Hemosiderin

Hemosiderin is an abnormal microscopic iron-containing compound found in the human body. Hemosiderin is composed of iron oxide and can accumulate in different organs in various diseases. Iron is required by many of the chemical reactions in the body but is toxic when not properly contained. Thus, many methods of iron storage have developed.

Humans typically store iron within a protein called ferritin. The form of iron in ferritin is iron (ferric) oxide-hydroxide. By complexing with ferritin, the iron is made water soluble. Several diseases result in deposition of iron (ferric) oxide-hydroxide in tissues in an insoluble form. These deposits of iron are called hemosiderin. Although these deposits often cause no symptoms, they can lead to organ damage. Abnormal deposition of an iron-containing compound (hemosiderin) in tissues is often associated with diseases in which there is extensive destruction of red blood cells (e.g., thalassemia).

Hemosiderin often forms after bleeding (hemorrhage) into an organ. When blood leaves a ruptured blood vessel, the cell dies and the hemoglobin of the red blood cells is released into the intracellular space. White blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and porphyrin.

Ferritin and hemosiderin

Ferritin is a protein that contains iron and is the primary form of iron stored inside of cells. The small amount of ferritin that is released and circulates in the blood is a reflection of the total amount of iron stored in the body.

Iron is an essential trace element and nutrient that, among other functions, is necessary for the production of healthy red blood cells (RBCs). The body cannot produce iron and must absorb it from the foods we eat or from supplements.

In healthy people, most of the iron absorbed by the body is incorporated into the hemoglobin of red blood cells. Most of the remaining is stored as ferritin or as hemosiderin, with additional small amounts used to produce other proteins such as myoglobin and some enzymes. Ferritin and hemosiderin are present primarily in the liver but also in the bone marrow, spleen, and skeletal muscles.

When the level of iron is insufficient to meet the body’s needs, the level of iron in the blood drops, iron stores are depleted and ferritin levels decrease. This may occur because:

• Not enough iron is consumed (either foods or supplements)
• The body is unable to absorb iron from the foods eaten in conditions such as celiac disease
• There is an increased need for iron such as during pregnancy or childhood, or due to a condition that causes chronic blood loss (e.g., peptic ulcer, colon cancer).

Insufficient levels of circulating and stored iron may eventually lead to iron deficiency anemia (decreased hemoglobin). In the early stage of iron deficiency, no physical effects are usually seen and the amount of iron stored may be significantly depleted before any signs or symptoms of iron deficiency develop. If a person is otherwise healthy and anemia develops over a long period of time, symptoms seldom appear before the hemoglobin in the blood drops below the lower limit of normal.

However, as the iron-deficiency progresses, symptoms eventually begin to appear. The most common symptoms of iron deficiency anemia include fatigue, weakness, dizziness, headaches and pale skin. (Read the article on Anemia to learn more.)

Conversely, iron storage and ferritin levels increase when more iron is absorbed than the body needs. Absorbing too much iron over time can lead to the progressive buildup of iron compounds in organs and may eventually cause their dysfunction and failure. An example of this is hemochromatosis, a rare genetic disease in which the body absorbs too much iron, even on a normal diet. Additionally, iron overload can occur when a person undergoes repeated blood transfusions.

Hemosiderin deposition

Hemosiderin deposition in the lungs is often seen after diffuse alveolar hemorrhage. Thus, diseases such as Goodpasture’s syndrome, granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis), and idiopathic pulmonary hemosiderosis. Mitral stenosis can also lead to pulmonary hemosiderosis. Hemosiderin collects throughout the body in hemochromatosis. Hemosiderin deposition in the liver is a common feature of hemochromatosis and is the cause of liver failure in the disease. Deposition in the pancreas leads to diabetes and in the skin leads to hyperpigmentation. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebral arteriovenous malformations, cavernous hemangiomata. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis.

Hemosiderin may deposit in diseases associated with iron overload. These diseases are typically diseases in which chronic blood loss requires frequent blood transfusions, such as sickle cell anemia and thalassemia.

