^[47] This imbalance ultimately promotes NTBI-mediated toxicity in organs such as the liver and heart.^[1]

Organ-specific damage

Excess iron accumulation in tissues triggers oxidative stress primarily through the Fenton reaction, where ferrous iron (\ce{Fe^{2+}}) reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals:

\ce{Fe^{2+} + H2O2 -> Fe^{3+} + OH^\bullet + OH^-}

These radicals damage cellular components, including DNA, proteins, and lipids, via peroxidation and other oxidative modifications.^[48] In the liver, iron overload promotes fibrosis and progression to cirrhosis through lipid peroxidation of hepatocyte membranes and activation of hepatic stellate cells, which deposit extracellular matrix.^[49] This chronic damage significantly elevates the risk of hepatocellular carcinoma, estimated at up to 200-fold in hereditary hemochromatosis patients with cirrhosis compared to the general population.^[50] Cardiac involvement manifests as dilated cardiomyopathy due to iron deposition in mitochondria, impairing respiratory chain function and leading to systolic dysfunction with reduced left ventricular ejection fraction.^[51] Mitochondrial iron overload exacerbates reactive oxygen species production, contributing to myocyte apoptosis and contractile impairment.^[52] Endocrine tissues are vulnerable to iron infiltration, particularly in the pituitary and gonads, resulting in hypogonadotropic hypogonadism characterized by impaired gonadotropin secretion and reduced libido or amenorrhea.^[7] Pancreatic iron deposition disrupts beta-cell function, causing diabetes mellitus often termed "bronze diabetes" due to concurrent skin pigmentation changes from iron excess.^[53] Joint pathology arises from iron-induced inflammation in the synovium, where excess iron polarizes macrophages toward a pro-inflammatory M1 phenotype, mimicking osteoarthritis with cartilage degradation and pain.^[54] Synovial iron overload accelerates extracellular matrix breakdown and osteoarthritic features in affected metacarpophalangeal and knee joints.^[55]

Diagnosis

Laboratory evaluation

Laboratory evaluation of iron overload primarily involves noninvasive blood tests to assess iron status, storage, and potential organ involvement, serving as the cornerstone for initial screening, diagnosis, and monitoring in at-risk individuals.^[1] These tests focus on quantifying circulating iron, its binding capacity, and storage proteins, with results interpreted in the context of clinical history to differentiate true overload from confounding factors like inflammation or chronic disease.^[24] Serum ferritin, a marker of total body iron stores, is a key initial test; levels exceeding 1000 ng/mL strongly suggest significant iron overload, though elevations can occur nonspecifically due to inflammation, infection, or liver disease as ferritin functions as an acute-phase reactant.^[1] Normal ranges are typically 20-300 ng/mL for men and 20-200 ng/mL for women, with values below 30 ng/mL indicating depleted stores in the absence of inflammation.^[24] In hereditary hemochromatosis, ferritin often rises progressively with advancing age and iron accumulation, guiding therapeutic endpoints during management.^[56] Transferrin saturation (TSAT), calculated as (serum iron divided by total iron-binding capacity [TIBC]) multiplied by 100, provides insight into iron transport and is particularly sensitive for early detection; a fasting TSAT greater than 45% is suggestive of overload, especially when combined with elevated ferritin.^[1] Serum iron levels are typically elevated in overload states, while TIBC remains normal or decreased, resulting in low unsaturated iron-binding capacity (UIBC), which reflects reduced available binding sites on transferrin.^[24] Fasting samples are preferred for TSAT to minimize diurnal variations and postprandial influences on accuracy.^[56] Additional markers enhance diagnostic specificity. The soluble transferrin receptor (sTfR) level is useful for distinguishing iron overload from anemia of chronic disease, as sTfR remains normal or low in overload but elevates in functional iron deficiency despite adequate stores.^[57] Liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are often monitored concurrently, with elevations indicating hepatic damage from iron deposition, though normal levels do not exclude overload.^[56] Screening protocols in at-risk populations, such as those with family history or symptoms suggestive of hereditary hemochromatosis, recommend initiating with TSAT measurement due to its sensitivity, followed by ferritin if TSAT exceeds 45%; abnormal results may prompt further genetic evaluation.^[24] In secondary overload, such as from transfusions, serial ferritin monitoring tracks response to chelation therapy, targeting levels below 1000 ng/mL to mitigate risks.^[1]

