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Hereditary hemochromatosis is a common inherited disorder of iron metabolism characterized by excessive intestinal iron absorption and progressive iron accumulation in body tissues. Although hereditary hemochromatosis has a high prevalence in populations of Northern European ancestry and occurs with similar frequency in the United States, Europe, and Australia, many affected individuals remain asymptomatic for years, leading to delayed or incidental diagnosis. When left unrecognized or untreated, iron overload can result in significant organ damage involving the liver, pancreas, heart, pituitary gland, and other endocrine organs, with a markedly increased risk of hepatocellular carcinoma. This educational activity provides a comprehensive overview of hereditary hemochromatosis, focusing on its pathophysiology, clinical presentation, and natural history. Learners gain insight into evidence-based diagnostic strategies, including the appropriate use of iron studies and genetic testing, as well as approaches to disease monitoring and long-term management. Emphasis is placed on early detection and timely intervention to prevent irreversible complications. Participation in this activity highlights the critical role of the interprofessional healthcare team, including pathologists, laboratory professionals, primary care providers, hepatologists, and nurses, in improving diagnostic accuracy, coordinating care, and optimizing patient outcomes. Through collaborative practice and informed clinical decision-making, healthcare professionals can significantly reduce morbidity and enhance the quality of care for patients with hereditary hemochromatosis. Objectives: Identify patients who may benefit from laboratory testing for hereditary hemochromatosis based on their clinical history. Determine the definitive diagnosis of hereditary hemochromatosis. Apply best practices when utilizing laboratory and other diagnostic testing to monitor disease progression in patients with hereditary hemochromatosis. Implement interprofessional team strategies to improve outcomes and prevent complications in patients with hereditary hemochromatosis. Access free multiple choice questions on this topic.

Hemochromatosis, a disorder caused by excessive iron absorption, was first described in the mid-1800s as bronze diabetes and pigmentary cirrhosis. The term hemochromatosis was believed to have been coined by von Recklinghausen in 1889. A genetic origin of this metabolic problem was first suggested in the 1930s. In 1977, Simon et al reported the association between an HLA class I–like molecule and the presumed hemochromatosis gene on chromosome 6p, establishing the genetic basis of what is now referred to as hereditary hemochromatosis.[1] Although one of the most common genetic disorders in the United States, affecting over 1 million people, hereditary hemochromatosis is often an incidental finding during routine laboratory iron measurements or the diagnostic workup of other conditions; however, increasing awareness of hereditary hemochromatosis has also contributed to early detection. Early diagnosis allows for intervention before tissue damage occurs due to excessive iron deposition. Iron can deposit in the liver, pancreas, heart, joints, and other endocrine organs if left untreated.[2] Hereditary hemochromatosis is currently classified into 4 major types, encompassing 5 distinct molecular subtypes. These classifications are based on age of onset, underlying genetic mutation, and mode of inheritance.[3] Type I hereditary hemochromatosis is considered the classic form of the disorder, and the onset of symptoms begins in adulthood. Loss-of-function mutations in the hereditary Fe [iron] (HFE) gene are present in approximately 70% of patients diagnosed with hereditary hemochromatosis. This form of hereditary hemochromatosis disproportionately affects males, although females can also be affected. Type 2 hereditary hemochromatosis is frequently called juvenile hemochromatosis, as symptoms begin in childhood, and the disease is typically more clinically severe. Unlike type I hereditary hemochromatosis, this form shows no sex preference. Type 2 hereditary hemochromatosis has 2 subtypes: 2a and 2b. Type 2a hereditary hemochromatosis is caused by mutations in the gene initially known as hemojuvelin (HJV) and is now referred to as HFE2. Type 2b hereditary hemochromatosis is due to hepcidin antimicrobial peptide (HAMP) gene mutations.[4]

