Materiały źródłowe

• #1 Pathophysiology of Hereditary Hemochromatosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2587012/

  Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. […] Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. […] The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE. […] The pathogenesis of nearly all forms of HH involves an inappropriately low expression of hepcidin, an iron-regulatory hormone that acts to decrease the export of iron from duodenal enterocytes and reticuloendothelial cells. […] Decreased circulating hepcidin would cause increased ferroportin-mediated efflux of iron from certain cell types, including reticuloendothelial cells and duodenal enterocytes.

• #2 Hemochromatosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430862/

  Hemochromatosis is a disorder characterized by excessive iron accumulation in body tissues that leads to the dysfunction of various organs. Normally, iron absorption is tightly regulated, but in hemochromatosis, the body absorbs too much iron, which it cannot excrete. Hereditary hemochromatosis, the most common form, is an autosomal recessive disorder predominantly found in individuals of European descent. The disorder is caused by mutations in HFE, resulting in increased iron absorption. Excess iron is deposited in organs, including the liver, pancreas, heart, and skin, often leading to conditions such as liver disease, diabetes, heart failure, and skin discoloration, known as „bronze diabetes.” The types of hereditary hemochromatosis vary based on genetic mutations. Type 1 is the most common, while types 2, 3, and 4 are rarer variants. Secondary hemochromatosis can occur due to frequent blood transfusions or certain hematological disorders.

• #2 Hemochromatosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430862/

  Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas transfusional hemochromatosis predominately results in iron deposition in the reticuloendothelial cells. The excess iron is deposited in the cells as hemosiderin, eventually leading to cell death and replacement of these cells by a fibrous deposition that causes destruction or impairment of organ function. Hereditary hemochromatosis is traditionally classified into 4 classes or types with some additional subtypes. […] HFE mutations cause increased iron absorption despite normal dietary iron intake. HFE regulates the production of hepcidin, the protein product of HAMP, which is a circulating peptide hormone. Hepcidin, made predominately in the liver, inhibits dietary iron absorption in the duodenum and its release by splenic macrophages. HFE-related mutations are responsible for 90% of the cases of hereditary hemochromatosis in people of Northern European descent.

• #2 Hemochromatosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430862/

  Hemochromatosis affects the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol consumption and viral hepatitis worsen liver and pancreatic toxicity. Micronodular cirrhosis occurs in 70% of patients with unmanaged hemochromatosis, significantly increasing the risk of hepatocellular carcinoma, a leading cause of death. Pancreatic iron deposition primarily manifests as diabetes, affecting about 50% of homozygous individuals; the risk of developing diabetes is elevated in heterozygotes. […] Iron overload in macrophages impairs phagocytosis, leading to decreased immunity and an increased risk of infections from organisms like Aeromonas, Listeria, Yersinia enterocolitica, and Vibrio vulnificus. Patients with hemochromatosis should avoid handling or consuming raw shellfish due to a heightened risk of sepsis from V vulnificus. Excess iron deposits in the thyroid gland can cause hypothyroidism, with men experiencing an 80-fold greater risk than normal. While iron deposition in the adrenal and parathyroid glands rarely results in clinical symptoms, iron overload in hemochromatosis can occur due to massive oral intake, increased absorption with normal intake, or excessive red blood cell production or transfusion.

• #3 Hemochromatosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/177216-overview

  Hepcidin is a human antimicrobial peptide synthesized in the liver that plays a key role in the downregulation of iron release by enterocytes and macrophages (inhibits iron absorption in the gut and iron mobilization from the hepatic stores). […] The absence of this peptide is associated with severe, early-onset, iron-loading phenotype. It is also inappropriately low in adult-onset HFE-related disease. […] The degradation of cellular iron exporter (ferroportin) caused by hepcidin is the mechanism of cellular iron efflux inhibition.