Genetic testing

Genetic testing plays a crucial role in diagnosing hereditary forms of iron overload, particularly hereditary hemochromatosis (HH), by identifying pathogenic variants in genes regulating iron homeostasis. The primary approach involves targeted genotyping of the HFE gene, most commonly using polymerase chain reaction (PCR)-based methods to detect the C282Y (c.845G>A; p.Cys282Tyr) and H63D (c.187C>G; p.His63Asp) variants, which account for the majority of HFE-related HH cases in populations of European descent. These tests are typically performed on individuals with biochemical evidence of iron overload, such as elevated transferrin saturation or serum ferritin levels. C282Y homozygosity (C282Y/C282Y) is associated with the highest risk, representing 82-90% of clinically diagnosed HH cases, though penetrance is incomplete and varies; recent estimates (as of 2025) indicate penetrance of approximately 10–25% in men and lower (∼1–10%) in women for developing significant iron overload (serum ferritin >300 µg/L in men or >200 µg/L in women), varying by population and modifiers such as polygenic risk scores.^[23]^[22]^[58] For cases suspected to be non-HFE-related HH, especially in younger patients or those without HFE variants, next-generation sequencing (NGS) panels are employed to analyze a broader set of iron metabolism genes. These panels often include genes such as HJV (hemojuvelin), which is implicated in juvenile hemochromatosis (type 2A HH), characterized by severe iron overload with onset typically before age 30 years and rapid progression to organ damage if untreated. Homozygous or compound heterozygous HJV mutations are the most common cause of this subtype, leading to markedly reduced hepcidin expression and profound iron accumulation. NGS enables comprehensive detection of rare variants across multiple genes, including TFR2, HAMP, and SLC40A1, offering higher diagnostic yield in atypical presentations compared to single-gene testing.^[28]^[59]^[60] Interpretation of results requires consideration of genotype-phenotype correlations and modifiers. Compound heterozygosity for C282Y/H63D confers a milder phenotype with low clinical penetrance, estimated at less than 2% risk of developing symptomatic iron overload, though iron indices may subtly elevate in some individuals. Penetrance differences by sex are notable, with men exhibiting higher rates of iron accumulation and clinical manifestations than women, partly due to menstrual blood loss and hormonal influences. According to the American College of Gastroenterology (ACG) clinical guidelines, genetic testing is recommended for probands with suspected HH and cascade screening of first-degree relatives of confirmed cases to enable early intervention; such testing is particularly cost-effective in high-prevalence populations of Northern European ancestry.^[61]^[62]^[63] As of 2025, advances in genetic risk assessment include the integration of polygenic risk scores (PRS) that incorporate multiple common variants beyond HFE, such as those in TMPRSS6 and TF, to refine predictions of iron overload severity in C282Y homozygotes. Studies from large cohorts like the UK Biobank demonstrate that higher PRS significantly modulates penetrance, increasing the odds of liver fibrosis or cirrhosis in at-risk individuals, thereby enhancing personalized screening and monitoring strategies. These tools are increasingly applied in research settings to identify environmental and genetic interactions influencing disease expression.^[64]^[65]

