Hemosiderosis pathophysiology

Hemosiderosis Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Hemosiderosis from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hemosiderosis pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hemosiderosis pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hemosiderosis pathophysiology
CDC on Hemosiderosis pathophysiology
Hemosiderosis pathophysiology in the news
Blogs on Hemosiderosis pathophysiology
Directions to Hospitals Treating Hemosiderosis
Risk calculators and risk factors for Hemosiderosis pathophysiology

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.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.

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 :

• 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, 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.