Materiały źródłowe

• #1 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 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. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. […] 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. As a consequence of this low hepcidin expression, HH patients with phenotypic expression have increased absorption of dietary iron and elevated Tf saturations.

• #3 HEMOCHROMATOSIS – Histopathology.guru

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

  Hemochromatosis is an iron storage disorder in which there is excessive accumulation of iron in parenchymal cells with eventual tissue damage and functional insufficiency of organs. […] It is an autosomal recessive disorder of excessive accumulation of iron. […] In hereditary hemochromatosis regulation of intestinal absorption of dietary iron is abnormal leading to net iron accumulation of 0.5 to 1gm/yr. […] Disease manifests itself typically after 20gm of stored iron are accumulated. […] Main regulator of iron absorption is Hepcidin. […] Hepcidin binds to the cellular iron efflux channel ferroportin causing its internalization and proteolysis, there by inhibiting the release of iron from intestinal cells and macrophages. […] Thus hepcidin lowers plasma iron levels and conversely deficiency of hepcidin causes iron overload.

• #4 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

  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). […] 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.

• #5

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

  Mutation of this gene in humans and disruption of this gene in mice cause iron overload through the reduction of hepcidin expression. […] Disruption of either the HFE or TFR2 gene causes downregulation of hepcidin expression. […] In patients with HH types 1, 2A, 2B, and 3, the serum hepcidin concentration is inappropriately low despite iron overload, and the diseases are inherited in the autosomal recessive pattern. […] In contrast, germline mutations of SLC40A1, which encodes FPN, the only cellular iron exporter and target of hepcidin, cause different types of iron overload disorders with appropriately elevated serum hepcidin levels in response to iron excess. […] The heterozygous mutation of SLC40A1 Q248H is frequently observed in African populations and is associated with mild microcytic anemia and the tendency to iron overload.

• #6 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 includes lipid peroxidation via iron catalysed free radical reaction, stimulation of collagen formation by activation of hepatic stellate cells, and interaction of reactive oxygen species and iron itself with DNA leading to lethal cell injury and predisposition to Hepatocellular carcinoma.

• #7 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. […] This disease is the most common cause of severe iron overload. […] 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.

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

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

  Hemochromatosis (HC) corresponds to systemic iron overload of genetic origin. […] In most HC forms, iron overload is explained by hepcidin deficiency, which increases iron delivery into the plasma from both duodenal and splenic sources, with subsequent organ iron deposition. […] When considering the mechanism of iron overload, the different HC forms can be divided into the following two main opposing categories. […] This mechanism, whose common denominator is hepcidin deficiency, applies to types 13 HC. In these settings, the corresponding mutations either decrease the hepatic production of hepcidin by altering the molecular cascade involved in its synthesis (types 1, 2A, and 3 HC) or totally prevent hepcidin synthesis (type 2B HC). […] A decrease in plasma hepcidin concentration leads to an increased plasma iron concentration by a double mechanism, enhanced intestinal absorption of iron, and enhanced release by the spleen of the iron originating from the normal degradation of old red blood cells (erythrophagocytosis).

• #9 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. […] 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.

• #10 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/

  Type 1 HH is an autosomal recessive disorder resulting in iron overload and variable multi-organ dysfunction. HFE is a MHC class 1-like protein that associates with 2m enabling efficient transport of the HFE protein to the cell surface where it interacts with TfR1. […] The lack of the HFE/TfR1 interaction increases the affinity of TfR1 for the transferrin-bound iron, thereby modulating iron absorption by the duodenal crypt cells. […] 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. […] Hepcidin expression can be modulated by mutations within HFE, HJV, and SLC40A1 that lead to iron disorders. Hepcidin is capable of regulating SLC40A1, affecting the iron absorption by enterocytes, iron export from macrophages into circulation, and deposition to cells or tissues.

• #11 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. […] 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.

