Hemosiderosis 

Updated: Aug 27, 2018
Author: Galia D Napchan, MD; Chief Editor: Denise Serebrisky, MD 

Overview

Background

Pulmonary hemosiderosis (PH) is characterized by repeated episodes of intra-alveolar bleeding that lead to abnormal accumulation of iron as hemosiderin in alveolar macrophages and subsequent development of pulmonary fibrosis and severe anemia. See the image below.

Image of a kidney viewed under a microscope. The b Image of a kidney viewed under a microscope. The brown areas contain hemosiderin.

Pulmonary hemosiderosis can occur as a primary disease of the lungs or can be secondary to cardiovascular or systemic disease. In children, primary pulmonary hemosiderosis is more common than secondary types.

Three variants of primary pulmonary hemosiderosis are recognized: (1) pulmonary hemosiderosis associated with antibody to the basement membrane of the lung and kidney (ie, Goodpasture syndrome), (2) pulmonary hemosiderosis associated with hypersensitivity to proteins in cow's milk (ie, Heiner syndrome), and (3) idiopathic pulmonary hemosiderosis (IPH).

The diagnosis of isolated pulmonary hemosiderosis or idopathic pulmonary hemosiderosis is a diagnosis of exclusion, requiring thorough review and elimination of other causes of primary and secondary pulmonary hemosiderosis.

Pathophysiology

In 1975, Thomas and Irwin divided pulmonary hemosiderosis into 3 categories: one category in which anti–glomerular basement membrane (anti-GBM) is present, a second category in which immune complexes are found, and a third category in which neither can be demonstrated.

Following this classification, the pathophysiology of pulmonary hemosiderosis[1] can be divided into 3 groups.

Group 1 pulmonary hemosiderosis is defined by pulmonary hemorrhage associated with circulating anti-GBM antibodies. This condition defines Goodpasture syndrome. This syndrome is characterized by linear immunofluorescence deposition of immunoglobulin and complement along the basement membrane of the lung tissue and the kidney glomeruli and is associated with vascular damage and diffuse defragmentation of the basement membrane on electron microscopy.

Group 2 pulmonary hemosiderosis is defined as pulmonary hemorrhage and immune complex disease. This combination has been reported as a rare manifestation of systemic lupus erythematosus (SLE) and other connective tissue disorders, including cryoglobulinemia, Henoch-Schönlein purpura, mixed connective tissue disease, and Wegener granulomatosis.

Studies of patients with pulmonary hemosiderosis associated with hypersensitivity to cow's milk (ie, Heiner syndrome) have demonstrated circulating immune complexes; alveolar deposits of immunoglobulin G (IgG), immunoglobulin A (IgA), and C3; peripheral blood eosinophilia; and delayed hypersensitivity to proteins from cow's milk.

Group 3 pulmonary hemosiderosis is defined as pulmonary hemorrhage without demonstrable immunologic association. This category includes idopathic pulmonary hemosiderosis, bleeding disorders, cardiovascular diseases, widespread infection, and toxic inhalation. Idiopathic pulmonary hemosiderosis is morphologically characterized by intra-alveolar hemorrhage and subsequent abnormal accumulation of iron in the form of hemosiderin inside pulmonary macrophages. Recurrent episodes of hemorrhage lead to thickening of the alveolar basement membrane and interstitial fibrosis. Transmission electron microscopy of lung biopsies has shown that the major damage in this disorder involves capillary endothelium and its basement membrane, but no electro-dense deposits have been identified.

In the early 1990s, the incidence of acute idiopathic pulmonary hemosiderosis in young infants increased in several midwestern US cities, especially in the Cleveland area. Epidemiological research led to the discovery of heavy growth of the toxigenic fungus Stachybotrys atra in almost all of the case homes, suggesting that exposure to that mold can cause idiopathic pulmonary hemosiderosis in infants. Subsequent data question this association.

Epidemiology

Frequency

United States

Idiopathic pulmonary hemosiderosis is an uncommon yet well-recognized disorder. Exact figures regarding prevalence are lacking. Familial recurrence has been reported but is rare.

International

Idiopathic pulmonary hemosiderosis is a rare disorder, with a reported yearly incidence of 0.24 (Sweden) and 1.23 (Japan) cases per million children.

Mortality/Morbidity

No national database monitors children with pulmonary hemosiderosis. Patients with idiopathic pulmonary hemosiderosis have a mean survival rate of 2.5-5 years after diagnosis. Death can occur acutely from massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

Sex

In patients younger than 10 years, reports of idiopathic pulmonary hemosiderosis show equal distribution between males and females in the United States, Sweden, and Greece; however, in Japan the female-to-male ratio was 2.25:1. In patients older than 10 years, the male-to-female ratio is 2:1.

Age

Idiopathic pulmonary hemosiderosis may occur in people of any age, from the neonatal period to late adulthood, but it is most common in children aged 1-7 years. Goodpasture syndrome usually occurs in young adult males and is rare in infants. Heiner syndrome is usually diagnosed in children aged 6 months to 2 years.