Histological confirmation

Histological confirmation of iron overload typically involves liver biopsy, which provides direct evidence of iron deposition in hepatocytes and Kupffer cells, as well as assessment of associated liver damage such as fibrosis or cirrhosis.^[66] The procedure is most commonly performed percutaneously under ultrasound guidance, where a needle is inserted through the skin to obtain a core sample of liver tissue; alternatively, transjugular biopsy is used in patients with coagulopathy, ascites, or obesity, accessing the liver via the jugular vein and hepatic vein.^[67]^[68] Once obtained, the biopsy specimen is stained with Perls' Prussian blue to visualize hemosiderin iron deposits as blue granules, allowing semiquantitative grading on a 0-4+ scale based on the extent and distribution of staining: 0 indicates no visible iron, 1+ is minimal (trace granules), 2+ mild (few granules in zone 1 hepatocytes), 3+ moderate (prominent in most hepatocytes), and 4+ severe (dense staining filling cells and extending to bile ducts).^[69]^[70] Grades greater than 3+ signify severe overload and correlate with higher risk of organ damage.^[66] In addition to staining, biochemical analysis of the biopsy measures hepatic iron concentration (HIC), expressed in μmol/g dry weight, with values exceeding 36 μmol/g indicate iron overload, with normal levels typically 5–36 μmol/g dry weight. The hepatic iron index (HII), calculated as HIC divided by the patient's age in years, helps differentiate hereditary hemochromatosis, with values greater than 1.9 suggestive of the condition when genetic testing is unavailable or inconclusive.^[71]^[72]^[73] While magnetic resonance imaging (MRI) can estimate HIC non-invasively to guide biopsy site selection, liver biopsy remains the gold standard for quantifying iron and evaluating fibrosis staging, often using the METAVIR score (F0-F4), where F3-F4 indicates advanced fibrosis or cirrhosis.^[74] Biopsy is indicated particularly when serum ferritin exceeds 1000 ng/mL, transferrin saturation is elevated, and chelation therapy is under consideration, as it helps confirm parenchymal iron overload and guides treatment decisions.^[73]^[75] Biopsies from other sites, such as bone marrow, are rarely performed for iron overload diagnosis but may reveal macrophage siderosis (iron-laden macrophages) in cases of secondary overload, such as from chronic transfusions, contrasting with the hepatocyte-predominant pattern in primary hereditary forms.^[76]^[77] Despite its diagnostic value, liver biopsy carries risks including bleeding (0.3-0.6% major complications), pain, and infection, and is subject to sampling error due to heterogeneous iron distribution, leading to its declining use in favor of advanced non-invasive methods.^[78]^[79]

Imaging techniques

Magnetic resonance imaging (MRI) serves as the primary non-invasive modality for quantifying iron overload in the liver, utilizing R2* relaxometry to measure transverse relaxation rates that inversely correlate with hepatic iron concentration (LIC). This technique allows calibration of R2* values to LIC in mg/g dry weight, with a cutoff of >3.2 mg/g indicating significant iron overload, enabling early detection and monitoring without biopsy.^[80] Similarly, cardiac MRI with T2* mapping assesses myocardial iron deposition, where values <20 ms signify overload and predict the development of cardiomyopathy, guiding timely intervention in at-risk patients.^[81] MRI also evaluates iron distribution in extrapancreatic organs such as the pancreas and spleen through signal intensity ratios relative to skeletal muscle or subcutaneous fat, revealing deposition patterns characteristic of underlying etiologies. In hereditary hemochromatosis (HH), hepatic-predominant overload typically shows reduced pancreatic signal intensity due to parenchymal iron accumulation, while the spleen remains relatively spared with normal signal, contrasting with secondary overloads like thalassemia where both organs exhibit marked hypointensity.^[82] Abdominal ultrasound is commonly employed as an initial screening tool to detect hepatomegaly or signs of cirrhosis, such as irregular liver contours or portal hypertension, in patients suspected of iron overload, though it lacks sensitivity for directly quantifying iron content.^[83] Computed tomography (CT) is infrequently utilized for iron assessment owing to ionizing radiation exposure, but it can identify siderotic nodules—iron-laden regenerative or dysplastic lesions in cirrhotic livers—as hyperdense foci, aiding in the differentiation of complications.^[84] As of 2025, quantitative susceptibility mapping (QSM) MRI emerges as a promising advancement for precise evaluation of brain iron in neurological variants of iron overload, such as neuroferritinopathy, by mapping magnetic susceptibility differences to delineate paramagnetic iron deposits with higher specificity than traditional R2* methods.^[85] These imaging approaches correlate well with histological findings for validation, though they emphasize repeatable non-invasive monitoring.^[80]

