Hemosiderosis

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

There are mainly two types of hemosiderosis.

Transfusion hemosiderosis

Idiopathic pulmonary hemosiderosis

Hemosiderin deposition in the lungs is often seen after diffuse alveolar hemorrhage, which occurs in diseases such asGoodpasture's syndrome, 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 diabetesand in the skin leads to hyperpigmentation. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebralarteriovenous 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 in the kidneys have been associated with marked hemolysis and a rare blood disorder called paroxysmal nocturnal hemoglobinuria.

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, though beta thalassemia minor has been associated with hemosiderin deposits in the liver in those with non-alcoholic fatty liver disease independent of any transfusions.

Transfusion hemosiderosis

Transfusionalhemosiderosis is the accumulation of iron in the liver and/or heart but also endocrine organs, in patients who receive frequent blood transfusions (such as those with thalassemia, sickle cell disease, aplastic anemia or myelodysplastic syndrome).

 

Idiopathic pulmonary hemosiderosis

Idiopathic pulmonary haemosiderosis (or idiopathic pulmonary hemosiderosis; IPH) is a lung disease of unknown cause that is characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs. It is rare, with an incidencebetween0.24 and 1.23 cases per million people.

What is hemosiderin?

Hemosiderin or haemosiderin is an iron-storage complex. It is always found within cells (as opposed to circulating in blood) and appears to be a complex of ferritin, denatured ferritin and other material. The iron within deposits of hemosiderin is very poorly available to supply iron when needed.

Several disease processes result in deposition of larger amounts of hemosiderin in tissues; although these deposits often cause no symptoms, they can lead to organ damage.

Hemosiderin is most commonly found in macrophages and is especially abundant in situations following hemorrhage, suggesting that its formation may be related to phagocytosis of red blood cells and hemoglobin. Hemosiderin can accumulate in differentorgans in various diseases.

Iron is required by many of the chemical reactions (i.e. oxidation-reduction reactions) in the body but is toxic when not properly contained. Thus, many methods of iron storage have developed.

Hemosiderin often forms after bleeding (hemorrhage).^[1] When blood leaves a ruptured blood vessel, the red blood cell dies, and the hemoglobin of the cell is released into the extracellular space. White blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and biliverdin.

Epidemiology

Transfusion hemosiderosis

 

 

Frequency

 

 

United States

Amongst 342 patients with transfusion-dependent hemosiderosis in the National Institutes of Health (NIH) registry, 23% had iron overload as documented by a liver iron concentration of 15 mg/g dry weight or greater.Around 15,000 patients with sickle cell disorder and estimated and 5,000 with myelodysplastic syndromes and other acquired refractory anemias require blood transfusions.

 

International

In a Japanese cohort of transfusion-dependent patients with hemosiderosis and aplastic anemia, one third of all deaths were attributable to iron overload (97% of the deceased had a serum ferritin >1000 ng/mL). Cardiac failure was responsible for 24% and liver failure for 7% of all deaths. On average, each patient was transfused with more than 60 units of red blood cells per year.

Mortality/Morbidity

Mortality in chronically transfused patients with hemosiderosis and sickle cell disease is 3 times that of the general United States population. The most common cause of morbidity is cardiomyopathy (30%) that is induced by iron overload.

Race

The prevalence of mild to moderate iron overload was similar in black and white veterans in one autopsy study that evaluated the hepatic iron concentration of 256 specimens.

Sex

An analysis of data from 1861 patients with hemosiderosis from Italy showed that failure of puberty was the major clinical endocrine problem in these patients, and it was present in 51% of boys and 47% of girls, all older than 15 years. Secondary amenorrhea was recorded in 23% of the patients with β-thalassemia major.

 

 

Age

Several distinct groups can be recognized in terms of the initiation of transfusion therapy. The average age of patients undergoing transfusion initiation is 4 years in thalassemia and 13 years in hemosiderosis in adults, the average age at transfusion initiation is in the 40s for aplastic anemia, and in the 60s for myelodysplasia.