Type 2 hereditary hemochromatosis is frequently called juvenile hemochromatosis, as symptoms begin in childhood, and the disease is typically more clinically severe. Unlike type I hereditary hemochromatosis, this form shows no sex preference. Type 2 hereditary hemochromatosis has 2 subtypes: 2a and 2b. Type 2a hereditary hemochromatosis is caused by mutations in the gene initially known as hemojuvelin (HJV) and is now referred to as HFE2. Type 2b hereditary hemochromatosis is due to hepcidin antimicrobial peptide (HAMP) gene mutations.[4] Type 3 hereditary hemochromatosis typically has an onset at approximately 30 years of age and is caused by mutations in the transferrin receptor 2 (TFR2) gene. Type 4 hereditary hemochromatosis, also known as ferroportin disease, is caused by mutations in the ferroportin/solute carrier family 40 member 1 (SLC40A1) gene. Ferroportin is an iron transmembrane transport protein, and Type 4 hereditary hemochromatosis is the only known form of hemochromatosis that can be inherited in an autosomal dominant fashion. The onset of type 4 hereditary hemochromatosis typically occurs in mid-adulthood.[5][6]

The clinical symptoms of hereditary hemochromatosis result from genetic defects in iron metabolism proteins, leading to iron overload and deposition in the liver, pancreas, myocardium, joints, and multiple endocrine organs, including the pituitary, thyroid, parathyroid, and adrenal glands. Humans cannot actively excrete iron; regulation of intestinal iron absorption is the primary mechanism for maintaining iron homeostasis. The total body iron pool in healthy adults ranges from 3 to 4 g; approximately 0.5 g is stored in the liver.[14] In severe, untreated hereditary hemochromatosis, total body iron stores may exceed 50 g, of which one-third is stored in hepatocytes. Excessive iron appears directly toxic to tissues, although cells that are not irreversibly injured recover function as the iron is removed. The characteristic findings of severe, untreated hereditary hemochromatosis are micronodular cirrhosis, diabetes mellitus, and abnormal skin pigmentation. Normal iron homeostasis is a complex mechanism that is incompletely understood. Humans must absorb iron from their diet; iron is used in multiple physiological processes, including DNA biosynthesis, oxygen transport, and cellular energy generation.[14] Hepcidin, the protein product of HAMP, is a circulating peptide hormone that is a negative regulator of iron absorption by enterocytes. When circulating hepcidin levels are high, iron absorption in the gut is reduced.[15] Ferroportin is an iron transmembrane transport protein encoded by SLC4OA1 that transports iron from the enterocyte into the vasculature. Ferroportin also transports iron out of reticuloendothelial cells. The proteolytic degradation of ferroportin is facilitated by hepcidin.[16] The HFE, HJV, and TFR2 gene products are hepatocyte membrane proteins that sense iron. In the presence of normal or elevated iron levels, these gene products activate hepcidin production, reducing enterocyte absorption and promoting ferroportin degradation.[7][14]

Normal iron homeostasis is a complex mechanism that is incompletely understood. Humans must absorb iron from their diet; iron is used in multiple physiological processes, including DNA biosynthesis, oxygen transport, and cellular energy generation.[14] Hepcidin, the protein product of HAMP, is a circulating peptide hormone that is a negative regulator of iron absorption by enterocytes. When circulating hepcidin levels are high, iron absorption in the gut is reduced.[15] Ferroportin is an iron transmembrane transport protein encoded by SLC4OA1 that transports iron from the enterocyte into the vasculature. Ferroportin also transports iron out of reticuloendothelial cells. The proteolytic degradation of ferroportin is facilitated by hepcidin.[16] The HFE, HJV, and TFR2 gene products are hepatocyte membrane proteins that sense iron. In the presence of normal or elevated iron levels, these gene products activate hepcidin production, reducing enterocyte absorption and promoting ferroportin degradation.[7][14] Mutations in HFE, HFE2, HAMP, HJV, and TFR2 significantly impair hepcidin synthesis, ultimately increasing intestinal iron absorption and iron deposition in tissues. The gain-of-function mutation of SLC40A1 impairs hepcidin-ferroportin binding. HFE-related mutations include C282Y, H63D, and S65C; together, these account for over 90% of cases of hereditary hemochromatosis, most of which are due to C282Y homozygosity.[17][18][19] The liver is most severely affected by untreated hereditary hemochromatosis. Whatever the underlying genetic defect, excess iron deposition within hepatocytes results in lipid peroxidation via iron-catalyzed free radical reactions, stimulation of collagen formation by stellate cells, and DNA damage by reactive oxygen species. Ferroptosis is a recently discovered form of nonapoptotic cell death mediated by reactive oxygen species and lipid peroxidation induction.[14] The risk of hepatocellular carcinoma in patients with hereditary hemochromatosis is increased 200-fold.