• #12 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. Normal iron absorption appears to require interaction between HFE and beta2 microglobulin and transferrin receptor (Tf R-1) to facilitate entry of transferrin-bound iron into 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.

• #13

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

  As a consequence, HFE is unable to reach the cell surface and aggregates intracellularly. […] This causes impaired signaling leading to reduced hepcidin mRNA expression, decreased plasma hepcidin levels, and excessive systemic iron accumulation in adults (aged over 40 years). […] The molecular mechanism by which HFE regulates hepcidin expression is not yet fully understood. […] These observations suggest a role of HFE in BMP/SMAD signaling and provide a first mechanistic explanation for the impairment of BMP/SMAD signaling in patients with HFE-hemochromatosis.

• #14 Haemochromatosis revisited

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

  Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. […] The C282Y/C282Y mutations (homozygosity for C282Y) lead to decreased synthesis of the iron hormone hepcidin, which in turn causes an increased activity of the iron export protein ferroportin both at the digestive and splenic levels. […] The adequate content of body iron requires the maintenance of plasma iron concentration within normal limits (12-25 M) and the regulation of TS. […] 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.

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

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

  Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. […] Dysfunction of molecules that control iron homeostasis leads to excessive iron absorption in the duodenum and upper section of the small intestine and its maldistribution. […] Bioactive iron ions produce oxidative stress that destroys involved tissues. […] In HH, the intestinal absorption of iron is high, and multi-organ iron overload with organ failure may occur over decades. […] Myocardial iron loading of the heart is well known as a possible complication in HH in diastolic and systolic functions. […] Genetic testing enables to detection of HH at an early stage and, consequently, to start treatment early enough to stop the alterations in different organs, including the heart.

• #16 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). […] Plasma non-transferrin bound iron (NTBI) has the kinetic property to be very avidly uptaken by various organs (liver, pancreas, and heart), in contrast with transferrin-bound iron whose target is essentially the bone marrow (in order to produce new erythrocytes). […] NTBI is therefore likely to be responsible for the type of iron overload distribution occurring in hepcidin deficiency-related HC. […] 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.

• #17

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

  Elevated iron levels in the blood stream subsequently lead to the saturation of the binding capacity of the iron transporter transferrin. […] Above a transferrin saturation of approximately 75% highly reactive, non-transferrin bound iron species (especially labile plasma iron, LPI) appear in the blood, which will preferentially be taken up by parenchymal cells of the liver, the pancreas and other organs, and ultimately provoke an HH phenotype. […] Mutations in either the hepcidin gene itself, in genes affecting upstream activators of hepcidin expression (HFE, TFR2, HJV), or in ferroportin (the iron exporter which acts as the hepcidin receptor) can cause different classes and subtypes of HH. […] The C282Y mutation disrupts the formation of a disulfide bond in the HFE protein and impairs its capability to bind 2-microglobulin.

• #18 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). […] Plasma non-transferrin bound iron (NTBI) has the kinetic property to be very avidly uptaken by various organs (liver, pancreas, and heart), in contrast with transferrin-bound iron whose target is essentially the bone marrow (in order to produce new erythrocytes). […] NTBI is therefore likely to be responsible for the type of iron overload distribution occurring in hepcidin deficiency-related HC. […] 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.

• #19 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). […] Plasma non-transferrin bound iron (NTBI) has the kinetic property to be very avidly uptaken by various organs (liver, pancreas, and heart), in contrast with transferrin-bound iron whose target is essentially the bone marrow (in order to produce new erythrocytes). […] NTBI is therefore likely to be responsible for the type of iron overload distribution occurring in hepcidin deficiency-related HC. […] 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.

• #20 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). […] Plasma non-transferrin bound iron (NTBI) has the kinetic property to be very avidly uptaken by various organs (liver, pancreas, and heart), in contrast with transferrin-bound iron whose target is essentially the bone marrow (in order to produce new erythrocytes). […] NTBI is therefore likely to be responsible for the type of iron overload distribution occurring in hepcidin deficiency-related HC. […] 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.

