Hemosiderosis

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

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown etiology characterized by repeated episodes of a diffuse alveolar hemorrhage which cause periodic attack of tachycardia, pyrexia, pallor, fatigue, cyanosis, increasing dyspnea, signs of congestive cardiac failure, severe anamia and hemoptysis. The repeated alveolar hemorrhage causes the accumulation of hemosiderin, a by-product of hemoglobin breakdown, in the alveoli. Alveolar macrophages take up these hemosiderin molecules, usually within 36 – 72 hours, and can remain in the lungs for up to 8 weeks. Between attacks, patients may remain well but commonly there is chronic ill-health. Over the time, It can lead to multiple respiratory complications and permanent lung damage. It is not familial and is found primarily in children from a few months to 16 years of age and rarely be seen in adults.

IPH was first described as “brown lung induration” by Rudolf Virchow in 1864 in patients after their death. Wilhelm Ceelen gave a more detailed description of the condition after autopsies revealed large amounts of hemosiderin in 2 children in 1931. In 1944, the antemortem diagnosis was made by Waldenstrom.

Based on the duration of symptoms, pulmonary hemosiderosis may be classified as either acute or chronic phase.Pulmonary hemosiderosis may be classified into three groups based on disease characteristic: first group with circulating anti-glomerular basement membrane (anti-GBM) antibodies, second group, with immune complex disease, and the third group without known immunologic association or (Idiopathic pulmonary hemosiderosis).

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, 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.

There are no established causes for idiopathic pulmonary hemosiderosis, but it is likely to be multifactorial. Some consider it to be an autoimmune condition. The evidence is backed by the fact that the disease responds to immunosuppressants. Other hypotheses for this condition include allergy, due to this frequent association with Cow’s milk protein allergy, or genetic cause, due to the rare finding of familial clustering (but without any identified genes yet), and environmental factors such as its association with the fungi (Stachybotrys atra) exposure, or toxic insecticides (based on epidemiological studies in rural Greece), and premature birth.

Idiopathic pulmonary hemosiderosis must be differentiated from other diseases that cause alveolar hemorrhage, such as those include infectious etiologies( ARDS, Streptococcus pneumonia, Staphylococcus aureus, and legionella, influenza A and Pneumocystis jirovecii), rheumatic diseases such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic granulomatous polyangiitis, and mixed cryoglobulinemias, drug-induced injury in medications such as amiodarone, nitrofurantoin, and infliximab, Penicillamine, or from thromboembolic disease, bleeding disorders, and neoplasms.

The prevalence and incidence of idiopathic pulmonary hemosiderosis are relatively unknown because of the rare nature. IPH is more commonly observed among children. 20% of cases are adult-onset IPH.IPH affects males and females equally in childhood-onset IPH. Males are more commonly affected by IPH than females in adult-onset IPH.

There are no established risk factors for Idipathic pulmonary hemosiderosis.

The clinical spectrum of IPH ranges from asymptomatic cases to a chronic cough and dyspnea to repetitive hemoptysis with fatigue, anemia, and slowly progressive dyspnea and life-threatening acute respiratory failure. Common complications of IPH include Iron deficiency anemia and pulmonary fibrosis. Prognosis is generally variable, and the mean survival rate of patients with IPH is 2.5 to 5 years after diagnosis. Deaths can occur from acute massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

There are no established criteria for the diagnosis of idiopathic pulmonary hemosiderosis. Lung biopsy is the gold standard for the diagnosis of IPH, where the hemosiderin-laden macrophages can be visualized. However, it is an invasive procedure and is often not practicable in children.

The most common symptoms of IPH in the acute phase include severe dyspnea, cough, hemoptysis. when the disease progress, weight loss, Failure to thrive, and respiratory failure occurs in severe cases.

Common physical examination findings of IPH include tachypnea, pallor during the acute phase, and hepatosplenomegaly, failure to thrive and weight loss, and signs of respiratory failure such as digital clubbing in the chronic phase in severe cases.

The laboratory findings consistent with IPH include reduced hemoglobin counts and hematocrit, leucocytosis, and elevated erythrocyte sedimentation rate.

A chest x-ray taken during an acute phase of IPH exacerbation may show diffuse alveolar infiltrates greatest at the base of the lungs. Lungs CT scans may be helpful in the diagnosis of IPH. Findings on CT scan suggestive of IPH include ground-glass attenuation in the base of lungs during the acute phase of IPH. Chromium and technetium based perfusion scans may be helpful in the diagnosis of IPH. Findings on these perfusion scans suggestive of IPH include: abnormal pulmonary uptake 12-24 hours after the injection in patients with pulmonary hemorrhage.

Other diagnostic studies for IPH include sputum testing and bronchoalveolar lavage (BAL) for intact erythrocytes and hemosiderin-laden macrophages, which demonstrate pulmonary hemorrhage, and pulmonary function tests, which generally shows a restrictive pattern of varying severity and decreased DLCO.

There is no treatment for IPH; the mainstay of therapy is supportive care based on the presentation and acute vs. chronic nature of the patient. Immuno-suppressants in combination with steroids is used for severe cases. Supportive therapy for IPH includes blood transfusion to correct severe anemia, and invasive ventilation support for respiratory failure secondary to alveolar hemorrhage.

Surgical intervention is not recommended for the management of IPH.

Preventive measures for the secondary prevention of IPH include: maintenance doses of prednisone or prednisolone of 10 to 15 mg/kg/day

More researches should be done in order to investigate the cause of idiopathic pulmonary hemosiderosis so that selective and directed therapeutic approaches can be undertaken.

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

IPH was first described as “brown lung induration” by Rudolf Virchow in 1864 in patients after their death. Wilhelm Ceelen gave a more detailed description of the condition after autopsies revealed large amounts of hemosiderin in 2 children in 1931. In 1944, the antemortem diagnosis was made by Waldenstrom.

