Hemosiderosis pathophysiology

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

Overview

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 that occurs in the setting of: Genetic (ie hemochromatosis), Transfusional, Abnormal clearance/use, Increase absorption, Abnormal Hepcidin, Hemolytic anemia, Hemotropic parasites.

Pathophysiology

Hemosdierosis:

A condition whenever there is a 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, lung, 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 except in hereditary hemochromatosis. With more extensive accumulations of iron and tissue injury, including liver fibrosis, lung fibrosis, heart failure, and diabetes mellitus. Hemosiderosis is Iron deposition and occurs in the setting of:

• Genetic (i.e., hemochromatosis occurs due to excessive iron absorption)
• Transfusional
• Abnormal clearance/use
• Increase absorption
• Abnormal Hepcidin
• Hemolytic anemia: Destruction of red blood cells within the blood vessels, leading to the release of iron into the blood followed by accumulation of iron inside the tissues the blood or direct bleeding into the tissues.
• Hemotropic parasites

Types of hemosiderosis include:

• Transfusion hemosiderosis
• Idiopathic pulmonary hemosiderosis
• Transfusional diabetes

Idiopathic pulmonary hemosiderosis (IPH)

Pulmonary 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 further lung damage. The exact pathogenesis of pulmonary hemosiderosis is not fully understood. However, it is thought that idiopathic pulmonary hemosiderosis is the result of the abnormal immune response towards alveolar capillaries. The immune response against the alveolar basement membrane or alveolar endothelial cell results in rupture and alveolar hemorrhage Pulmonary hemosiderosis can occur either as a primary lung disorder or as the sequela to other pulmonary, cardiovascular, or immune system disorder. Pulmonary hemosiderosis is typically grouped into three categories based on disease characteristics:

• PH1 involves PH with circulating anti-GMB antibodies. Anti-GBM diseases are small vessel vasculitis affecting the capillary system, where there is immunoglobulin and complement deposition along basement membranes of primarily the lungs and the kidneys such as in Goodpasture syndrome. Most of these patients will develop glomerular crescent formation with rapidly progressive glomerulonephritis; however, on average, 40-60% of patients with anti-GBM diseases will develop an alveolar hemorrhage. Unlike idiopathic pulmonary hemosiderosis, group 1 pulmonary hemosiderosis is stratified based on kidney biopsy, showing linear deposits of IgG under direct immunofluorescence. Lung biopsy samples are not used in the diagnosis of anti-GBM disease.
• PH2 involves PH with the immune complex disease such as systemic lupus erythematosus, SLE. Recurrent episodes of these immune complex-mediated lung injuries lead to pulmonary scarring and fibrosis. Associated conditions, although rare, include systemic lupus erythematosus (SLE), Henoch-Schonlein purpura, Wegener’s granulomatosis, and mixed connective tissue disease.
• PH3 involves no demonstrable immune system involvement with episodes of diffuse alveolar hemorrhage results in the accumulation of iron in the form of hemosiderin inside Idiopathic Pulmonary Hemosiderosis

Introduction Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by repeated episodes of a diffuse alveolar hemorrhage, which over time, can lead to multiple respiratory complications and permanent lung damage. Though the exact cause of IPH is not well-understood, some believe the disease is from autoimmune damage to the capillaries of the alveoli leading to repeated bleeding into the alveolar space. It is because of this repetitive bleeding that permanent damage occurs, leading to significant morbidity and mortality. When no cause for repeated episodes of diffuse alveolar hemorrhage is apparent, the entity is referred to as IPH.[1] The diagnosis of IPH is the diagnosis of exclusion, requiring a thorough review and elimination of other causes of primary and secondary pulmonary hemosiderosis.

Etiology Etiology is uncertain but likely to be multifactorial. Possible associations include toxic insecticides (epidemiological studies in rural Greece), premature birth, and fungal toxin exposure. In the 1990s, the incidence of acute idiopathic pulmonary hemosiderosis (IPH) in young infants in several midwestern US cities, especially in the Cleveland area.

Epidemiological research led to the discovery of substantial growth of the toxigenic fungus Stachybotrys atra in homes of almost all of the cases, suggesting that exposure to that mold can cause IPH in infants. Subsequent data did not prove this association. Pulmonary hemosiderosis is associated with rheumatoid arthritis, thyrotoxicosis, coeliac disease, and autoimmune hemolytic anemia, suggesting a potential autoimmune mechanism.