Management

Phlebotomy

Phlebotomy, also known as venesection, is the cornerstone of treatment for iron overload in hereditary hemochromatosis, involving the regular removal of blood to deplete excess iron stores. This procedure mimics natural iron loss and is preferred as the first-line therapy due to its safety, efficacy, and low cost when patients are suitable candidates.^[86] The standard procedure entails the weekly removal of approximately 500 mL of blood, which eliminates about 250 mg of iron per session, with treatment continuing until serum ferritin levels fall below 50 ng/mL. Hemoglobin levels are monitored prior to each session to ensure they remain above 11-12.5 g/dL, and electrolytes are checked periodically to manage potential imbalances from volume depletion. The induction phase typically lasts 1-2 years, depending on the initial iron burden, after which patients transition to maintenance phlebotomy every 2-4 months to sustain ferritin below 50-100 ng/mL and transferrin saturation (TSAT) below 50%.^[87] Phlebotomy is contraindicated in patients with anemia (hemoglobin <11 g/dL), congestive heart failure, or active infection, as these conditions increase procedural risks. Close monitoring is essential during treatment to adjust frequency and prevent complications such as hypotension or fatigue. When initiated before the onset of cirrhosis or diabetes, phlebotomy normalizes life expectancy in patients with hereditary hemochromatosis by preventing organ damage from iron accumulation. Sustained efficacy requires high compliance with the regimen, as incomplete adherence can lead to recurrent iron overload and reduced benefits.^[88] As the mainstay treatment since the 1950s, phlebotomy revolutionized management of hereditary hemochromatosis following early demonstrations of its ability to reduce iron stores without toxicity. It remains highly cost-effective, with sessions costing approximately $136-365, making it accessible for long-term use.^[89] In transfusion-dependent cases, phlebotomy serves as an adjunct to other therapies when feasible.^[90]

Chelation therapy

Chelation therapy involves the use of pharmacological agents that bind to excess iron in the body, forming complexes that are excreted primarily through urine or feces, and is particularly indicated for patients with iron overload who cannot undergo phlebotomy due to anemia or other contraindications. While phlebotomy remains the preferred initial treatment for iron removal in suitable patients, chelation provides an essential alternative for maintaining iron balance in transfusion-dependent conditions or hereditary hemochromatosis with poor venous access.^[91] Deferoxamine, the first-line parenteral iron chelator, is administered via subcutaneous infusion at doses of 20-60 mg/kg body weight over 8-12 hours per day, typically 5-7 days per week, promoting iron excretion through both urinary and fecal routes. This regimen effectively reduces hepatic and cardiac iron stores but is associated with poor patient compliance due to the inconvenience of prolonged infusions and need for specialized equipment.^[92] Deferasirox, an oral iron chelator approved by the FDA in 2005 for chronic iron overload secondary to blood transfusions, is dosed at 20-40 mg/kg per day and has demonstrated reductions in serum ferritin levels, with mean decreases of approximately 1,000-3,000 ng/mL over one year in clinical trials, depending on dose and patient factors.^[93] Common side effects include gastrointestinal disturbances such as nausea, diarrhea, and abdominal pain, which occur in up to 30% of patients but are generally manageable with dose adjustments.^[91] Deferiprone, another oral chelator, is given at 75-100 mg/kg per day in three divided doses and is noted for its cardioprotective effects, including significant improvements in myocardial T2* magnetic resonance imaging values, indicating reduced cardiac iron deposition. However, it carries a risk of agranulocytosis in approximately 0.7% of patients, necessitating weekly complete blood count monitoring during the initial treatment phase.^[94] For severe iron overload refractory to monotherapy, combination therapy with deferasirox and deferiprone has been studied and shown superior iron removal compared to single agents in clinical trials for patients with transfusion-dependent thalassemia or similar conditions.^[95] Patients on chelation therapy require annual audiometry and ophthalmological examinations to monitor for potential toxicities, such as sensorineural hearing loss or retinal changes associated with deferoxamine.^[96] As of 2025, ongoing research explores novel chelators, such as apotransferrin mimics, to improve efficacy and compliance in iron overload management.^[97]