 

Presentation

History

See the list below:

  • A triad of hemoptysis, iron deficiency anemia, and diffuse pulmonary infiltrates characterizes pulmonary hemosiderosis (PH).

  • Clinical presentation can range from an insidious onset to a fulminant course.

  • Hemoptysis may or may not be present in children. The absence of this symptom does not rule out the diagnosis of pulmonary hemosiderosis.

  • Sudden decrease in hematocrit levels associated with the onset of active respiratory disease is strongly suggestive of pulmonary hemosiderosis.

  • Nonspecific recurrent or chronic pulmonary symptoms, such as cough (dry or productive), dyspnea, tachypnea, and wheezing, are observed in most patients.

  • With severe pulmonary hemorrhage, hypoxemia and frank respiratory failure may result.

  • Symptoms of chronic fatigue, severe exercise limitation, and growth failure may accompany long-standing pulmonary hemosiderosis.

  • In Heiner syndrome, common clinical symptoms include chronic rhinitis, recurrent otitis media, recurrent cough, and poor weight gain. In these patients, symptoms improve when cow's milk is removed from the diet.

  • Pulmonary hemosiderosis, while uncommon, can occur in association with a wide variety of clinical disorders, many of which have overlapping features of glomerulonephritis and immune complex diseases.

  • von Willebrand disease, the most common inherited bleeding disorder, has multiple variants. Patients with this condition tend to have mucocutaneous bleeding and can present with pulmonary hemorrhage.

  • The combination of idiopathic pulmonary hemosiderosis (IPH) and celiac disease is extremely rare. In this case, pulmonary bleeding can occur in association with severe anemia and GI symptoms (eg, diarrhea, steatorrhea, flatulence) or even in the absence of the latter.

Physical

See the list below:

  • After an acute episode of pulmonary hemorrhage, the physical examination may reveal the following:

    • Tachypnea

    • Dyspnea (use of accessory muscles, retractions, flaring)

    • Pallor

    • Tachycardia

    • Cyanosis

    • Crackles

    • Wheezing

    • Fever

  • Long-standing severe pulmonary hemosiderosis is associated with the following:

    • Clubbing

    • Growth failure

Causes

See the list below:

  • 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, Wegener 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 -S atra, Memnoniella echinata

    • Miscellaneous causes - Retained foreign body, pulmonary trauma, pulmonary alveolar proteinosis, congenital hyperammonemia

 

DDx

 

Workup

Laboratory Studies

The following studies are indicated in pulmonary hemosiderosis (PH)

  • CBC count

    • Microcytic and hypochromic anemia are present.

    • Eosinophilia has been present in approximately one eighth of reported cases. Most of these cases are associated with Heiner syndrome.

  • Stool guaiac test results - Frequently positive

  • Analysis of gastric lavages - Positive for iron-laden macrophages

  • Immunoglobulin E level - High levels possible in Heiner syndrome

  • 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 Wegener 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

See the list below:

  • 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 RBCs 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

Other Tests

See the list below:

  • After an episode of acute hemorrhage, pulmonary function testing (PFT) demonstrates decreased compliance, airflow obstruction, and an increase in the diffusing capacity for carbon monoxide (due to increased hemoglobin uptake of carbon monoxide by sequestrated RBCs in the lungs).

  • In long-standing pulmonary hemosiderosis, PFT results demonstrate a restrictive pattern.

Procedures

See the list below:

  • Flexible bronchoscopy

    • Performed to assess the anatomy of the airways for pulmonary malformations, endobronchial lesions, retained foreign body, and airway compression

    • Used to perform bronchoalveolar lavage (BAL)

  • Bronchoalveolar lavage

    • Hemosiderin-laden macrophages: Hemosiderin-laden macrophages are diagnostic for PH. They are usually cleared from the alveoli and airways within a few months of the bleeding. The microphages are observed 2-3 days after acute bleeding.

    • Malignant cells in cases of neoplasms (extremely uncommon in pediatric patients)

    • Positive stains and cultures for bacteria, fungi, and mycobacteria in cases of infection

  • Open lung biopsy

Histologic Findings

See the list below:

  • Findings in the lung vary with the stage of the disease.

  • In the early stages, interstitial and intra-alveolar hemorrhages predominate, with collections of both free hemosiderin and hemosiderin-laden macrophages found in the alveolar spaces and in the interstitium.

  • As the disease progresses, interstitial fibrosis develops.

  • Immunofluorescence and electron microscopy of the lung and kidney tissue may differentiate idiopathic pulmonary hemosiderosis (IPH) from Goodpasture syndrome and immune complex–mediated diseases.

 

Treatment

Medical Care

The treatment of pulmonary hemosiderosis (PH) is directed toward management of the acute crises and long-term therapy.