• #3 Hemochromatosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/177216-overview

  Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. […] Hereditary hemochromatosis is an adult-onset disorder that represents an error of iron metabolism characterized by inappropriately high iron absorption resulting in progressive iron overload. […] Mutations in least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) in hereditary hemochromatosis have been recognized as being involved in hepcidin production/activity, which may disrupt regulation of systemic iron homeostasis. […] Excess iron is hazardous, because it produces free radical formation. The presence of free iron in biologic systems can lead to the rapid formation of damaging reactive oxygen metabolites, such as the hydroxyl radical and the superoxide radical. These can produce DNA cleavage, impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and fibrosis.

• #4 Pathogenesis, Diagnostics, and Treatment of Hereditary Haemochromatosis: A 150 Year-Long Understanding of an Iron Overload Disorder – European Medical Journal

  https://www.emjreviews.com/hepatology/article/pathogenesis-diagnostics-and-treatment-of-hereditary-haemochromatosis-a-150-year-long-understanding-of-an-iron-overload-disorder/

  Haemochromatosis is characterised by excess endogenous iron stores in the bodys tissues and organs, particularly in the skin, spleen, heart, liver, pancreas, and joints. […] The liver, as one of the main iron storage compartments and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Overload of iron is a primary risk factor in the pathogenesis of liver disease. […] HFE mutations lead to inadequate production of hepcidin, which results in increased iron uptake by the enterocytes, the release of iron from macrophages into the circulation, and increased deposition of excess iron in numerous tissues, which promotes excessive damage. […] The modified molecular signalling between the HFE protein and the TfR1 is being intensively studied as the main regulatory mechanism in the pathogenesis of HH.

• #5

  https://apcz.umk.pl/JEHS/article/view/58359

  Hereditary hemochromatosis is the most common genetic disorder in Northern Europe. It involves an overload of iron in the tissues due to a deficiency of the protein hepcidin. 85-90% of cases are associated with homozygous mutations of the C282Y gene in the HFE gene. […] Hereditary hemochromatosis is a disease that in most patients runs a covert course. If unrecognized and untreated, it carries many life-threatening complications.

• #6 Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

  https://www.mdpi.com/2075-4418/11/7/1279

  The present review aims to systematize, based on the recent discoveries, the current state of knowledge concerning cardiac involvement in HH from a molecular mechanism of iron regulation to clinical presentation. […] HFE gene encodes HFE protein; a ubiquitously expressed atypical major histocompatibility class I-like molecule. […] C282Y mutation disrupts a disulfide bond in the α3 domain of HFE; it abrogates its binding to β2-microglobulin and, consequently, prevents HFE presentation on the cell surface. […] Several studies have demonstrated that mutation in the HFE gene and some other genes involved in iron homeostasis leads to down-regulation of hepcidin (Hepc) expression, and in consequence, promotes intestinal iron absorption, resulting in systemic iron overload. […] Our current iron metabolism knowledge and regulation in cardiomyocytes derives from studies on mice with targeted cardiac-specific disruption of iron-related genes.

• #6 Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

  https://www.mdpi.com/2075-4418/11/7/1279

  Oxidative stress in heart muscle decreases electromechanical coupling, inhibits SERCA2 enzyme function, and leads to the increase in cytoplasmic concentration of Ca ions in cardiomyocytes, leading to impaired relaxation and delayed contraction. […] The accumulation of iron deposits occurs starting from the epicardial, then through the myocardium to the endocardial layer. […] The increased risk of coronary artery disease due to an increased iron level is the next cause. […] All this results in initial hypertrophy, diastolic dysfunction, heart dilatation, systolic dysfunction, and arrhythmias as possible clinical presentations of the HH. […] The discovery of the HFE gene in 1996 and introduction to routine diagnostics of genetic tests in patients with abnormal iron management parameters indicating its excessive accumulation makes possible HH diagnosis at the early stages before the patients demonstrate symptoms of advanced diseases.