Supportive measures

Supportive measures in iron overload focus on lifestyle modifications, vigilant monitoring, and preventive strategies to mitigate complications and support primary therapies. Dietary guidance plays a central role, emphasizing adjustments to reduce iron absorption and protect affected organs. Patients are advised to avoid vitamin C supplements exceeding 500 mg daily, as ascorbic acid enhances non-heme iron uptake in the gastrointestinal tract, potentially accelerating overload. Intake of red meat should be limited, given its high heme iron content, which is readily absorbed, while alcohol consumption must be restricted or eliminated to prevent exacerbation of liver fibrosis and oxidative stress. In contrast, beverages like tea and foods containing tannins, such as certain fruits and grains, can inhibit iron absorption by forming complexes with dietary iron, offering a practical way to moderate uptake during meals.^[98] Routine screening for organ-specific complications is essential to enable early intervention. Annual oral glucose tolerance testing is recommended to detect impaired glucose metabolism or diabetes, a common sequela due to pancreatic iron deposition.^[99] Bone mineral density evaluation via dual-energy X-ray absorptiometry (DXA) should be performed at baseline for adults over 40 years, with periodic reassessment, as iron overload increases osteoporosis risk through disrupted bone metabolism. For patients with cirrhosis, hepatocellular carcinoma (HCC) surveillance entails abdominal ultrasound and serum alpha-fetoprotein (AFP) measurement every 6 months, conducted by experienced clinicians to improve detection of early lesions. Family screening is a key preventive measure for hereditary hemochromatosis (HH), targeting first-degree relatives to identify at-risk individuals early. Guidelines recommend initiating evaluation with transferrin saturation and ferritin levels, followed by HFE genetic testing, starting at age 20-25 or upon adulthood, as penetrance rises with age and timely phlebotomy can avert progression.^[24] In pregnancy, management prioritizes maternal and fetal safety amid fluctuating iron demands. Phlebotomy can be safely continued or initiated after the first trimester if ferritin remains elevated, helping maintain iron balance without significant risks. Iron chelators, however, are contraindicated due to potential teratogenic effects and lack of safety data.^[100] A multidisciplinary approach optimizes care, involving hepatologists for liver monitoring, endocrinologists for metabolic issues, and other specialists as needed. Vaccination against hepatitis A and B is strongly advised to safeguard hepatic function, given the heightened vulnerability to viral injury in iron-overloaded livers.^[22]

Prognosis

Short-term outcomes

In patients with hereditary hemochromatosis (HH), the primary treatment modality, therapeutic phlebotomy, induces a progressive decline in serum ferritin levels during the induction phase, typically targeting normalization of iron stores within the first 6 to 12 months of regular sessions. Normalization of transferrin saturation (TSAT) to below 50% serves as an early prognostic indicator of successful iron depletion and correlates with reduced risk of immediate complications.^[86]^[101] Early treatment can lead to partial reversal of certain manifestations, with improvements observed in early-stage arthropathy through symptom relief and reduced joint inflammation following iron depletion, though advanced arthropathy persists in most cases. In contrast, established cirrhosis does not regress with phlebotomy or chelation, although progression may be halted.^[102]^[103]^[8] Adverse events from phlebotomy are uncommon but include hypotension or dizziness in a minority of patients, often managed by hydration adjustments. Chelation therapy with agents like deferasirox, reserved for those intolerant to phlebotomy, carries a risk of nephrotoxicity, with glomerular filtration rate reductions reported in 30-100% of cases depending on dose and baseline renal function.^[86]^[104] Short-term survival in the first 5 years exceeds 90% among treated HH patients, approaching population norms when initiated early, compared to substantially lower rates (around 50% reduction relative to controls) in untreated individuals with advanced disease. Diagnosis at a younger age, typically under 40 years, facilitates better initial control by limiting cumulative organ damage prior to therapy onset.^[103]^[105]^[4]

