There are mainly two types
of 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.
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 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.
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
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.
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 .
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
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· Pyrexia
References