The liver is most severely affected by untreated hereditary hemochromatosis. Whatever the underlying genetic defect, excess iron deposition within hepatocytes results in lipid peroxidation via iron-catalyzed free radical reactions, stimulation of collagen formation by stellate cells, and DNA damage by reactive oxygen species. Ferroptosis is a recently discovered form of nonapoptotic cell death mediated by reactive oxygen species and lipid peroxidation induction.[14] The risk of hepatocellular carcinoma in patients with hereditary hemochromatosis is increased 200-fold. Iron uptake into pancreatic beta-cells leads to impaired insulin synthesis and release, whereas liver fibrosis leads to high levels of circulating insulin and insulin resistance.[20] Iron deposition in the pancreas can result in hyperglycemia; hereditary hemochromatosis should be suspected if there is skin hyperpigmentation, joint pain, hypogonadism, or features of liver disease in addition to persistent hyperglycemia.[21] The pathogenesis of diabetes mellitus in hereditary hemochromatosis is considered multifactorial; both insulin deficiency and resistance may contribute. Iron overload can impair insulin secretion and glucose tolerance early in hereditary hemochromatosis before cirrhosis occurs.[22] The myocardium is also affected by iron deposition. In hereditary hemochromatosis, iron deposition initially occurs within subepicardial cardiac myocytes; as the disease progresses, it spreads throughout the myocardium. Myocardial hypertrophy leads to diastolic dysfunction. If iron deposition continues, cardiomyopathy, systolic dysfunction, and arrhythmias ensue.[23] Deposition of iron in the cells of the anterior pituitary gland may result in reduced production of luteinizing hormone and follicle-stimulating hormone.[24] In non-HFE forms of hereditary hemochromatosis, iron deposition starts early, is more severe, and occurs in the pituitary, especially the gonadotropes, although other lineages are affected.[25]

Deposition of iron in the cells of the anterior pituitary gland may result in reduced production of luteinizing hormone and follicle-stimulating hormone.[24] In non-HFE forms of hereditary hemochromatosis, iron deposition starts early, is more severe, and occurs in the pituitary, especially the gonadotropes, although other lineages are affected.[25] Joint pain affects up to 75% of patients with hereditary hemochromatosis even before the diagnosis is made. Overt clinical symptoms related to joint involvement typically appear in the fifth decade of life but may appear as early as the third decade.[26] Hemochromatosis-associated pseudogout (chondrocalcinosis) is not common, but in patients with severe chondrocalcinosis, the frequency of association may justify screening for hemochromatosis, especially in younger males.[27] The inhibition of pyrophosphatases and synovial iron sequestration are likely mechanisms causing damage to the articular cartilage.[28]

Improving outcomes for patients with hereditary hemochromatosis requires a coordinated, interprofessional approach that integrates early recognition, accurate diagnosis, longitudinal monitoring, and patient-centered management. Clinicians, advanced practitioners, nurses, laboratory professionals, genetic counselors, pharmacists, and other healthcare professionals each play a critical role across the care continuum. Core clinical skills include recognizing characteristic laboratory patterns of iron overload, appropriately utilizing genetic testing, and assessing organ involvement to guide timely intervention and prevent irreversible complications. Strategic management of hereditary hemochromatosis relies on evidence-based protocols for diagnostic evaluation, therapeutic phlebotomy, and long-term surveillance. Ethical considerations are central to care, particularly regarding informed consent for genetic testing, confidentiality, and counseling of affected family members. Clearly defined professional responsibilities support shared decision-making and ensure accountability, while flattening traditional hierarchies to value each team member's contributions. Effective interprofessional communication facilitates accurate interpretation of laboratory results, coordination of specialty referrals, and consistent patient education. Nurses and allied health professionals reinforce adherence to treatment and monitoring plans, whereas pharmacists support medication safety and the management of comorbidities. Through structured care coordination, the interprofessional team enhances patient safety, improves clinical outcomes, and delivers comprehensive, high-quality care for individuals with hereditary hemochromatosis.