• #21 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). […] Plasma non-transferrin bound iron (NTBI) has the kinetic property to be very avidly uptaken by various organs (liver, pancreas, and heart), in contrast with transferrin-bound iron whose target is essentially the bone marrow (in order to produce new erythrocytes). […] NTBI is therefore likely to be responsible for the type of iron overload distribution occurring in hepcidin deficiency-related HC. […] 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.

• #22 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. […] This disease is the most common cause of severe iron overload. […] 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.

• #23 Iron overload – Wikipedia

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

  Iron overload (also known as haemochromatosis or hemochromatosis) is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. […] In hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including HFE (hemostatic iron regulator), hemojuvelin and transferrin receptor 2 lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization and thus leads to iron overload. […] The resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which coupled with oxidative stress leads to organ damage or joint damage and the pathological findings seen in hemochromatosis.

• #24 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. […] This disease is the most common cause of severe iron overload. […] 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.

• #25 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.

• #26 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. […] 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.

• #27 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.

• #28 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.

• #29 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.

• #30 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 includes lipid peroxidation via iron catalysed free radical reaction, stimulation of collagen formation by activation of hepatic stellate cells, and interaction of reactive oxygen species and iron itself with DNA leading to lethal cell injury and predisposition to Hepatocellular carcinoma.

• #31 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. […] 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.

• #32 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. […] 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.

• #33 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. […] 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.

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

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

  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. […] 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. […] The last hypothesis assumes the possibility of autoimmune process participation as a cause of heart failure in HH.

• #35

  https://journals.lww.com/cardiologyinreview/fulltext/9900/cardiovascular_manifestations_of_hemochromatosis_.171.aspx

  Hemochromatosis is a genetic disorder characterized by excessive absorption and accumulation of iron in the body. […] The primary cardiovascular manifestation of hemochromatosis is dilated cardiomyopathy (DCM), characterized by the enlargement and weakened pumping function of the heart. […] Excessive iron deposition in the myocardium triggers oxidative stress and inflammation, causing cellular damage and fibrosis, which ultimately impair cardiac contractility. […] Arrhythmias are another common cardiovascular manifestation of hemochromatosis. […] Heart failure is a severe consequence of hemochromatosis-related cardiomyopathy. […] Hemochromatosis-related iron deposition can also affect the heart valves, leading to valvular heart disease. […] Although less common, myocardial infarction (MI) is recognized as a cardiovascular complication in hemochromatosis.

• #36

  https://journals.lww.com/cardiologyinreview/fulltext/9900/cardiovascular_manifestations_of_hemochromatosis_.171.aspx

  The excessive production of ROS overwhelms the antioxidant defense mechanisms within the heart, leading to a state of increased oxidative stress. […] The development of cardiac fibrosis in hemochromatosis is influenced by various factors, including the duration and severity of iron overload, genetic variations, and individual susceptibility. […] The pathogenesis of MI in hemochromatosis involves multiple mechanisms, including oxidative stress, endothelial dysfunction, inflammation, and the promotion of a pro-thrombotic state. […] The pathogenesis of valvular heart disease in hemochromatosis involves iron deposition within the heart valves, resulting in thickening, fibrosis, and impaired valve movement.

• #37 Iron Overload (Hemochromatosis) – Life Extension

  https://www.lifeextension.com/protocols/metabolic-health/hemochromatosis?srsltid=AfmBOoqrV7CdsFL6DtQ_d6gos__RkpKqBEPnqi2wsBUNmUvVvwdBpQmJ

  Hemochromatosis, the most common disease of primary iron overload, can be partitioned into 4 types. […] These defective genes are thought to increase iron absorption by lowering production of hepcidin, and increasing iron uptake from intestinal cells. […] Type IV may also cause the intestines to become insensitive to hepcidin, resulting in uncontrolled iron absorption. […] Chronic liver disease can compromise the liver’s ability to produce the iron regulatory hormone hepcidin and the iron transport protein transferrin. […] Excess iron accumulates in the pituitary gland and disrupts synthesis of gonadotropin-releasing hormone (GnRH), which is responsible for stimulating the production of sex hormones from the gonads. […] Thus, iron accumulation in the brain and the liver among those with iron overload may precipitate considerable hormonal irregularities.