Long-term complications

Iron overload, particularly in hereditary hemochromatosis, predisposes individuals to a markedly elevated risk of hepatocellular carcinoma (HCC), with estimates indicating up to a 200-fold increase in patients who develop cirrhosis compared to the general population. This heightened malignancy risk is primarily confined to intrahepatic cancers, while associations with extrahepatic malignancies remain inconsistent and less strongly linked.^[106] Cardiovascular manifestations, including cardiomyopathy due to myocardial iron deposition, carry substantial mortality risks primarily in secondary iron overload from transfusion-dependent conditions like thalassemia; severe cases with cardiac T2* values below 10 ms at diagnosis are linked to heart failure and account for a majority of cardiac deaths in those cohorts, contributing to overall mortality rates of 20-30% in untreated or advanced disease. In HH, cardiac involvement is less common and does not significantly impact survival.^[107]^[81] Endocrine complications often become irreversible, with permanent diabetes mellitus developing due to pancreatic iron accumulation; prevalence is approximately 5-10% in patients detected early through screening. Hypogonadism, secondary to pituitary iron deposition, affects up to 42% of cases with advanced overload. Osteoporosis is another common sequela, associated with an elevated fracture risk—studies report a 55% increase in fracture incidence among those with iron overload, particularly affecting sites such as the hip, vertebrae, and humerus.^[103]^[108]^[109]^[110] Overall life expectancy in iron overload disorders normalizes with early intervention prior to cirrhosis onset, yielding survival rates comparable to the general population; however, presentation with established cirrhosis reduces life expectancy by an average of 10-15 years due to progressive organ failure and complications.^[111]

Prognosis in secondary iron overload

In secondary iron overload, such as from frequent transfusions in thalassemia or myelodysplastic syndromes, long-term outcomes depend heavily on chelation adherence. With effective chelation started early, survival approaches normal levels, but delays lead to high rates of cardiac failure (up to 70% of deaths in thalassemia) and endocrinopathies. Short-term response to chelators mirrors phlebotomy in iron reduction but with higher toxicity risks; 5-year survival exceeds 85% in compliant patients versus under 50% without.^[81]^[103]

Epidemiology

Global prevalence

Iron overload, encompassing both hereditary hemochromatosis (HH) and secondary forms, exhibits significant global variation in prevalence, influenced by genetic, demographic, and environmental factors. Hereditary HH, primarily driven by HFE gene mutations such as C282Y homozygosity, affects approximately 1 in 200 to 400 individuals of Caucasian descent, making it the most common autosomal recessive disorder in these populations.^[7] This prevalence is notably higher in regions of Celtic and Northern European ancestry, including Ireland and Scandinavia, where homozygote frequencies can reach 1 in 100 to 200 due to elevated carrier rates of up to 10-11%.^[112] In contrast, HH is rare among Asian and African populations, with homozygote prevalence below 1 in 1,000, often approaching negligible levels (e.g., 0.000039% in East Asians).^[24]^[113] Secondary iron overload, commonly associated with chronic transfusions in conditions like β-thalassemia major, impacts a substantial proportion of affected patients worldwide, with rates of significant iron accumulation reported in 80-98% of transfusion-dependent cases without adequate chelation.^[114] This form is most prevalent in regions with high thalassemia incidence, such as the Mediterranean basin and Southeast Asia, where carrier rates exceed 10-40% in some communities, leading to tens of thousands of new symptomatic cases annually.^[115] Globally, transfusion-dependent thalassemia affects over 100,000 individuals, with an additional approximately 25,000 infants born yearly requiring lifelong transfusions and thus at high risk for iron overload; broader estimates including other anemias suggest up to 400,000-500,000 patients worldwide are vulnerable, a number rising due to aging populations with conditions like myelodysplastic syndromes necessitating multiple transfusions.^[116]^[117]^[118] Underdiagnosis remains a critical issue, as clinical penetrance of HH is low and variable: only 10-25% of C282Y homozygotes develop overt iron overload-related disease, with many remaining asymptomatic due to factors like incomplete expressivity.^[24]^[119] There is a pronounced sex bias, with men 2-3 times more likely to exhibit clinical manifestations than women, attributable to physiological iron loss via menstruation and pregnancy in females.^[120] Alcohol consumption exacerbates iron accumulation in susceptible individuals, increasing overload risk by 3-5 fold with moderate-to-heavy intake (>2 drinks/day) and contributing as a cofactor in approximately 30% of advanced HH cases through enhanced intestinal absorption and hepatic damage.^[121]^[122]