Idiopathic pulmonary hemosiderosis

 

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.

Etiology 

Causes of Hemosiderosis 

The follow list shows some of the possible medical causes of Hemosiderosis .

·         Iron compounds

·         GRACILE syndrome

·         Ineffective erythropoiesis

·         Blood transfusion and complications

·         Porphyria cutaneatarda type 1 (sporadic)

·         Beta thalassaemia (heterozygous)

·         Ceruloplasmin deficiency

·         Atransferrinaemia, hereditary

·         Haemochromatosis

·         Haemoglobin E disease

·         Porphyria cutaneatarda type 2 (familial)

·         Beta thalassaemia (severe / homozygous)

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 hemosiderosiscan be divided into 3 groups.

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 Stachybotrysatra 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.

Clinical findings

Physical examination for pulmonary hemosiderosis

Symptoms

·        Persistent Cough

·        Breathlessness       

·         Coughing up blood  

·         Fatigue                                                                                                          

Signs 

·        Cyanosis

·        Rapid pulse

·        Difficulty in breathing

Investigation

 Acute stage

-  Chest X – ray demonstrates

-          B/L alveolar infiltrate

-         Sputum Examination

-         Heamosiderin laden

-          Alveolar macrophages

Laboratory tests

The following studies are indicated in pulmonary hemosiderosis (PH)

·         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

o    Titers of serum precipitins to casein and lactalbumin are elevated in Heiner syndrome.

o    Circulating anti-GBM antibodies are present in patients with Goodpasture syndrome.

o    Antineutrophil cytoplasmic antibodies (C-ANCA) are present in patients with Wegener granulomatosis.

o    Antinuclear antibodies and anti-DNA antibodies are positive in systemic lupus erythematosus (SLE).

o    Serologic markers for celiac disease include gliadin antibodies and reticulin antibodies. If findings are positive, then consider performing a jejunal biopsy.

·         Sputum analysis

o    Perform stain, culture, and sensitivity for bacteria, fungi, and mycobacteria.

o    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 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

Hemosiderosis Management &Treatment

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:

o    Oxygen supplementation

o    Blood transfusion to correct severe anemia and shock

o    Supportive respiratory therapy for excessive secretions and bronchospasm

o    Mechanical ventilatory support for respiratory failure

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

o    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. 

• Outcome
  
  
  
  
  IPH is a severe condition with variable prognosis and has a better outcome when diagnosis is made at an early age. We believe that it is necessary to include in the screening of any severe, recurrent, hypochromic anemia a well-interpreted chest radiograph and to look for hemosiderin-laden phages in bronchoalveolar lavage.
  Complications
  
  
  ·         Digital clubbing
  ·         Haemoptysis
  ·         Pulmonary hypertension
  ·         Pulmonary fibrosis
  ·         Breathlessness
  ·         Pyrexia
  
  
  
  
  
  
  References
  
  
  http://www.ncbi.nlm.nih.gov
  
  
  http://www.rightdiagnosis.com/h/hemosiderosis/
  
  
  http://emedicine.medscape.com/article/1002002-treatment
  
  
  http://www.uptodate.com/
  
  
  http://www.nejm.org/doi/full/10.1056/NEJM195912032612303
  
  
  http://en.wikipedia.org/wiki/Idiopathic_pulmonary_haemosiderosis
  
  
  http://www.madisonsfoundation.org/
  
  
  http://emedicine.com/ped/topic970.htm
  http://pediatrics.aappublications.org/
  http://www.madisonsfoundation.org
  http://www.steadyhealth.com/
  http://www.uptodate.com/contents/idiopathic-pulmonaryhemosiderosis
  http://rarediseases.about.com/cs/hemosiderosis/a/092103.htm
  http://www.webmedcentral.com/article_view/907
  http://www.hawaii.edu/medicine/pediatrics/pedtext/s08c07.html
  http://www.hindawi.com/crim/medicine/2012/267857/