• #38 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. […] However, carriers may experience iron overload themselves at a later stage if certain factors come into play.

• #39 Hereditary Hemochromatosis & Wilson’s Disease – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/hereditary-hemochromatosis-wilsons-disease

  Consequently, iron overload occurs, leading to iron deposits in organs such as the liver, pancreas, heart, pituitary, and joints. […] Excess iron generates hydroxyl free radicals that cause cellular damage, leading to symptoms such as liver fibrosis, cirrhosis, bronze hyperpigmentation, diabetes mellitus (also known as „bronze diabetes”), and cardiac conditions among others.

• #40 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 different types of HH are classified by the underlying genetic mutations and mode of inheritance.

• #41 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. […] Mutations in several genes can cause hereditary hemochromatosis. 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. […] 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. […] Types 1, 2, and 3 hemochromatosis are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. […] Type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern.

• #42 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 are conditions that can lead to increased body iron stores and end-organ damage in affected organs. […] The HFE gene C282Y homozygous mutation is the most common cause of hereditary hemochromatosis (HH). […] Other genes implicated in HH include TFR2, HAMP, HJV, and SLC40A1. […] 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. […] Other causes of HH include mutations in TFR2, HJV, or HAMP, and a gain-of-function mutation of SLC40A1. […] These mutations also lead to iron overload by decreasing the production/activity of hepcidin or the sensitivity of hepcidin to FPN.

• #43 Hereditary Hemochromatosis | AAFP

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

  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. […] Approximately 85 to 90 percent of affected patients are homozygous for the C282Y mutation.

• #44

  https://bpac.org.nz/bt/2015/april/haemochromatosis.aspx

  Most cases of hereditary haemochromatosis (approximately 80%) are due to a patient inheriting a C282Y allele of the HFE gene from both parents (homozygous for the C282Y HFE allele). […] This C282Y allele is known as the major risk allele. Another risk allele is H63D; this is more prevalent in the population but less likely to cause haemochromatosis and is referred to as a minor risk allele. […] Patients with unexplained elevated ferritin or transferrin saturation, or clinical signs suggestive of haemochromatosis but without identified HFE risk alleles after referral to genetic testing services should be followed up, particularly if aged 20 years and under. […] Some patients, with a family history of the condition, develop haemochromatosis but without identifiable risk alleles or mutations in the HFE gene, and are classified as having non-HFE hereditary haemochromatosis.

• #45 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 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. […] 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. […] Juvenile hemochromatosis associated with HJV mutations results in iron accumulation at an accelerated rate leading to the early age of diagnosis, with cardiomyopathy and endocrine failure often present at diagnosis. […] Gain-of-function mutation of SLC40A1 results in phenotypic expression similar to HH, whereas loss-of-function mutation of the SLC40A1 gene results in ferroportin disease (FD).

• #46 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. […] Mutations in several genes can cause hereditary hemochromatosis. 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. […] 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. […] Types 1, 2, and 3 hemochromatosis are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. […] Type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern.

• #47

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

  Mutations in genes that control the absorption of iron result in primary hemochromatosis. […] 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. […] 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.

• #48

  https://www.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 involved in some of the rare types of hemochromatosis is still being discovered. […] As NGS becomes more widely available, it may become a more economically viable diagnostic tool, facilitating an earlier diagnosis and providing better understanding of mutation types and incidence in the general population.