Historical and evolutionary aspects

The condition now known as iron overload, particularly in its hereditary form (hemochromatosis), was first clinically described in 1865 by French physician Armand Trousseau, who termed it "bronze diabetes" due to the characteristic skin pigmentation and associated diabetes mellitus resulting from iron deposition in the pancreas.^[123] This early recognition highlighted the triad of symptoms—cirrhosis, diabetes, and pigmentation—but the underlying iron accumulation mechanism remained unclear for decades. Therapeutic advancements began in the mid-20th century, with phlebotomy (therapeutic bloodletting) introduced in the 1950s as a method to reduce excess iron stores by removing iron-rich red blood cells, marking a shift from symptomatic palliation to targeted iron depletion.^[124] The genetic basis of hereditary hemochromatosis was elucidated in 1996 when the HFE gene was cloned through positional cloning efforts, revealing it as a major histocompatibility complex class I-like molecule that regulates iron absorption in the intestine.^[125] The most common mutation, C282Y in the HFE gene, is estimated to have originated approximately 4,000–6,000 years ago during the Neolithic period in Europe, based on linkage disequilibrium analyses of haplotype diversity.^[126] This timing aligns with the transition to agriculture, suggesting the mutation arose in early farming populations where dietary changes may have influenced its persistence. Evolutionary hypotheses propose that heterozygosity for the C282Y mutation conferred a survival advantage by enhancing iron absorption from iron-poor diets or providing resistance to infections; specifically, HFE heterozygotes exhibit altered iron handling in macrophages, potentially limiting iron availability to pathogenic bacteria and reducing infection severity.^[127] Some models also suggest protection against malaria in endemic regions, though evidence is stronger for bacterial pathogens.^[128] The mutation's spread across Europe is linked to migrations, including Viking expansions from Scandinavia around 800-1000 CE, which distributed the allele along trade and settlement routes, with highest frequencies today in Celtic and Northern European populations.^[129] In the Stone Age, low iron overload prevalence likely stemmed from frequent blood loss due to parasitic infections like hookworms, common in hunter-gatherer lifestyles, which counteracted any genetic predisposition by depleting iron stores.^[130] The Neolithic shift to agriculture introduced grain-based diets high in phytates that inhibit iron absorption, paradoxically favoring mutations like C282Y for better nutrient utilization, while reduced parasitism from settled living allowed iron accumulation to become problematic.^[131] Recent genomic studies as of 2025 reaffirm the Celtic origins of the C282Y mutation through ancient DNA analyses, identifying the variant in Bronze Age populations (over 4,000 years old) in Ireland and Britain, with incomplete penetrance—where only 10-20% of homozygotes develop clinical iron overload—explaining discrepancies between high genotype prevalence and lower disease incidence in modern epidemiology. This variable expressivity is influenced by environmental factors like diet and modifiers such as other genetic variants, highlighting why the mutation persists without universal harm.^[132]^[133]