• #6 Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

  https://www.mdpi.com/2075-4418/11/7/1279

  Under physiological conditions, diferric Tf that binds to the high-affinity TfR1 is used by cardiomyocytes as the main source of iron taken from the serum. […] Multiple routes of iron entry into cardiomyocytes exist under iron overload conditions. […] Studies on mice with a cardiomyocyte-specific deletion of the Fpn gene showed a high increase in both iron and ferritin levels in cardiomyocytes. […] It is known that systemic Hepc insufficiency causes hyperabsorption of dietary iron, hyperferremia, and tissue iron overload, which are hallmarks of HH. […] The heart is mentioned among organs most charged with iron in various animal models of hemochromatosis. […] Although many studies have been devoted to the molecular aspect of HH, the mechanism of heart failure induced by iron excess is not known.

• #6 Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

  https://www.mdpi.com/2075-4418/11/7/1279

  The essential laboratory parameter in HH assessment is NTBI level, which, due to the participation of these molecules in the generation of oxidative stress damaging the tissues, is particularly important. […] High levels of NTBI may indicate earlier initiation of appropriate treatment to avoid damage to organs, including the heart muscle. […] The appropriate treatment proved to reverse cardiac damages.

• #7 HFE gene: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/gene/hfe/

  The HFE gene provides instructions for producing a protein that is located on the surface of cells, primarily liver and intestinal cells. […] The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. […] The HFE protein regulates the production of a protein called hepcidin. […] When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. […] Researchers have identified more than 100 mutations in the HFE gene that cause type 1 hemochromatosis, a form of hereditary hemochromatosis that begins during adulthood. […] Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. […] The Cys282Tyr mutation prevents the altered HFE protein from reaching the cell surface.

• #7 HFE gene: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/gene/hfe/

  These mutations prevent the HFE protein from interacting with transferrin receptor 1 and other proteins. […] As a result, iron regulation is disrupted, and too much iron is absorbed from the diet. […] This increase in the absorption of dietary iron leads to the iron overload characteristic of type 1 hemochromatosis.

• #8 Hereditary hemochromatosis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hereditary-hemochromatosis/

  Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The proteins produced from these genes play important roles in regulating the absorption, transport, and storage of iron in the body. Mutations in any of these genes impair the control of the intestine’s absorption of iron from foods during digestion and alter the distribution of iron to other parts of the body. As a result, iron accumulates in tissues and organs, which can disrupt their normal functions. […] Type 1 hemochromatosis results from mutations in the HFE gene, and type 2 hemochromatosis results from mutations in either the HJV or HAMP gene. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in the SLC40A1 gene cause type 4 hemochromatosis. […] Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.

• #9 SciELO Brasil – Non-HFE hemochromatosis Non-HFE hemochromatosis

  https://www.scielo.br/j/rbhh/a/htc3gD8PwSBywXrwphZzHZz/?lang=en

  Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2A juvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis. […] Considering that the group of non-HFE hemochromatosis has many peculiarities, the aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.

• #9 SciELO Brasil – Non-HFE hemochromatosis Non-HFE hemochromatosis

  https://www.scielo.br/j/rbhh/a/htc3gD8PwSBywXrwphZzHZz/?lang=en

  Both types 2A and 2B HH are associated, in their final pathophysiology, with hepcidin regulation. Hepcidin is a hormone produced by hepatocytes, which plays an important role in iron homeostasis by regulating its absorption and release in the enterocytes and macrophages. […] The HJV gene is constituted by 4 exons located in chromosome 1. It was identified in 2004 and encodes a protein called hemojuvelin. This protein is critical for iron homeostasis regulation and for hepcidin expression in response to iron. In this scope, patients with type 2A JH and HJV knockout mice models demonstrate low hepcidin levels suggesting that hemojuvelin is involved in hepcidin synthesis. […] The HAMP gene directly encodes hepcidin which is produced by hepatocytes and plays a role in iron absorption related to ferroportin degradation of the enterocytes.

