Hemosiderosis

Hemosiderosis is an abnormal deposition of hemosiderin (iron-containing compound) in tissues, a form of iron overload disorder often associated with diseases in which there is extensive destruction of red blood cells (e.g., thalassemia), with chronic blood transfusion therapy being the major cause of iron overload in thalassemia. The lungs and kidneys are often sites of hemosiderosis.

Thalassemias are inherited blood disorders. “Inherited” means that the disorder is passed from parents to children through genes. Thalassemias cause the body to make fewer healthy red blood cells and less hemoglobin than normal. Hemoglobin is an iron-rich protein in red blood cells. It carries oxygen to all parts of the body. Hemoglobin also carries carbon dioxide (a waste gas) from the body to the lungs, where it’s exhaled. People who have thalassemias can have mild or severe anemia. Anemia is caused by a lower than normal number of red blood cells or not enough hemoglobin in the red blood cells.

Hemosiderosis can result from:

• Direct bleeding into the tissues that is followed by breakdown of red blood cells and release of iron to the tissues
• Destruction of red blood cells within the blood vessels, leading to release of iron into the blood followed by accumulation of iron inside the kidneys as the kidneys filter waste from the blood

Organs may be damaged by the iron deposits. The extent of the damage depends on how much iron is deposited in the organs. Some people have no damage at all, whereas others have some damage. Hemosiderosis caused by bleeding and red blood cell breakdown does not usually require treatment.

If there is bleeding within an organ, such as in the lungs of people who have certain types of lung disease (e.g., idiopathic pulmonary hemosiderosis, Goodpasture syndrome), iron from the blood cells often remains in that organ. Depending on the amount of iron that remains in the lungs people may have no problems or varying degrees of lung damage. Idiopathic pulmonary hemosiderosis is a rare disease characterized by repeated episodes of bleeding into the lungs, which can cause anemia and lung disease. The body is able to remove most of the blood from the lungs, but a large amount of iron is left behind. Over time, this iron can cause permanent damage to the lungs (fibrosis). Symptoms can resemble pneumonia and include coughing, coughing up blood (hemoptysis), difficulty breathing, and wheezing ¹. The cause of idiopathic pulmonary hemosiderosis is unknown. Diagnosis is based on ruling out other kinds of pulmonary hemosiderosis, and tests may include imaging, laboratory tests, and a lung biopsy. Treatment often includes corticosteroids or other immunosuppressive medications ². The prognosis may vary depending on the amount of pulmonary bleeding and age of diagnosis.

Disorders that cause inflammation that lasts for an extended period, such as nonalcoholic fatty liver disease and the metabolic syndrome, can cause hemosiderosis.

If people have a disorder that causes excessive breakdown of red blood cells within the blood vessels (for example, hemolytic anemia), iron released from the red blood cells can accumulate within the kidneys (renal hemosiderosis). Most cases of renal hemosiderosis do not cause kidney damage.

Hemosiderosis can also occur due to excessive iron absorption, but in that case, doctors call the condition hemochromatosis. Hemochromatosis more often requires treatment.

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) ². 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 ¹.

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 ¹. 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 ¹:

• 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

Hemosiderosis treatment

The treatment of idiopathic pulmonary hemosiderosis is aimed at managing acute crises and providing long-term therapy. Potential therapies may include ¹:

• 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. Hemosiderosis. https://emedicine.medscape.com/article/1002002-overview
2. 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
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