• #49

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

  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. […] 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 consequent decrease in circulating hepcidin levels is severe, and accounts for presentation at an early age and the severity of disease. […] The disease is not gender specific, with both males and females affected similarly.

• #50 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 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. […] 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. […] Juvenile hemochromatosis associated with HJV mutations results in iron accumulation at an accelerated rate leading to the early age of diagnosis, with cardiomyopathy and endocrine failure often present at diagnosis. […] Gain-of-function mutation of SLC40A1 results in phenotypic expression similar to HH, whereas loss-of-function mutation of the SLC40A1 gene results in ferroportin disease (FD).

• #51 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. […] Mutations in several genes can cause hereditary hemochromatosis. 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. […] 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. […] Types 1, 2, and 3 hemochromatosis are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. […] Type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern.

• #52 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

  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. […] Hepcidin is a small antimicrobial peptide which was serendipitously found to inhibit iron absorption. […] Hepcidin expression is decreased in the setting of iron deficiency and increased in the setting of iron overload. […] Type 3 HH results from mutations in the gene for transferrin receptor 2 (TfR 2), which like the classical transferrin receptor (TfR 1), mediates hepatic uptake of transferrin bound iron. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] The former leads to accumulation of iron in macrophages and enterocytes, with a depleted plasma iron pool. […] 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.

• #53

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

  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. […] 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 consequent decrease in circulating hepcidin levels is severe, and accounts for presentation at an early age and the severity of disease. […] The disease is not gender specific, with both males and females affected similarly.

• #54

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

  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. […] 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 consequent decrease in circulating hepcidin levels is severe, and accounts for presentation at an early age and the severity of disease. […] The disease is not gender specific, with both males and females affected similarly.

• #55 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. […] Mutations in several genes can cause hereditary hemochromatosis. 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. […] 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. […] Types 1, 2, and 3 hemochromatosis are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. […] Type 4 hemochromatosis is distinguished by its autosomal dominant inheritance pattern.

• #56 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 are conditions that can lead to increased body iron stores and end-organ damage in affected organs. […] The HFE gene C282Y homozygous mutation is the most common cause of hereditary hemochromatosis (HH). […] Other genes implicated in HH include TFR2, HAMP, HJV, and SLC40A1. […] 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. […] Other causes of HH include mutations in TFR2, HJV, or HAMP, and a gain-of-function mutation of SLC40A1. […] These mutations also lead to iron overload by decreasing the production/activity of hepcidin or the sensitivity of hepcidin to FPN.

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

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

  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. […] The therapeutic future for counteracting iron overload involves hepcidin supplementation (or induction) in all forms of hepcidin deficiency-related HC.

• #58 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 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. […] Because this disease is not associated with greatly increased body iron stores but rather sequestration in the RES compartment, it has been suggested to have milder clinical manifestations than HH. […] Further studies are needed to elucidate the pathophysiologic mechanisms for iron overload in this disorder because, based on the proposed mechanism, this condition should lead to an FD-like iron distribution.

• #59 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

  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. […] Hepcidin is a small antimicrobial peptide which was serendipitously found to inhibit iron absorption. […] Hepcidin expression is decreased in the setting of iron deficiency and increased in the setting of iron overload. […] Type 3 HH results from mutations in the gene for transferrin receptor 2 (TfR 2), which like the classical transferrin receptor (TfR 1), mediates hepatic uptake of transferrin bound iron. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] The former leads to accumulation of iron in macrophages and enterocytes, with a depleted plasma iron pool. […] 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.

• #60 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. […] 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.

• #61 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. […] 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.

• #62 Haemochromatosis revisited

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

  A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) proposed a new classification for haemochromatosis. The recent advances of pathophysiology and molecular basis of iron metabolism have highlighted that haemochromatosis is caused by mutations in at least five genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. […] Rigorously speaking, the term haemochromatosis should now be reserved for a unique genetic clinicopathological condition characterized by increased TS, iron overload in the liver (but not in the spleen), prevalent involvement of periportal hepatocytes with iron spared Kupffer cells, and signs and/or symptoms associated with iron overload.