• #9 SciELO Brasil – Non-HFE hemochromatosis Non-HFE hemochromatosis

  https://www.scielo.br/j/rbhh/a/htc3gD8PwSBywXrwphZzHZz/?lang=en

  Type 3 HH leads to an iron overload similar to HFE hemochromatosis, and, consequently, may present with abnormal liver function, diabetes, hypogonadism, cardiomyopathy and arthritis. […] TFR2 gene is constituted by 18 exons and encodes the transferrin receptor 2 protein (TFR2). Different to TFR1, TFR2 expression is restricted almost entirely to the liver. Rather than only being involved with the uptake of transferrin bound iron by hepatocytes, TFR2 is a sensor of iron levels and is also involved in hepcidin synthesis. […] Type 4 HH, or ferroportin disease, is an autosomal dominant disease that has been associated with mutations in the SLC40A1 gene since 2001. The SLC40A1 gene encodes a protein named ferroportin, which is a transmembrane iron transporter expressed in macrophages, enterocytes, hepatocytes and syncytiotrophoblasts. Ferroportin is responsible for iron transportation across the enterocyte surface and for iron recycling in the reticuloendothelial system. It is known that hepcidin binds to ferroportin, promoting its internalization and degradation leading to a decrease in iron absorption and, consequently, to a reduction in serum iron. […] Excluding HFE mutations and secondary iron overload are crucial steps before considering the diagnosis of non-HFE HH. Thus, genetic testing can lead to more adequate and faster therapeutic management.

• #10

  https://xiahepublishing.com/2310-8819/JCTH-2022-00373

  Iron homeostasis is a complex process in which iron uptake and use are tightly balanced. […] However, four types of hemochromatosis do not involve the HFE gene. […] Non-HFE hemochromatosis is extremely rare. […] While less common, non-HFE hemochromatosis can cause iron overload as severe as the HFE type. […] This review updates the mutations and their pathogenetic consequences, the clinical picture, diagnostic guidelines, and treatment of hemochromatosis. […] The understanding of mutations underlying non-HFE hemochromatosis has significantly expanded with the wider availability and use of gene sequencing. […] Our focus in this review is on non-HFE hemochromatosis, the mutations involved in pathogenesis, and recent guidelines on diagnosis and management. […] Mutations in genes that control the absorption of iron result in primary hemochromatosis.

• #10

  https://xiahepublishing.com/2310-8819/JCTH-2022-00373

  Hemojuvelin protein (HJV), a glycophosphatidylinositol (GPI)-linked membrane protein, is a coreceptor in the BMP6 signaling pathway, and is required for the upregulation of hepcidin gene expression. […] Additionally, the extracellular signal-regulated kinase and mitogen-activated protein kinase (ERK-MAPK) pathway transduces extracellular signals intracellularly, including stimulation of the HAMP promoter, which leads to increased synthesis of hepcidin. […] A homozygous mutation at a single locus in the HAMP gene that leads to downregulation of hepcidin synthesis causes 80-90% of all hemochromatosis cases. […] The understanding of mutations underlying non-HFE hemochromatosis has significantly expanded with the wider availability and use of gene sequencing. […] The 2019 guidelines of the American College of Gastroenterology (ACG) hemochromatosis recommend magnetic resonance imaging (MRI) in evaluating liver iron concentrations in this patient population, followed by liver biopsy if necessary.

• #10

  https://xiahepublishing.com/2310-8819/JCTH-2022-00373

  The remaining cases originate from mutations of other than the HFE gene, and fall under the broad umbrella of non-HFE hemochromatosis. […] The allele frequencies of HJV (HFE2), TFR2, and HAMP mutations, range from 0.00007 to 0.0004. […] Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A, 20/100,000 for type 2B, 30/100,000 for type 3, and 90/100,000 for type 4 hemochromatosis. […] HFE protein, encoded by the HFE gene on chromosome 6p, is a major histocompatibility complex (MHC) class I protein that is an upstream regulator of hepcidin. […] HFE interacts with transferrin receptor 2 (TFR2), leading to increased stabilization and activation of bone morphogenic protein 6 (BMP6). […] BMP6 phosphorylates SMAD 1/5/8 and recruits SMAD 1/5/8 and SMAD 4 to HAMP proximal promoter, leading to increased transcription and synthesis of hepcidin.