Epidemiology Due to the rare nature of idiopathic pulmonary hemosiderosis (IPH), the incidence and prevalence of the disease are relatively unknown. Many patients previously reported to have IPH are likely misdiagnosed and have a diffuse alveolar hemorrhage. A Swedish study from 1984 estimated an incidence of 0.24 per million children per year, data collected from 1950-1979.[2] A retrospective study from Japan estimated approximately 1.23 cases per million per year.[3]

Approximately 80% of cases occur in children, most of which are diagnosed in the first decade of life.[4] Adult-onset IPH accounts for approximately 20% of cases; however, there may be an unknown fraction of these cases, which were un-diagnosed childhood-onset IPH. Gender distribution of IPH appears to be equally balanced between males and females in childhood-onset IPH. However, there are almost twice as many males as females diagnosed in adult-onset IPH.[5][6] Familial clustering has been noted in several reports suggestive of some genetic component.[7][8][9]

Pathophysiology The alveolar macrophages are responsible for the repeated clean up of excess blood. As the macrophages degrade the erythrocytes, the excess iron from heme degradation within the alveolar macrophages stimulates intracellular ferritin molecules. Further processing of the ferritin leads to hemosiderin complexes; unfortunately, this form of iron is unable to be used by the body and leads to iron-deficient states. Meanwhile, the increased iron load from repetitive bleeding quickly saturates the alveolar macrophages intra-cytoplasmic ferritin, and each macrophage is unable to synthesize any additional iron. Unbound free iron leads to oxidative stress on the alveoli, which can lead to pulmonary fibrosis. This has been demonstrated in prior studies of patients with hemochromatosis and concomitant idiopathic pulmonary fibrosis.

Pulmonary hemosiderosis is typically grouped into three categories based on disease characteristics.

Group 1 pulmonary hemosiderosis is defined by pulmonary hemorrhage associated with circulating anti-glomerular basement membrane (anti-GBM) antibodies. Anti-GBM diseases are small vessel vasculitis affecting the capillary system, where there is immunoglobulin and complement deposition along basement membranes of primarily the lungs and the kidneys such as in Goodpasture syndrome. A majority of these patients will develop glomerular crescent formation with rapidly progressive glomerulonephritis; however, on average, 40-60% of patients with anti-GBM diseases will develop an alveolar hemorrhage. Diffuse alveolar hemorrhage presents clinically in these patients, and a diagnostic broncho-alveolar lavage may demonstrate hemosiderin-laden macrophages. Unlike idiopathic pulmonary hemosiderosis, group 1 pulmonary hemosiderosis is stratified based on kidney biopsy, showing linear deposits of IgG under direct immunofluorescence. Lung biopsy samples are not used in the diagnosis of anti-GBM disease and would likely have no specific information.[2][10]

Group 2 pulmonary hemosiderosis is defined by pulmonary hemorrhage with immune complex disease. Immune complexes are antigen-antibody complexes formed by joining IgG or IgM to a soluble antigen, which triggers complement activation. The result of this immune complex formation was a break in the vascular-endothelial barrier and alveolar-epithelial barrier, leading to alveolar edema, hemorrhage, and massive infiltration of polymorphonuclear neutrophils (PMNs). This activation of PMNs and macrophages release large amounts of oxidants and proteases, leading to damage to the alveolar wall leading to potential acute lung injury and alveolar hemorrhage, which may present itself as an acute respiratory distress syndrome (ARDS). Recurrent episodes of these immune complex-mediated lung injuries inevitably lead to pulmonary scarring and fibrosis. Associated conditions, although rare, include systemic lupus erythematosus (SLE), Henoch-Schonlein purpura, Wegener’s granulomatosis, and mixed connective tissue disease.

Group 3 pulmonary hemosiderosis is defined as pulmonary hemorrhage without known immunologic association, also known as idiopathic pulmonary hemosiderosis (IPH). As previously noted, repeated episodes of diffuse alveolar hemorrhage result in the accumulation of iron in the form of hemosiderin inside pulmonary macrophages. These recurrent episodes also lead to the thickening of alveolar basement membranes and interstitial fibrosis. It should be considered idiopathic pulmonary hemosiderosis is a diagnosis of exclusion after having ruled out primary and secondary causes of pulmonary hemosiderosis such as immune complex diseases or anti-GBM diseases.

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, and found in the liver cells, spleen, and bone marrow. On-demand, it is released slowly. Hemosiderin formation

• The principle iron storage protein, ferritin, comprises heavy (H) and light (L) chain monomers, which co-assemble to form heteropolymers of 24 subunits. Ferritin can 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 the 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 finds its 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 the loss of part of their protein shell to form hemosiderin.