Hemosiderosis pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
After the repeated episodes of a diffuse [[alveolar]] [[hemorrhage]], the [[alveolar|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.9see below for more information). In the early stages of [[pulmonary hemosiderosis]], [[interstitial]] and intra-alveolar [[hemorrhage]] predominate, with collections of both free [[hemosiderin]] and [[hemosiderin]]-filled [[macrophages]] found in the [[Alveolar|alveolar space]]s and the [[interstitium]]. When the disease progresses, [[interstitial fibrosis]] ensues. Pulmonary hemosiderosis can occur either as a [[primary]] lung disorder ([[Idiopathic pulmonary hemosiderosis]]) or as the [[sequela]] to other [[pulmonary]], [[cardiovascular]], or [[immune system disorder]]. | |||
== Pathophysiology == | == Pathophysiology == | ||
After the repeated episodes of a diffuse [[alveolar]] [[hemorrhage]], the [[alveolar|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.( see below for more information). In the early stages of [[pulmonary hemosiderosis]], [[interstitial]] and intra-alveolar [[hemorrhage]] predominate, with collections of both free [[hemosiderin]] and [[hemosiderin]]-filled [[macrophages]] found in the [[Alveolar|alveolar space]]s and the [[interstitium]]. When the disease progresses and with repeated bleeds, there is hemosiderin deposit in the lungs and progressive pulmonary fibrosis occurs. Pulmonary hemosiderosis can occur either as a [[primary]] lung disorder (Idiopathic pulmonary hemosiderosis) or as the [[sequela]] to other [[pulmonary]], [[cardiovascular]], or [[immune system disorder]].<ref name="pmid27644948">{{cite journal |vauthors=Castellazzi L, Patria MF, Frati G, Esposito AA, Esposito S |title=Idiopathic pulmonary haemosiderosis in paediatric patients: how to make an early diagnosis |journal=Ital J Pediatr |volume=42 |issue=1 |pages=86 |date=September 2016 |pmid=27644948 |pmc=5029079 |doi=10.1186/s13052-016-0296-x |url=}}</ref><ref name="pmid20442117">{{cite journal |vauthors=Lara AR, Schwarz MI |title=Diffuse alveolar hemorrhage |journal=Chest |volume=137 |issue=5 |pages=1164–71 |date=May 2010 |pmid=20442117 |doi=10.1378/chest.08-2084 |url=}}</ref><ref name="pmid24125570">{{cite journal |vauthors=Taytard J, Nathan N, de Blic J, Fayon M, Epaud R, Deschildre A, Troussier F, Lubrano M, Chiron R, Reix P, Cros P, Mahloul M, Michon D, Clement A, Corvol H |title=New insights into pediatric idiopathic pulmonary hemosidrosis: the French RespiRare(®) cohort |journal=Orphanet J Rare Dis |volume=8 |issue= |pages=161 |date=October 2013 |pmid=24125570 |pmc=3852822 |doi=10.1186/1750-1172-8-161 |url=}}</ref><ref name="pmid30125478">{{cite journal |vauthors=Welsh SK, Casey AM, Fishman MP |title=Pulmonary hemorrhage in infancy: A 10-year single-center experience |journal=Pediatr. Pulmonol. |volume=53 |issue=11 |pages=1559–1564 |date=November 2018 |pmid=30125478 |doi=10.1002/ppul.24142 |url=}}</ref> | |||
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=== | Based on disease characteristics, there are three types of pulmonary hemosiderosis: | ||
===Group 1 pulmonary hemosiderosis=== | |||
Group 1 pulmonary hemosiderosis is defined by [[pulmonary hemorrhage]] associated with circulating [[Anti-GBM antibody|anti-glomerular basement membrane]] ([[Anti-GBM antibody|anti-GBM]]) antibodies. [[Anti-GBM disease|Anti-GBM diseases]] are small vessel [[vasculitis]] affecting the [[capillary]] system, where there are [[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 disease|anti-GBM diseases]] will develop an [[alveolar]] [[hemorrhage]]. Unlike idiopathic pulmonary hemosiderosis, group 1 pulmonary hemosiderosis is stratified based on [[kidney]] [[biopsy]], which shows linear deposits of [[IgG]] under [[Immunofluorescence|direct immunofluorescence]]. Lung biopsy samples are not used in the diagnosis of [[Anti-GBM disease|anti-GBM disease]] because it would likely have no specific information. | |||
===Group 2 pulmonary hemosiderosis=== | |||
Group 2 [[pulmonary hemosiderosis]] is defined by [[pulmonary hemorrhage]] associated with [[immune complex disease]]. [[Immune complexes]] are antigen-antibody complexes formation, which triggers [[complement]] activation and this activation can cause a break in the [[vascular]]-[[endothelial]] [[barrier]] and [[alveolar]]-[[epithelial]] barrier, leading to [[alveolar]] [[edema]], [[hemorrhage]], and massive infiltration of [[Polymorphonuclear neutrophil|polymorphonuclear neutrophils]] ([[Polymorphonuclear neutrophil|PMNs]]). This activation of [[Polymorphonuclear neutrophil|PMNs]] and [[macrophages]] release large amounts of [[oxidant|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 lead to pulmonary [[scarring]] and [[fibrosis]]. Associated conditions, although rare, include [[systemic lupus erythematosus]] ([[Systemic Lupus Erythematosus (SLE)|SLE]]), [[Henoch-Schonlein purpura]], [[Wegener’s granulomatosis]], and [[Mixed connective tissue disease|mixed connective tissue disease]]. | |||
=== | ===Group 3 pulmonary hemosiderosis or [[Idiopathic pulmonary hemosiderosis]]=== | ||