• #11 About Hemochromatosis

  https://www.genome.gov/Genetic-Disorders/Hereditary-Hemochromatosis

  Hereditary hemochromatosis is a genetic disease that alters the body’s ability to regulate iron absorption. […] HH causes the body to absorb too much iron. Normally humans extract needed iron from food via the intestines. When there is an adequate amount of iron, the body reduces its absorption to avoid excessive accumulations. In a person with HH, the mechanism for regulating iron absorption is faulty and the body absorbs too much iron. […] Over time – several years – this excess iron is deposited in the cells of the liver, heart, pancreas, joints and pituitary gland, leading to diseases such as cirrhosis of the liver, liver cancer, diabetes, heart disease and joint disease. […] The gene that causes hereditary hemochromatosis, called HFE, was identified on chromosome 6 in 1996. Most cases of HH result from a common mutation in this gene, known as C282Y. But other mutations that cause this disease have also been identified, including one known as H63D.

• #12 Hereditary haemochromatosis – Wikipedia

  https://en.wikipedia.org/wiki/Hereditary_haemochromatosis

  However, carriers may experience iron overload themselves at a later stage if certain factors come into play. […] Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive. […] When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. […] People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus, the iron stores of the body increase. […] As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.

• #12 Hereditary haemochromatosis – Wikipedia

  https://en.wikipedia.org/wiki/Hereditary_haemochromatosis

  Hereditary haemochromatosis type 1 (HFE-related haemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. […] Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the liver, heart, pancreas, skin, joints, gonads, thyroid and pituitary gland; patients can present with cirrhosis, polyarthropathy, hypogonadism, heart failure, or diabetes. […] The disease follows an autosomal recessive pattern of inheritance, meaning that an individual must inherit two copies of the mutated gene involved in each cell to develop the condition. […] In most cases, when a person has this autosomal recessive condition, their parents act as carriers.

• #13 Hereditary Hemochromatosis: Genetics, Pathogenesis, and Clinical Management | Annals of Hepatology

  https://www.elsevier.es/es-revista-annals-hepatology-16-articulo-hereditary-hemochromatosis-genetics-pathogenesis-clinical-S1665268119320460

  Recent findings have led to major advances in our understanding of genetics and pathophysiology of hereditary hemochromatosis. […] Despite the recent advances, our understanding of iron homeostasis and pathogenesis of hemochromatosis remain incomplete. […] HFE is a transmembrane protein involved in the uptake of iron from plasma into macrophages and intestinal epithelial cells. […] The mutated HFE protein is trapped intracellularly and fails to traverse the cell membrane; it has been suggested that this results in impaired HFE-mediated entry of transferrin into crypt cells and results in a state of intracellular iron deficiency. […] The recent discovery of hepcidin has further complicated our understanding of iron metabolism but also established the role of the liver as essential to the maintenance of iron homeostasis.

• #13 Hereditary Hemochromatosis: Genetics, Pathogenesis, and Clinical Management | Annals of Hepatology

  https://www.elsevier.es/es-revista-annals-hepatology-16-articulo-hereditary-hemochromatosis-genetics-pathogenesis-clinical-S1665268119320460

  Hepcidin inhibits the release of iron from intestinal epithelial cells and from macrophages into plasma possibly via binding to ferroportin. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] Ferroportin mutations can be classified into 2 groups: one resulting in a loss of iron export function, and a second which is characterized by decreased sensitivity to the effect of hepcidin on ferroportin. […] It has been proposed, but not proven, that iron-restricted erythropoiesis resulting from reduced supply of iron to the bone marrow by macrophages, somehow stimulates enterocytes to increase iron absorption in spite of defective ferroportin function and increased iron in enterocytes. […] The mutation which causes hepcidin resistance produces a situation analogous to hepcidin deficiency, and results in a phenotype similar to Type 1 HH, with inappropriately high duodenal absorption of iron, increased transferrin saturation, and iron deposition in hepatocytes.