• #63 Haemochromatosis revisited

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

  A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) proposed a new classification for haemochromatosis. The recent advances of pathophysiology and molecular basis of iron metabolism have highlighted that haemochromatosis is caused by mutations in at least five genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. […] Rigorously speaking, the term haemochromatosis should now be reserved for a unique genetic clinicopathological condition characterized by increased TS, iron overload in the liver (but not in the spleen), prevalent involvement of periportal hepatocytes with iron spared Kupffer cells, and signs and/or symptoms associated with iron overload.

• #64 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 different types of HH are classified by the underlying genetic mutations and mode of inheritance.

• #65

• #66 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 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. […] Because this disease is not associated with greatly increased body iron stores but rather sequestration in the RES compartment, it has been suggested to have milder clinical manifestations than HH. […] Further studies are needed to elucidate the pathophysiologic mechanisms for iron overload in this disorder because, based on the proposed mechanism, this condition should lead to an FD-like iron distribution.

• #67 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 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. […] Because this disease is not associated with greatly increased body iron stores but rather sequestration in the RES compartment, it has been suggested to have milder clinical manifestations than HH. […] Further studies are needed to elucidate the pathophysiologic mechanisms for iron overload in this disorder because, based on the proposed mechanism, this condition should lead to an FD-like iron distribution.

• #68 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 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. […] Because this disease is not associated with greatly increased body iron stores but rather sequestration in the RES compartment, it has been suggested to have milder clinical manifestations than HH. […] Further studies are needed to elucidate the pathophysiologic mechanisms for iron overload in this disorder because, based on the proposed mechanism, this condition should lead to an FD-like iron distribution.

• #69 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

  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. […] Hepcidin is a small antimicrobial peptide which was serendipitously found to inhibit iron absorption. […] Hepcidin expression is decreased in the setting of iron deficiency and increased in the setting of iron overload. […] Type 3 HH results from mutations in the gene for transferrin receptor 2 (TfR 2), which like the classical transferrin receptor (TfR 1), mediates hepatic uptake of transferrin bound iron. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] The former leads to accumulation of iron in macrophages and enterocytes, with a depleted plasma iron pool. […] 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.

• #70 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

  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. […] Hepcidin is a small antimicrobial peptide which was serendipitously found to inhibit iron absorption. […] Hepcidin expression is decreased in the setting of iron deficiency and increased in the setting of iron overload. […] Type 3 HH results from mutations in the gene for transferrin receptor 2 (TfR 2), which like the classical transferrin receptor (TfR 1), mediates hepatic uptake of transferrin bound iron. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] The former leads to accumulation of iron in macrophages and enterocytes, with a depleted plasma iron pool. […] 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.

• #71 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

  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. […] Hepcidin is a small antimicrobial peptide which was serendipitously found to inhibit iron absorption. […] Hepcidin expression is decreased in the setting of iron deficiency and increased in the setting of iron overload. […] Type 3 HH results from mutations in the gene for transferrin receptor 2 (TfR 2), which like the classical transferrin receptor (TfR 1), mediates hepatic uptake of transferrin bound iron. […] Type 4 HH results from mutations in the gene for Ferroportin (Fpn). […] The former leads to accumulation of iron in macrophages and enterocytes, with a depleted plasma iron pool. […] 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.

• #72 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. […] 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.