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There were 35 (1.1%) cardiac deaths. Of these patients, myocardial T2* at first scan had been less than 10ms in 85.7% and less than 20ms in 97.1%.
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Increased Risk of Fracture Among Patients With Iron Overload
While iron overload is associated with decreased BMD, imaging studies have demonstrated iron overload disorders may increase fracture risk due to the influence ...<|separator|>
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Endocrine complications in patients with Thalassaemia Major
Patients with multi-transfused thalassaemia major may develop severe endocrine complications due to iron overload. The anterior pituitary is particularly ...
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Survival and causes of death in hemochromatosis ... - PubMed
Cumulative survival was 76% at 10 years and 49% at 20 years. Life expectancy was reduced in patients who presented with cirrhosis or diabetes.
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A phase 1b randomised clinical trial evaluating BBI-001, a non ...
May 17, 2025 · Delayed diagnosis or noncompliance with treatment may lead to irreversible organ damage leading to a reduced life expectancy, especially for ...
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Famine, tea, and bread in Ireland: C282Y and modern human ...
Apr 8, 2022 · The HFE gene variant allele C282Y connected with hereditary hemochromatosis occurs at a frequency of about 10%–11% in Ireland, the highest known ...<|separator|>
[119]
Ethnic Differences in Iron Status - ScienceDirect.com
The lowest prevalence of C282Y homozygosity in the HEIRS study was reported among Asians (0.000039%), followed by Pacific Islanders (0.0132%), African Americans ...
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Prevalence and Management of Transfusional Iron Overload in ...
Sep 14, 2023 · Our findings revealed that 98% and 89% of the patients had iron overload (SF ≥ 1500 ng/mL) and comparable elevated median SF concentrations ( ...Abstract · Background · Results · Discussion
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Global distribution of β-thalassemia mutations: An update
Feb 20, 2024 · The prevalence can range between 10 % and 20 % in sub-Saharan Africa, up to 40 % in certain Middle Eastern and Indian populations, and as high ...
[122]
Thalassemia | Boston Children's Hospital
More than 1 million people have non-transfusion-dependent thalassemia, while more than 100,000 people have transfusion-dependent thalassemia.<|separator|>
[123]
Global Thalassaemia Review – TIF
More than 60% of patients in low- and middle- income countries report recurring interruptions or postponements in their regular blood transfusions more than 15 ...
[124]
Full article: The disease burden of β-thalassaemia revisited
At this point, it is worth mentioning that in a meta-analysis of 26,893 worldwide TDT patients with a mean age of 22.6 (SD = 1.7) years, the overall prevalence ...
[125]
Clinical penetrance in hereditary hemochromatosis: estimates of the ...
The overall clinical penetrance in terms of iron overload–related clinical symptoms, including liver fibrosis, among male homozygotes has been estimated as 28%, ...
[126]
Does hereditary hemochromatosis (HH) affect men, women, or both?
Jun 9, 2025 · Hereditary hemochromatosis (HH) affects both men and women, but men are about twice as likely to develop symptoms as women.Missing: sex presentation
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Role of alcohol in the regulation of iron metabolism - PubMed Central
Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload.
[129]
Hemochromatosis: Ancient to the Future - PMC - NIH
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[130]
Hemochromatosis: Discovery of the HFE Gene - PMC - NIH
In 1996, Feder et al. identified HFE, a novel major histocompatibility complex (MHC) class I-like gene; homozygosity for a single missense mutation (C282Y) of ...
[131]
Evidence that the Cys282Tyr mutation of the HFE gene originated ...
It has been estimated that the C282Y mutation appeared 60-70 generations ago. It was initially suggested that the ancestral C282Y mutation occurred within the ...Missing: Neolithic | Show results with:Neolithic
[132]
Epidemic pathogenic selection: an explanation for hereditary ...
For example, individuals with iron-deficient macrophages due to hereditary hemochromatosis gene mutations appear to have elevated resistance to microorganisms ...
[133]
The evolutionary adaptation of the C282Y mutation to culture and ...
Current analyses suggest that the temporal origin of the C282Y mutation, occurred 200 to 250 generations ago or at approximately 6,000 BP (4000 BCE) (Raha‐ ...Missing: 60 | Show results with:60
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The origin and spread of the HFE-C282Y haemochromatosis mutation
It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation.
[135]
[PDF] Hemochromatosis - Digital Commons @ Wayne State
Mar 6, 2015 · Toomajian and Kreitman (2002) discovered that the C282Y allele was a young mutation at high frequency; his team later suggested it was due to ...
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Hemochromatosis: a Neolithic adaptation to cereal grain diets
The Neolithic period in Europe marked the transition from a hunter-gatherer diet rich in red meat to an iron-reduced cereal grain diet.Missing: Stone parasites blood loss agriculture
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Celtic Origin of the C282Y Mutation of Hemochromatosis
Aug 5, 2025 · The C282Y mutation has been estimated to have arisen 60-70 generations ... Neolithic people. They demonstrate marked specificities ...