• #14

  https://link.springer.com/article/10.1007/s12185-017-2365-3

  Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. […] Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. […] The central regulator of systemic iron homeostasis is hepcidin, a peptide hormone mainly produced by hepatocytes. Hepcidin downregulates FPN expression, resulting in decreases of intestinal iron absorption and iron release from macrophages. […] Disruption of either the HFE or TFR2 gene causes downregulation of hepcidin expression. […] The mechanism by which iron regulates hepcidin expression seems very complex and has not been fully clarified yet, but at least products of HH-responsible genes, HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV) are involved in sensing body iron status.

• #15 HEMOCHROMATOSIS – Histopathology.guru

  https://www.histopathology.guru/hemochromatosis/

  Decreased hepcidin synthesis is caused by mutations in hepcidin, HJV, TFR2 and HFE has a central role in the pathogenesis of hemocromostasis. […] Mechanism of liver injury: Lipid peroxidation via iron catalysed free radical reaction. […] Interaction of reactive oxygen species and iron itself with DNA leading to lethal cell injury and predisposition to Hepatocellular carcinoma.

• #16 Hereditary Hemochromatosis – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/iron-overload/hereditary-hemochromatosis

  Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. […] The mechanism for iron overload in both HFE and non-HFE hemochromatosis is increased iron absorption from the gastrointestinal tract, leading to chronic deposition of iron in the tissues. Hepcidin, a liver-derived peptide, is the critical control mechanism for iron absorption. Hepcidin is normally up-regulated when iron stores are elevated and, through its inhibitory effect on ferroportin (which participates in iron absorption), it prevents excessive iron absorption and storage in normal people. Hemochromatosis types 1 through 4 share the same pathogenic basis (eg, lack of hepcidin synthesis or activity) and key clinical features. […] In general, tissue injury appears to result from reactive free hydroxyl radicals generated when iron deposition in tissues catalyzes their formation. Other mechanisms may affect particular organs (eg, skin hyperpigmentation can result from increased melanin as well as iron accumulation). In the liver, iron-associated lipid peroxidation induces hepatocyte apoptosis, which stimulates Kupffer cell activation and release of pro-inflammatory cytokines. These cytokines activate hepatic stellate cells to produce collagen, resulting in pathologic accumulation of liver fibrosis and risk of hepatocellular carcinoma.

• #17 A Review of New Concepts in Iron Overload – Gastroenterology & Hepatology

  https://www.gastroenterologyandhepatology.net/archives/february-2024/a-review-of-new-concepts-in-iron-overload/

  Iron overload disorders may be caused by genetic or acquired causes (transfusion, dyserythropoiesis, and chronic liver disease). […] The most common genetic iron overload disorder is caused by the homozygous C282Y mutation in the HFE gene and is referred to as hereditary hemochromatosis (HH) type 1. […] Mutations in the hepcidin-FPN axis cause HH. […] The most common mutation is the C282Y mutation in the HFE gene. […] These mutations also lead to iron overload by decreasing the production/activity of hepcidin or the sensitivity of hepcidin to FPN. […] The pathophysiology of iron overload in HH is described in Figure 1. […] The C282Y mutation in the HFE gene leads to inappropriately low levels of hepcidin. This results in uncontrolled circulatory iron pool expansion and progressive tissue iron accumulation, among those patients expressing the phenotype.

• #17 A Review of New Concepts in Iron Overload – Gastroenterology & Hepatology

  https://www.gastroenterologyandhepatology.net/archives/february-2024/a-review-of-new-concepts-in-iron-overload/

  The clinical penetrance of C282Y homozygotes is low, and it has been reported that half of the patients with this mutation will have no signs of iron overload. […] The mechanism of iron deposition in HH caused by a gain-of-function mutation in SLC40A1 (type 4 HH) and FD is presented in Figure 3. […] Genetic iron overload disorders that are not caused by decreased hepcidin levels or resistance of hepcidin, but caused by other mutations, include FD and hereditary aceruloplasminemia. […] The loss-of-function mutation in the SLC40A1 impairs the export function of FPN. […] This prevents the release of iron from the RES and leads to a greater increase in the splenic iron content and a moderate increase in the hepatic iron content. […] The pattern of iron deposition can also help differentiate between HH and other secondary iron overload disorders. Iron is primarily located in periportal hepatocytes in patients with HFE-related HH (type 1), juvenile HH (type 2), and HH caused by mutations in the TFR2 gene (type 3). […] In contrast, in patients with FD and secondary iron overload disorders, the iron is found mainly in the Kupffer cells and little to no iron is present in the hepatocytes.

