eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Hemosiderosis

Author: Galia D Napchan, MD, Assistant Professor of Pediatrics, Pediatric Pulmonologist, University of Miami, Miller School of Medicine and Jackson Memorial Hospital; Director of the Asthma Center and Director of the Infant Pulmonary Function Test Lab, Jackson Memorial Hospital
Coauthor(s): Isaac Talmaciu, MD, Clinical Assistant Professor, Department of Pediatrics, Florida Atlantic University School of Medicine
Contributor Information and Disclosures

Updated: Sep 28, 2009

Introduction

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.

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 hemosiderosis¹ 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.

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.

Clinical

History

• 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

• 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

• 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

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