Hemosiderosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

A condition whenever there is systemic overload of iron and hemosiderin is deposited in many organs and tissues. It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. With progressive accumulation, parenchymal cells throughout the body (but principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment.Hemosiderosis is Iron deposition occurs in the setting of: Genetic (ie hemochromatosis), Transfusional, Abnormal clearance/use, Increase absorption, Abnormal Hepcidin, Hemolytic anemia, Hemotropic parasites.

Pathophysiology

70% of iron is found in the hemoglobin of RBCs.
30% of iron stored in the form of :

• Ferritin.
• Hemosiderin
  

Hemosiderin is:

• Aggregated, partially deproteinized ferritin.
• Insoluble in the aqueous solution.
• Found in the liver cells, spleen, and bone marrow.
• On-demand, it is released slowly.
  

Hemosiderin formation

• The principle iron storage protein, ferritin, is comprised of heavy (H) and light (L) chain monomers which co-assemble to form heteropolymers of 24 subunits. Ferritin is able to carry up to 4,500 iron atoms to attenuate cytosolic and nuclear-free labile iron pools (Harrison and Arosio, 1996). The H-chain subunit, owing to its ferroxidase activity, oxidizes Fe2+ to Fe3+ to enhance iron sequestration by ferritin (Muhoberac and Vidal, 2013). On the other hand, the L-subunit facilitates iron-core formation and has a greater storage capacity than the H-subunit.All ferritins have 24 protein subunits arranged in 432 symmetry to give a hollow shell with an 80 Å diameter cavity capable of storing up to 4500 Fe(III) atoms as an inorganic complex. Autophagy is the dominant process degrading cytosolic ferritin and mitochondrial electron transport proteins in lysosomes, liberating iron, and increasing cytosolic iron levels. Protein aggregation is able to trigger autophagy (Grune et al., 2004; Williams et al., 2006), tempting the postulation that ferritin aggregates are a preliminary step to lysosomal uptake.As ferritin in the cell sap find their way into secondary lysosomes by becoming engulfed within autophagic vacuoles made by folding of large sections of endoplasmic reticulum around intracellular organelles and cell sap. These vacuoles then fuse with lysosomes to become autophagosomes, where the ingested organelles and the ferritin are subjected to digestion.Thus the fate of iron taken up from the blood and trapped by ferritin in vesicles, or cell sap ferritin engulfed by autophagic vacuoles, is digestion in secondary lysosomes. The ferritin molecules are digested with loss of part of their protein shell to form hemosiderin.

Hemosdierosis:

A condition whenever there is systemic overload of iron and hemosiderin is deposited in many organs and tissues. It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. With progressive accumulation, parenchymal cells throughout the body (but principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment.In most instances of systemic hemosiderosis, the iron pigment does not damage the parenchymal cells or impair organ function despite an impressive accumulation ecept in hereditary hemochromatosis  With more extensive accumulations of iron and tissue injury including liver fibrosis, heart failure, and diabetes mellitus.

Hemosiderosis is Iron deposition and occurs in the setting of:

• Genetic (ie hemochromatosis)
• Transfusional
• Abnormal clearance/use
• Increase absorption
• Abnormal Hepcidin
• Hemolytic anemia
• Hemotropic parasites

Types include:

• Transfusion hemosiderosis
• Idiopathic pulmonary hemosiderosis
• Transfusional diabetes

Idiopathic pulmonary hemosiderosis (IDH)

Hemosiderosis is an uncommon or rare condition in which bleeding in the lungs causes additional problems especially a collection of iron (FE) which, in itself causes additional lung damage. Iron is an essential component of a hemoglobin molecule. This molecule is responsible for transporting Oxygen through the blood stream and to the individual cells. Such transport is essential for cellular respiration to occur and for life to continue.
The exact pathogenesis of idiopathic pulmonary hemosiderosis (IDH) is not fully understood. However, it is thought that idiopathic pulmonary hemosiderosis is the result of abnormal immune response towards alveolar capillaries.

• IDH is more commonly seen in patients with underlying structural defect in alveolar capillaries.
• Immune response against the alveolar basement membrane or alveolar endothelial cell results in rupture and alveolar hemorrhage.
  • Over time, alveolar hemorrhage results in breakdown of hemoglobin into heme and globin chains which leads to recruitment of neutrophil and monocyte inflammatory response.
• Patients with prolonged duration of idiopathic pulmonary hemosiderosis have been associated with development of other autoimmune disorders such as celiac disease.
• It is not yet clear but

Hemosiderosis can occur either as a primary lung disorder or as the sequela to other pulmonary, cardiovascular or immune system disorder.

• PH1 involves PH with circulating anti-GMB antibodies.
• PH2 involves PH with immune complex disease such as systemic lupus erythematosus, SLE.
• PH3 involves no demonstrable immune system involvement.

Associated conditions

There are many pulmonary problems that may seem to mimic hemosiderosis but do not necessarily include the deposits of iron into the lung. The deposition of iron in the lungs, occurring in the form of hemosiderin, is the defining characteristic of this illness. These other conditions may occur separately or together with hemosiderosis.

• Pulmonary Fibrosis
• Adult Respiratory Distress Syndrome (ARDS)
• Immune Complex Disease
• intra-alveolar bleeding