Hemosiderosis causes

Primary pulmonary hemosiderosis

• Idiopathic pulmonary hemosiderosis – The most common cause of pulmonary hemosiderosis in childhood
• Heiner syndrome – Hypersensitivity to proteins from cow’s milk
• Goodpasture syndrome – Anti-glomerular basement membrane (GBM) antibody–mediated hemosiderosis

Secondary pulmonary hemosiderosis

• Congenital or acquired cardiopulmonary abnormalities -Bronchogenic cyst, pulmonary sequestration, congenital arteriovenous fistula, tetralogy of Fallot, Eisenmenger complex, mitral valve stenosis, pulmonic valve stenosis, congenital pulmonary vein stenosis, pulmonary arterial stenosis, pulmonary embolism, left ventricular failure
• Infections and their complications – Bacterial pneumonia, sepsis (disseminated intravascular coagulation [DIC]), pulmonary abscess, bronchiectasis, bronchiolitis obliterans
• Immunologically mediated diseases – Systemic lupus erythematosus (SLE), periarteritis nodosa, granulomatosis with polyangiitis (Wegener’s granulomatosis), Henoch-Schönlein purpura, immune complex–mediated glomerulonephritis, allergic bronchopulmonary aspergillosis
• Neoplasms – Primary bronchial tumors (adenoma, carcinoid, sarcoma, hemangioma, angioma) or metastatic lesions (sarcoma, Wilms tumor, osteogenic sarcoma)
• Drugs – Penicillamine, cocaine
• Toxins – Pesticide substances (synthetic peritroids)
• Environmental molds -Salamandra atra, Memnoniella echinata
• Miscellaneous causes – Retained foreign body, pulmonary trauma, pulmonary alveolar proteinosis, congenital hyperammonemia

Hemosiderosis symptoms

The classic symptoms associated with idiopathic pulmonary hemosiderosis include hemoptysis, anemia, and the collection of substances such as iron in the lungs (pulmonary infiltrates) ¹. Other symptoms associated with the disease may include coughing, wheezing, difficulty breathing, weakness, fatigue, and a limited ability to exercise. When the disease occurs in children, they may not grow as quickly as they should ².

For some people, signs and symptoms of idiopathic pulmonary hemosiderosis begin suddenly, while for others the progression of the disease may be slower. For most, signs and symptoms begin between the age of 1-7 years, but signs and symptoms can begin at any age of life from childhood through adulthood ³.

Hemosiderosis diagnosis

Idiopathic pulmonary hemosiderosis is typically diagnosed by a combination of laboratory tests, imaging, and sometimes a lung biopsy ². Diagnosis of the disease is based on ruling out other possible causes of the symptoms, including other types of pulmonary hemosiderosis. The diagnosis of idiopathic pulmonary hemosiderosis may include procedures such as ²:

• Complete blood count
• Analysis of blood serum for antibodies that could indicate other conditions
• Chest x-ray
• CT scan
• Pulmonary function testing
• Lung biopsy
• Serologic analysis
  • Titers of serum precipitins to casein and lactalbumin are elevated in Heiner syndrome.
  • Circulating anti-GBM antibodies are present in patients with Goodpasture syndrome.
  • Antineutrophil cytoplasmic antibodies (C-ANCA) are present in patients with granulomatosis with polyangiitis (Wegener’s granulomatosis).
  • Antinuclear antibodies and anti-DNA antibodies are positive in systemic lupus erythematosus (SLE).
  • Serologic markers for celiac disease include gliadin antibodies and reticulin antibodies. If findings are positive, then consider performing a jejunal biopsy.
• Sputum analysis
  • Perform stain, culture, and sensitivity for bacteria, fungi, and mycobacteria.
  • Cytology may reveal hemosiderin-laden macrophages, which suggests bleeding during the preceding months and ongoing bleeding for more than 3-4 days.
• Urinalysis – Hematuria and/or proteinuria in pulmonary hemosiderosis secondary to immune-mediated glomerulonephritis, Goodpasture syndrome, and SLE
• Prothrombin time/activated partial thromboplastin time – Used to rule out bleeding disorders
• von Willebrand factor antigen and Ristocetin cofactor levels – May be obtained to assess for von Willebrand disease
• IgA antiendomysial antibody level – Facilitates the diagnosis of celiac disease. However, histologic examination of a duodenal biopsy sample remains the criterion standard.