• IPH was first described as “brown lung induration” by Rudolf Virchow in 1864 in patients after their death.^[1]
• Wilhelm Ceelen gave a more detailed description of the condition after autopsies revealed large amounts of hemosiderin in 2 children in 1931.
• In 1944, the antemortem diagnosis was made by Waldenstrom

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

Based on the duration of symptoms, pulmonary hemosiderosis may be classified as either acute or chronic phase.Pulmonary hemosiderosis may be classified into three groups based on disease characteristic: first group with circulating anti-glomerular basement membrane (anti-GBM) antibodies, second group, with immune complex disease, and the third group without known immunologic association or (IPH).

Based on the duration of symptoms, pulmonary hemosiderosis may be classified as either acute or the chronic phase.

• In the acute phase, patients present with sudden onset of severe dyspnea and hemoptysis, which, if not treated immediately, could be fatal.
• In the chronic phase, some children may present with weight loss, and failure to thrive or hypoxemic respiratory failure.

IPH may be classified into three groups based on disease characteristic:^[1]

• Group 1 pulmonary hemosiderosis involves PH with circulating anti-GMB antibodies which affecting the capillary system.
• Group 2 pulmonary hemosiderosis involves PH with an immune complex disease such as systemic lupus erythematosus (SLE).
• Group 3 pulmonary hemosiderosis involves no demonstrable immune system involvement.

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

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.

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 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 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 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.

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.

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.

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

There are no established causes for idiopathic pulmonary hemosiderosis, but it is likely to be multifactorial. Some consider it to be an autoimmune condition. The evidence is backed by the fact that the disease responds to immunosuppressants. Other hypotheses for this condition include allergy, due to this frequent association with Cow’s milk protein allergy, or genetic cause, due to the rare finding of familial clustering (but without any identified genes yet), and environmental factors such as its association with the fungi (Stachybotrys atra) exposure, or toxic insecticides (based on epidemiological studies in rural Greece), and premature birth.

• There are no established causes for idiopathic pulmonary hemosiderosis, but it is likely to be multifactorial. Some consider it to be an autoimmune condition. The evidence is backed by the fact that the disease responds to immunosuppressants. ^[1]
• Other hypotheses for this condition include allergy, due to this frequent association with Cow’s milk protein allergy, or genetic cause, due to the rare finding of familial clustering (but without any identified genes yet), and environmental factors such as its association with the fungi Stachybotrys atra exposure, or toxic insecticides (based on epidemiological studies in rural Greece), and premature birth.

Template:WH Template:WS

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

Idiopathic pulmonary hemosiderosis must be differentiated from other diseases that cause alveolar hemorrhage, such as those include infectious etiologies( ARDS, Streptococcus pneumonia, Staphylococcus aureus, and legionella, influenza A and Pneumocystis jirovecii), rheumatic diseases such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic granulomatous polyangiitis, and mixed cryoglobulinemias, drug-induced injury in medications such as medication such as amiodarone, nitrofurantoin, and infliximab, Penicillamine, or from thromboembolic disease, bleeding disorders, and neoplasms.

Idiopathic pulmonary hemosiderosis must be differentiated from other diseases that cause pulmonary hemorrhage and pulmonary hemosiderosis such as:^[1]

• Infectious etiologies which can cause pulmonary hemorrhage ( ARDS, Streptococcus pneumoniae, Staphylococcus aureus, and legionella, influenza A, and pneumocystis jirovecii)
• Rheumatic diseases such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic and granulomatous polyangiitis, and mixed cryoglobulinemias
• Drug-induced injury in medications such as:
  • Amiodarone
  • Nitrofurantoin
  • Infliximab
  • Penicillamine
• Thromboembolic disease such as von Willebrand disease, thrombocytopenia, pulmonary embolism, pulmonary infarction
• Bleeding disorders
• Lung cancers

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

• The prevalence and incidence of idiopathic pulmonary hemosiderosis are relatively unknown because of the rare nature. IPH is more commonly observed among children. 20% of cases are adult-onset IPH.IPH affects males and females equally in childhood-onset IPH. Males are more commonly affected by IPH than females in adult-onset IPH.

• The prevalence and incidence of idiopathic pulmonary hemosiderosis are relatively unknown because of the rare nature.

• IPH is more commonly observed among children. ( approximately 80% of cases are seen in children who are diagnosed in the first decade of life.) ^{[1] [2]}
• 20% of cases are adult-onset IPH.

• IPH affects males and females equally in childhood-onset IPH
• Adult-onset IPH are almost twice as many males as females.
• Males are more commonly affected by IPH than females in adult-onset IPH.

• There is no racial predilection for IPH.

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

There are no established risk factors for IPH.

There are no established risk factors for IPH.

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

Not applicable

Not applicable

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

The clinical spectrum of IPH ranges from asymptomatic cases to a chronic cough and dyspnea to repetitive hemoptysis with fatigue, anemia, and slowly progressive dyspnea and life-threatening acute respiratory failure. Common complications of IPH include Iron deficiency anemia and pulmonary fibrosis. Prognosis is generally variable, and the mean survival rate of patients with IPH is 2.5 to 5 years after diagnosis. Deaths can occur from acute massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

• The clinical spectrum of IPH ranges from asymptomatic cases to a chronic cough and dyspnea to repetitive hemoptysis with fatigue, anemia, and slowly progressive dyspnea and life-threatening acute respiratory failure.

• Common complications of IPH include:
• Iron deficiency anemia
• Pulmonary fibrosis

• Prognosis is generally variable
• The mean survival rate of patients with IPH is 2.5 to 5 years after diagnosis.
• Deaths can occur from acute massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

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