  • Management of episodes of acute pulmonary hemorrhage includes the following:

    • Oxygen supplementation

    • Blood transfusion to correct severe anemia and shock

      • A study by de Jongh et al recommended screening for hemosiderosis in all patients receiving multiple transfusions.[2]

    • Supportive respiratory therapy for excessive secretions and bronchospasm

    • Mechanical ventilatory support for respiratory failure

    • Extracorporeal membrane oxygenation (proven to be effective after failure of conventional mechanical ventilation)

    • Immunosuppressive therapy

  • Long-term immunosuppressive therapy in hemosiderosis management remains controversial.

  • The main treatment for milk-associated pulmonary hemosiderosis is avoidance of milk and dairy products.

  • Treatment of secondary hemosiderosis is usually directed toward the underlying condition. A gluten-free diet is indicated in cases of celiac disease associated with pulmonary hemosiderosis, even in the absence of GI symptoms.[3]

Surgical Care

See the list below:

  • Surgical care is not indicated.

Consultations

See the list below:

  • Pediatric pulmonologist

  • Pediatric nephrologist when pulmonary hemosiderosis is associated with abnormal urinalysis findings

Diet

See the list below:

  • In patients with Heiner syndrome, the main treatment is avoidance of milk and dairy products.

  • Patients with hemosiderosis associated with celiac disease who are treated with a gluten-free diet show improvement of clinical symptoms and show improvement on radiography findings within 2 weeks.[3]

Activity

See the list below:

  • No activity limitation is indicated.

 

Medication

Medication Summary

For isolated pulmonary hemosiderosis (IPH), corticosteroids are believed to be useful in the management of the acute alveolar hemorrhage stage. Failure to respond adequately to corticosteroids alone or unacceptable corticosteroid adverse effects may be indications for using other forms of immunosuppression (eg, azathioprine, chloroquine, cyclophosphamide). Published experience with these medications has been very limited and is confined to case reports.[4] Inhaled corticosteroids also have been used, but current reports are insufficient.

Case reports have described the use of other immunosuppressive medications in the long-term management of idiopathic pulmonary hemosiderosis. One report commented on the use of chloroquine in 3 children with idiopathic pulmonary hemosiderosis, with improvement in the course of their disease. Another report mentioned the efficacy of a combination of azathioprine and corticosteroids in abating acute exacerbations of the disease in a child with idiopathic pulmonary hemosiderosis. The long-term efficacy of immunosuppressive therapy is still in doubt.

Immunosuppressive agents

Class Summary

These agents are used for patients with conditions caused by immune dysregulation and autoimmunity. A lack of knowledge about the pathogenetic mechanisms involved in idiopathic pulmonary hemosiderosis makes the theoretical basis of such therapies unclear.[5]

Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

High doses of prednisone or the equivalent dosage of an IV preparation (eg, methylprednisolone) should be used in the management of acute crisis. For IPH, high-dose corticosteroid usage should be continued for at least 7 d after substantial bleeding has subsided, and the dosage should be tapered over several wk. Some children tolerate complete weaning from corticosteroids in this fashion, but other children demonstrate the need for long-term use.

 

Follow-up

Further Outpatient Care

See the list below:

  • Periodic evaluation of growth, oxygen saturation, pulmonary and renal function, and hemography and chest radiography findings is appropriate in patients with pulmonary hemosiderosis.

  • Long-term steroid use requires frequent monitoring for possible adverse effects.

Deterrence/Prevention

See the list below:

  • Patients with Heiner syndrome should avoid milk and dairy products.

Complications

See the list below:

  • Respiratory failure requiring mechanical ventilatory support may occur after an episode of acute pulmonary hemorrhage.

  • Chronic cor pulmonale with pulmonary hypertension secondary to pulmonary fibrosis has been described in a minority of patients with idiopathic pulmonary hemosiderosis (IPH) who have lived for an exceptionally long time after the onset of their disease.

Prognosis

See the list below:

  • The prognosis for the pulmonary hemosiderosis syndromes as a group is difficult to determine because of the infrequency of the diagnosis and the variability among cases and etiologies. Furthermore, no national database monitors children with PH.

  • When focusing on idiopathic pulmonary hemosiderosis, the clinical course widely varies; however, the prognosis has always been regarded as poor, with a mean survival of 2.5-3 years after diagnosis. Death can occur acutely from massive hemorrhage or after progressive pulmonary insufficiency and right heart failure. The available therapeutic modalities are not associated with a better outcome.

  • One study of 30 children with idiopathic pulmonary hemosiderosis listed the following prognostic criteria:

    • The severity of the disease at its onset does not correlate with the survival.

    • Females survive longer than males.

    • Young age at the onset of disease seems to carry a less favorable prognosis.

    • Common therapeutic modalities have not improved outcome.

  • Another retrospective study of 15 children with idiopathic pulmonary hemosiderosis found that the presence of antineutrophil cytoplasmic antibodies (ANCA) or other autoantibodies signal poor prognosis. The same study, in which the mean duration of follow-up was 17.2 years (range, 10-36 y), reported a survival rate of 80%

  • In pulmonary hemosiderosis associated with milk protein allergy, avoidance of dairy products is usually associated with complete remission.[6]