Group 3 [[pulmonary hemosiderosis]] is defined as [[pulmonary hemorrhage]] without a known [[Immunological|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 membrane|basement membranes]] and [[interstitial fibrosis]]. It is a [[diagnosis]] of exclusion after having ruled out primary and secondary causes of [[pulmonary hemosiderosis]] such as [[immune complex disease|immune complex diseases]] or [[Anti-GBM disease|anti-GBM diseases]]. | |||
==Hemosiderin== | |||
70% of [[iron]] is found in the hemoglobin of [[RBCs]].<br> | |||
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 [[Ferritin heavy chain 1 pseudogene 3|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. The [[H-chain]] subunit, has its [[ferroxidase]] activity, oxidizes Fe2+ to Fe3+ to enhance [[iron]] sequestration by [[ferritin]]. On the other hand, the [[Ferritin light chain|L-subunit]] facilitates the iron-core formation and has a greater storage capacity than the H-subunit. All [[ferritin|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|electron transport proteins]] in [[lysosomes]], liberating iron, and increasing [[cytosolic]] [[iron]] levels. Protein aggregation is able to trigger [[autophagy]], 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. The ferritin molecules are digested with the loss of part of their protein shell to form [[hemosiderin]]. | |||
==References== | ==References== | ||
Latest revision as of 08:25, 28 September 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
After the repeated episodes of a diffuse alveolar hemorrhage, 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.9see below for more information). In the early stages of pulmonary hemosiderosis, interstitial and intra-alveolar hemorrhage predominate, with collections of both free hemosiderin and hemosiderin-filled macrophages found in the alveolar spaces and the interstitium. When the disease progresses, interstitial fibrosis ensues. Pulmonary hemosiderosis can occur either as a primary lung disorder (Idiopathic pulmonary hemosiderosis) or as the sequela to other pulmonary, cardiovascular, or immune system disorder.
Pathophysiology
After the repeated episodes of a diffuse alveolar hemorrhage, 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.( see below for more information). In the early stages of pulmonary hemosiderosis, interstitial and intra-alveolar hemorrhage predominate, with collections of both free hemosiderin and hemosiderin-filled macrophages found in the alveolar spaces and the interstitium. When the disease progresses and with repeated bleeds, there is hemosiderin deposit in the lungs and progressive pulmonary fibrosis occurs. Pulmonary hemosiderosis can occur either as a primary lung disorder (Idiopathic pulmonary hemosiderosis) or as the sequela to other pulmonary, cardiovascular, or immune system disorder.[1][2][3][4]
Based on disease characteristics, there are three types of pulmonary hemosiderosis:
Group 1 pulmonary hemosiderosis
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 are 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, which shows linear deposits of IgG under direct immunofluorescence. Lung biopsy samples are not used in the diagnosis of anti-GBM disease because it would likely have no specific information.
Group 2 pulmonary hemosiderosis
Group 2 pulmonary hemosiderosis is defined by pulmonary hemorrhage associated with immune complex disease. Immune complexes are antigen-antibody complexes formation, which triggers complement activation and this activation can cause 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 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 or Idiopathic pulmonary hemosiderosis
Group 3 pulmonary hemosiderosis is defined as pulmonary hemorrhage without a 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 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.
Hemosiderin
70% of iron is found in the hemoglobin of RBCs.
30% of iron stored in the form of :
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. The H-chain subunit, has its ferroxidase activity, oxidizes Fe2+ to Fe3+ to enhance iron sequestration by ferritin. 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, 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. The ferritin molecules are digested with the loss of part of their protein shell to form hemosiderin.
References
- ↑ Castellazzi L, Patria MF, Frati G, Esposito AA, Esposito S (September 2016). "Idiopathic pulmonary haemosiderosis in paediatric patients: how to make an early diagnosis". Ital J Pediatr. 42 (1): 86. doi:10.1186/s13052-016-0296-x. PMC 5029079. PMID 27644948.
- ↑ Lara AR, Schwarz MI (May 2010). "Diffuse alveolar hemorrhage". Chest. 137 (5): 1164–71. doi:10.1378/chest.08-2084. PMID 20442117.
- ↑ Taytard J, Nathan N, de Blic J, Fayon M, Epaud R, Deschildre A, Troussier F, Lubrano M, Chiron R, Reix P, Cros P, Mahloul M, Michon D, Clement A, Corvol H (October 2013). "New insights into pediatric idiopathic pulmonary hemosidrosis: the French RespiRare(®) cohort". Orphanet J Rare Dis. 8: 161. doi:10.1186/1750-1172-8-161. PMC 3852822. PMID 24125570.
- ↑ Welsh SK, Casey AM, Fishman MP (November 2018). "Pulmonary hemorrhage in infancy: A 10-year single-center experience". Pediatr. Pulmonol. 53 (11): 1559–1564. doi:10.1002/ppul.24142. PMID 30125478.