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

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

  The description of a digenic mode of inheritance has recently completed our knowledge of the molecular basis of haemochromatosis and, thus, definitively altered the monogenic perception of this old disease. […] The search for other modifier genes is crucial as it could enable us to distinguish more precisely those C282Y homozygous patients at increased risk of developing severe iron overload and, consequently, clinical complications. […] The predominant iron loading of liver macrophages, in contrast to hepatocytes in the HFE haemochromatosis form, with the manifestation of high-serum ferritin concentrations contrasting with normal or slightly elevated transferrin saturation, is the characteristic phenotype of ferroportin disease. […] The iron metabolism function of TFR2 has yet to be clearly defined, but there are cumulative arguments to suggest that this second receptor for transferrin acts as a liver sensor of circulating iron and thereby plays a significant role in HAMP expression.

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

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

  The description of a digenic mode of inheritance has recently completed our knowledge of the molecular basis of haemochromatosis and, thus, definitively altered the monogenic perception of this old disease. […] The search for other modifier genes is crucial as it could enable us to distinguish more precisely those C282Y homozygous patients at increased risk of developing severe iron overload and, consequently, clinical complications. […] The predominant iron loading of liver macrophages, in contrast to hepatocytes in the HFE haemochromatosis form, with the manifestation of high-serum ferritin concentrations contrasting with normal or slightly elevated transferrin saturation, is the characteristic phenotype of ferroportin disease. […] The iron metabolism function of TFR2 has yet to be clearly defined, but there are cumulative arguments to suggest that this second receptor for transferrin acts as a liver sensor of circulating iron and thereby plays a significant role in HAMP expression.

• #77 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. […] 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.

• #78 About Hemochromatosis

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

  A child who inherits two copies of a mutated gene (one from each parent) is highly likely to develop the disease. However, not all people who have two mutated copies develop signs and symptoms of HH. […] People who inherit only one copy of the mutated gene are carriers, but usually have no symptoms, or have very mild symptoms since one correct copy of the gene appears to adequately regulate iron absorption. „Silent” carriers, without symptoms of the disease, can still pass on the defect to their children. […] If two parents are silent carriers, each child has a 25 percent chance of inheriting two copies of the defective gene, and will most likely develop the disease. An estimated 10 percent of the U.S. population carries the gene. Carriers are most likely to exhibit signs of the disease if there are triggers such as diabetes or alcoholism.

• #79 About Hemochromatosis

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

  A child who inherits two copies of a mutated gene (one from each parent) is highly likely to develop the disease. However, not all people who have two mutated copies develop signs and symptoms of HH. […] People who inherit only one copy of the mutated gene are carriers, but usually have no symptoms, or have very mild symptoms since one correct copy of the gene appears to adequately regulate iron absorption. „Silent” carriers, without symptoms of the disease, can still pass on the defect to their children. […] If two parents are silent carriers, each child has a 25 percent chance of inheriting two copies of the defective gene, and will most likely develop the disease. An estimated 10 percent of the U.S. population carries the gene. Carriers are most likely to exhibit signs of the disease if there are triggers such as diabetes or alcoholism.

• #80 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from excess iron absorption because the patient is producing excessive amounts of red blood cells. This often occurs due to an underlying disease of the red blood cells that causes them to be more fragile and, therefore, to have a shortened lifespan. […] If left untreated, hemochromatosis can lead to progressive liver damage and cirrhosis, hepatocellular carcinoma, and other complications associated with iron overload in the tissues and organs. The prognosis has improved in the last few decades with advances in diagnosis and management of this condition.

• #81 Hemochromatosis – StatPearls – NCBI Bookshelf

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

  Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from excess iron absorption because the patient is producing excessive amounts of red blood cells. This often occurs due to an underlying disease of the red blood cells that causes them to be more fragile and, therefore, to have a shortened lifespan. […] If left untreated, hemochromatosis can lead to progressive liver damage and cirrhosis, hepatocellular carcinoma, and other complications associated with iron overload in the tissues and organs. The prognosis has improved in the last few decades with advances in diagnosis and management of this condition.

• #82

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

  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. […] 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 consequent decrease in circulating hepcidin levels is severe, and accounts for presentation at an early age and the severity of disease. […] The disease is not gender specific, with both males and females affected similarly.