• #18 Hereditary Hemochromatosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2013/0201/p183.html

  Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the body’s regulation of iron. […] Hereditary hemochromatosis is an autosomal recessive disorder in which iron regulation is disrupted, resulting in the toxic accumulation of iron in vital organs and the development of cirrhosis, bone and joint disease, diabetes mellitus, and heart disease. […] The mechanism for increased risk is the effect of excess iron in promoting oxidative DNA damage and free radical activity. […] In patients with hereditary hemochromatosis, the principal gene defect alters the expression of the HFE protein responsible for regulating hepcidin, the primary iron regulatory hormone. […] When the HFE gene exhibits a missense mutation at amino acid position 282, the protein product (C282Y) causes decreased hepcidin expression in response to elevated iron levels and subsequent unregulated control of iron levels.

• #19

  https://haematologica.org/article/view/8060

  The observation that C282Y HFE mutations are frequent but only cause a disease-related phenotype in a subgroup of carriers led to the hypothesis that this HFE gene variant may be of an environmental or genetic advantage to asymptomatic carriers and that this is the reason for which it has been inherited with such a high frequency. […] Increased iron uptake, a hallmark of HH, may have helped humankind, and especially women of reproductive age, to better cope with the iron-reduced cereal grain-based diet which replaced the paleo diet rich in red meat in Europe in the Neolithic Age, at the time when the first HFE mutation occurred. […] Recent studies have provided evidence that the HFE C282Y variant as well as the H63D and S65C variants can positively influence the immune system, the general fitness and reproductive status of mutation carriers, and might even diminish the risk of developing diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease, and atherosclerosis.

• #20

  https://www.xiahepublishing.com/2310-8819/JCTH-2022-00373

  The remaining cases originate from mutations of other than the HFE gene, and fall under the broad umbrella of non-HFE hemochromatosis. […] The allele frequencies of HJV (HFE2), TFR2, and HAMP mutations, range from 0.00007 to 0.0004. […] The SLC40A1 variant has been associated with persons of African descent and has a reported allele frequency of around 0.0004. […] The consequent decrease in circulating hepcidin levels is severe, and accounts for presentation at an early age and the severity of disease. […] HAMP mutation leads to one of the more severe forms of hemochromatosis because of complete or nearly complete absence of hepcidin and the consequent unrestrained FPN activity and iron transport. […] Mutation in the TFR2 gene leads to dysregulation in the interaction of the iron-transferrin complex with its receptor, and subsequent interruption in ERK-MAPK cascade, which decreased HAMP transcription and leads to low hepcidin level.

• #20

  https://www.xiahepublishing.com/2310-8819/JCTH-2022-00373

  Hepcidin levels are also helpful in the diagnosis of non-HFE hemochromatosis. […] That differs from type 4B hemochromatosis, in which there is a lack of sensitivity of FPN to hepcidin, and levels of the latter are markedly increased. […] Successful lowering of ferritin levels improves survival and liver and skin manifestations, but it usually does not have a significant therapeutic effect on extrahepatic manifestations such as hypogonadism, joint symptoms, and diabetes mellitus. […] The exception to that rule are non-HFE hemochromatosis types, e.g., 4A, that present with chronic anemia that precludes phlebotomy. […] As we learn more about mutation types, there is an opportunity for the development of more effective targeted therapies.

• #20

  https://www.xiahepublishing.com/2310-8819/JCTH-2022-00373

  In type 4A, mutations in SLC40A1 result in decreased sensitivity of FPN to hepcidin or complete loss of FPN activity resulting in two major presentations. […] The disease is not gender specific, with both males and females affected similarly. […] Overall, JH is associated with an early and severe iron overload state, and a more aggressive disease course compared with HFE hemochromatosis. […] For that reason, early detection is important, as timely phlebotomy can prevent significant organ damage. […] The 2019 guidelines of the American College of Gastroenterology (ACG) hemochromatosis recommend magnetic resonance imaging (MRI) in evaluating liver iron concentrations in this patient population, followed by liver biopsy if necessary. […] Knowledge of the severity of iron deposition within the liver can guide therapy.