Imaging studies

Chest radiography

• The most common finding is patchy alveolar infiltrates that are often perihilar or basilar and are usually bilateral. Infiltrates may be migratory.
• Interstitial changes are found in long-standing pulmonary hemosiderosis.
• Occasionally, chest radiograph findings may be normal.
• Hilar lymph nodes may be enlarged, especially in the acute stage.
• Resolution, often with a persistent reticular pattern, occurs in less than 2 weeks.

CT scanning

• May show areas of increased pulmonary density due to intra-alveolar hemorrhage and/or hemosiderin-laden macrophages, even when the chest radiograph findings appear normal
• Useful in distinguishing superimposed infections from fresh hemorrhages
• Helpful if focal pulmonary causes, endobronchial lesions, or vascular malformations are suspected
• Useful in demonstrating the exact localization of lesions for open lung biopsy

Nuclear scanning

• The lungs of healthy patients do not take up red blood cells labeled with chromium isotope (51 Cr) or technetium Tc 99 (99 Tc) pertechnetate.
• Scans with abnormal pulmonary uptake 12-24 hours after the injection have been observed in patients with pulmonary hemorrhage.

Ventilation/perfusion scanning – Important if pulmonary embolism is suspected

Hemosiderin treatment

Treatment for hemosiderin focuses on treating of the underlying disease leading to continued iron deposition. In hemochromatosis, this entails frequent phlebotomy. In diseases such as granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis), immune suppression is required. Limiting blood transfusions and institution of iron chelation therapy when iron overload is detected are important when managing sickle-cell anemia and other chronic hemolytic anemias.

The treatment of idiopathic pulmonary hemosiderosis is aimed at managing acute crises and providing long-term therapy. Potential therapies may include ²:

• Oxygen supplementation
• Blood transfusion to correct severe anemia and shock
• Supportive respiratory therapy for excessive secretions and bronchospasm
• Mechanical ventilation for respiratory failure
• Immunosuppressive therapy, especially corticosteroids. Long-term immunosuppressive therapy in hemosiderosis management remains controversial.

Some individuals with idiopathic pulmonary hemosiderosis may also have celiac disease. For these individuals, a gluten-free diet is recommended in addition to other therapies ⁴.

Treatment of secondary hemosiderosis is usually directed toward the underlying condition. The main treatment for milk-associated pulmonary hemosiderosis is avoidance of milk and dairy products.

Iron chelation therapy

The hemoglobin in red blood cells is an iron-rich protein. Thus, regular blood transfusions can lead to a buildup of iron in the blood. This condition is called iron overload. It damages the liver, heart, and other parts of the body.

To prevent this damage, doctors use iron chelation therapy to remove excess iron from the body. Two medicines are used for iron chelation therapy.

• Deferoxamine is a liquid medicine that’s given slowly under the skin, usually with a small portable pump used overnight. This therapy takes time and can be mildly painful. Side effects include problems with vision and hearing.
• Deferasirox is a pill taken once daily. Side effects include headache, nausea (feeling sick to the stomach), vomiting, diarrhea, joint pain, and tiredness.

References

1. Chin CIC, Kohn SL, Keens TG, Margetis MF, and Kato RM. A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis. Orphanet J Rare Dis. August 20, 2015; 10:98. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545926
2. Hemosiderosis. https://emedicine.medscape.com/article/1002002-overview
3. 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, and Corvol H. New insights into pediatric idiopathic pulmonary hemosiderosis: the French RepsiRare cohort. Orphanet Journal of Rare Diseases. 2013; 8:161. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852822
4. Idiopathic pulmonary hemosiderosis. https://www.uptodate.com/contents/idiopathic-pulmonary-hemosiderosis