• #83 Laboratory medicine and iron overload: diagnostic and therapeutic aspects – Brissot – Journal of Laboratory and Precision Medicine

  https://jlpm.amegroups.org/article/view/5705/html

  These different forms of hemochromatosis share a common mechanism at the origin of iron overload, namely hepcidin deficiency which produces iron overload through an increased ingress of iron, and more precisely of NTBI, into the parenchymal cells (hepatocytes). […] The phlebotomy management can be divided into two main phases. […] The initial or induction phase. […] The biochemical parameters are critical for starting the treatmenthigh CTS + ferritin 300 ng/mL in men and 200 ng/mL in womenas well as for following the progressive decrease of iron stores which is paralleled by the diminution of hyperferritinemia. […] Importantly, the CTS is not useful at this period because it remains elevated until the very end of the induction phase; the final goal of the induction phase is reached as soon as plasma ferritin concentration is 50 ng/mL and CTS 50% (without anemia). […] In terms of timing, ferritin should be checked every month until ferritinemia decreases to the upper normal of limits, and every 2 weeks thereafter (and then together with CTS).

• #84 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. […] These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations. […] 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.

• #85

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

  The study provides an insight into specific mutations in non-HFE hemochromatosis. […] 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. […] The ACG 2019 guidelines, on the other hand, recommend against further genetic screening in patients who test negative for type 1 hemochromatosis. […] 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.

• #86

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

  The study provides an insight into specific mutations in non-HFE hemochromatosis. […] 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. […] The ACG 2019 guidelines, on the other hand, recommend against further genetic screening in patients who test negative for type 1 hemochromatosis. […] 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.

• #87

  https://bpac.org.nz/bt/2015/april/haemochromatosis.aspx

  The key clinical intervention for treating haemochromatosis is venesection (phlebotomy) to reduce iron stores. […] Clinical guidelines recommend that all patients with haemochromatosis are offered venesection to normalise ferritin levels. […] Patients undergoing venesection often experience improvement in subjective symptoms of lethargy and abdominal pain, and changes in skin pigmentation. […] However, venesection does not reverse all the characteristic symptoms and sequelae of iron overload: liver cirrhosis, arthropathy,

• #88

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

  The study provides an insight into specific mutations in non-HFE hemochromatosis. […] 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. […] The ACG 2019 guidelines, on the other hand, recommend against further genetic screening in patients who test negative for type 1 hemochromatosis. […] 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.

• #89 Haemochromatosis revisited

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

  Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. […] The C282Y/C282Y mutations (homozygosity for C282Y) lead to decreased synthesis of the iron hormone hepcidin, which in turn causes an increased activity of the iron export protein ferroportin both at the digestive and splenic levels. […] The adequate content of body iron requires the maintenance of plasma iron concentration within normal limits (12-25 M) and the regulation of TS. […] 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.

• #90 Haemochromatosis revisited

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

  Haemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. […] The C282Y/C282Y mutations (homozygosity for C282Y) lead to decreased synthesis of the iron hormone hepcidin, which in turn causes an increased activity of the iron export protein ferroportin both at the digestive and splenic levels. […] The adequate content of body iron requires the maintenance of plasma iron concentration within normal limits (12-25 M) and the regulation of TS. […] 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.

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

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

  Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. […] Dysfunction of molecules that control iron homeostasis leads to excessive iron absorption in the duodenum and upper section of the small intestine and its maldistribution. […] Bioactive iron ions produce oxidative stress that destroys involved tissues. […] In HH, the intestinal absorption of iron is high, and multi-organ iron overload with organ failure may occur over decades. […] Myocardial iron loading of the heart is well known as a possible complication in HH in diastolic and systolic functions. […] Genetic testing enables to detection of HH at an early stage and, consequently, to start treatment early enough to stop the alterations in different organs, including the heart.

• #92 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.

• #93 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.

• #94 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.

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