• #21 Hereditary Hemochromatosis: Genetics, Pathogenesis, and Clinical Management | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-hereditary-hemochromatosis-genetics-pathogenesis-clinical-S1665268119320460

  Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] It has been proposed, but not proven, that iron-restricted erythropoiesis resulting from reduced supply of iron to the bone marrow by macrophages, somehow stimulates enterocytes to increase iron absorption in spite of defective ferroportin function and increased iron in enterocytes.

• #22 Clinical management of hemochromatosis: current perspectives | IJCTM

  https://www.dovepress.com/clinical-management-of-hemochromatosis-current-perspectives-peer-reviewed-fulltext-article-IJCTM

  This double source of increased iron delivery into the plasma is due to the activation (caused by hepcidin deficiency) of the cell iron exporter function of ferroportin (particularly present at the duodenal and spleen levels). […] Labile plasma iron (LPI) is an NTBI form defined by its potential cellular toxicity through its high propensity to generate reactive oxygen species and might be involved in HC tissue toxicity. […] The typical situation is type 4A HC, which is the most frequent form of ferroportin disease. The involved mutations affect the cell iron export function of ferroportin. Therefore, there is decreased cell iron delivery into the plasma causing iron overload by intracellular iron retention. […] It has been proposed that iron overload is due to cellular iron retention related to a decreased ferroxidase activity of CP, which, in turn, would alter the cell export function of ferroportin, according to a mechanism similar to that involved in type 4A HC. […] Withdrawing iron by phlebotomies (and/or chelation) is only a symptomatic approach; therefore, hepcidin supplementation (or induction) in all forms of hepcidin deficiency-related HC is an attractive option.

• #23 The molecular genetics of haemochromatosis | European Journal of Human Genetics

  https://www.nature.com/articles/5201490

  The molecular basis of haemochromatosis has proved more complex than expected. […] Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. […] Recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body’s iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. […] The discovery of the HFE gene and the development of simple tests for C282Y mutation genotyping were important steps in the diagnosis of haemochromatosis and the identification of related individuals at risk of developing iron overload.

• #24 Haemochromatosis revisited

  https://www.wjgnet.com/1948-5182/full/v14/i11/1931.htm

  The standard treatment for haemochromatosis remains phlebotomy (or therapeutic bleeding). This treatment has been shown to be effective and safe and has contributed to the reduction of morbidity and mortality in patients with haemochromatosis. […] In the future, hepcidin-based treatments could potentially become an adjunct treatment to phlebotomy in the intensive phase or a substitute in the maintenance phase. The interest of restoring hepcidin levels is, of course, based on the fact that hepcidin deficiency is the mechanism accounting for the development of iron overload in patients with haemochromatosis.

• #25 Hereditary Hemochromatosis – Iron Overload – Liver Diseases – Gastroenterology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.7.9.1.

  Hereditary hemochromatosis (HH) is a genetically determined disease in which excessive absorption of iron in the small intestine leads to iron overload. Iron deposition in parenchymal organs (especially in the liver, heart, pancreas, pituitary gland, skin, and joints) results in tissue and organ damage. […] HFE-HH is an autosomal recessive disease resulting in an abnormality in the membrane protein, which stimulates hepatic synthesis of hepcidin, thus affecting the regulation of gastrointestinal iron absorption and macrophage release of iron. […] The following 5 pathophysiologic mechanisms are implicated in primary hemochromatosis: 1) Altered HFE protein function. 2) Decreased expression of hepcidin for iron regulation. 3) Increased upper intestinal absorption of dietary iron. 4) Dysregulated iron retention by macrophages. 5) Tissue injury and fibrogenesis related to iron overload, particularly liver damage.

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