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Hemosiderosis

Hemosideroses

Hemosiderosis is a type of iron disorders associated with the accumulation of iron in the body leading to excessive deposition of hemosiderin. There are different types of hemosiderosis including transfusion hemosiderosis, idiopathic pulmonary hemosiderosis (IPH) and transfusional diabetes.


Presentation

There are different types of signs and symptoms which are commonly associated with hemosiderosis. The clinical manifestation of pulmonary hemosiderosis has three main features which include hemoptysis, iron deficiency anemia, and diffuse pulmonary infiltrates. The presentation may range from a slow onset of symptoms to a fulminant pattern. Affected individuals may present with or without hemoptysis. However, absence of hemoptysis does not rule out the diagnosis of pulmonary hemosiderosis. A rapid decrease in hematocrit is related to the development of active respiratory disease and strongly indicative of pulmonary hemosiderosis. There are nonspecific, persistent, and chronically manifesting symptoms which include, dry or productive cough, dyspnea, tachypnea, and wheezing. Also, severe pulmonary bleeding, hypoxemia and specific respiratory failure may develop. Patient may show signs of chronic fatigue, severe exercise impairment and growth failure along with chronic pulmonary hemosiderosis. Although pulmonary hemosiderosis is a rare condition, it may occur along with different types of clinical disorders, most of which may have interrelated characteristics such as, glomerulonephritis and immunological complex diseases. 

Patients with Heiner syndrome usually have clinical symptoms such as chronic rhinitis, persistent otitis media, frequent cough, and weight loss. There is a significant recovery in the affected patients, following exclusion of cow milk in their diets. Another disorder which can cause pulmonary bleeding is von Willebrand disease. This disorder is the most common type of bleeding disorder, which is genetically inherited with different variants. Affected patients usually present with bleeding of the mucocutaneous tissues and sometimes show pulmonary hemorrhage. A comorbidity involving idiopathic pulmonary hemosiderosis and celiac disease is very rare, but pulmonary bleeding may develop in relation to severe anemia and gastrointestinal tract symptoms such as diarrhea, steatorrhea and flatulence

Hemosiderosis of the kidneys rarely causes significant clinical manifestations. The deposition of hemosiderin in the brain may lead to sensorineural hearing loss, ataxia and pyramidal signs. Hepatic hemosiderosis may cause symptoms of hemochromatosis and liver cirrhosis.

Movement Disorder
  • Abstract Secondary parkinsonism has comprised about 20 to 40 percent of all parkinsonism patients in movement disorders clinic. Most of them are induced by certain medications.[ncbi.nlm.nih.gov]
Rhinitis
  • She complained of headache, dyspnea, rhinitis, weakness and recurrent severe hemoptysis. Chest radiographs revealed bilateral patchy infiltrates, predominantly in the lower parts of both lungs.[ncbi.nlm.nih.gov]
  • Patients with Heiner syndrome usually have clinical symptoms such as chronic rhinitis, persistent otitis media, frequent cough, and weight loss.[symptoma.com]
Urticaria
  • Biopsy of the urticaria like skin lesions demonstrated leukocytoclastic vasculitis. Rheumatological markers were negative. Levels of complement fractions 3 and 4 were normal. Chest x-ray demonstrated diffuse alveolar infiltrative images.[ncbi.nlm.nih.gov]

Workup

Various techniques are used in the workup of hemosiderosis. The diagnosis of some etiologies of hemosiderosis such as hemochromatosis may be difficult because initial symptoms which include stiff joints and fatigue are similar to other clinical disorders. Most individuals with hemochromatosis may not have any observable signs or symptoms except an increase of the iron levels in the blood. Most diagnosed cases are detected accidentally as a result of blood tests conducted either for other medical purposes or screening of family members with previous history of the disease.

Abnormal increase of iron in the blood can be estimated using two different laboratory test. These include estimation of serum transferrin saturation and serum ferritin. Serum transferrin saturation involves estimation of the amount of iron attached to a protein called transferrin. Transferrin is an iron carrying protein in the blood. Transferrin saturation level higher than 45% is considered to be abnormal. Serum ferritin on the other hand, estimates the amount of iron which is stored in the liver. If laboratory results shows a marked increase in the serum transferrin level, serum ferritin may be required. Since other clinical conditions may also cause an increase in the ferritin level, both laboratory investigations are important to establish diagnoses of the disorder. 

Other additional tests may also be done to confirm the diagnosis depending on the etiology. These frequently include, liver function tests, complete blood count, imaging, DNA analysis (e.g PCR) and histological examination (e.g liver biopsy, lung biopsy). Liver function tests may assist in detecting the level of disease progression or liver damage. Magnetic resonance imaging (MRI) is a rapid, noninvasive method to measure the level of iron overload in the liver. When compared with liver biopsy, MRI is not affected by errors associated with sampling variability and may be employed repeatedly [7]. Also, histopathological samples such as biopsy and fine needle aspirated cytology may be done to detect iron overload. For example, tissue biopsy of the liver may be conducted if the iron overload is suspected to be involved in liver damage. 

Iron Increased
  • In a sampling of one such review,[91] the causes of iron overload included increased ingestion of iron, increased intestinal iron absorption, up-regulation of hepatic transferrin receptor 1, secondary anemia caused by hemolysis, hypersplenism, ineffective[es.slideshare.net]

Treatment

Hemosiderosis develops due to excess accumulation hemosiderin and if not properly treated, it may have severe complications. Treatment for hemosiderosis varies and depends on the possible etiology. Generally, hemosiderosis may be managed by different therapeutic approaches. This may include blood transfusions if necessary or in case of blood loss. Low oxygen levels in the blood may require oxygen supplement. Most often, the use of corticosteroids and other medications which suppress the immune system may be required and cases of hemosiderosis, which develop due to Heiner syndrome may be corrected by a diet free of cow milk. There are controversial opinions about the use of long-term immunosuppressive therapy in managing hemosiderosis.

In patient with pulmonary hemosiderosis, treatment focuses on managing the acute episode and include a long-term regimen. Acute pulmonary hemorrhage may be managed by supplementing oxygen, blood transfusions (in conditions such as severe anemia or shock), respiratory therapeutic support (in cases of excessive secretions or bronchospasm) and immunosuppresive therapy. In patient with respiratory failure, mechanical ventilator may be used and if ineffective, extra-corporeal membrane oxygenation has been found to be efficient. 

The treatment approach for managing secondary hemosiderosis usually focuses on the underlying condition. In patient which develop pulmonary hemosiderosis secondary to celiac disease, a gluten-free diet is usually indicated, even without any noticeable development of gastrointestinal symptoms [8]. Radiography evaluation of patients with hemosiderosis that results from celiac disease managed using gluten-free diets, showed significant improvement in symptoms and disease resolution.

Immunosuppressive agents are selected for use in patient with hemosiderosis resulting from immune hyperactivity or autoimmunity. However, the choice of these agents is restricted due to unclear mechanisms of disease development and pathological features of idiopathic pulmonary hemosiderosis, thereby making the theoretical understanding of these therapies difficult [10]. In cases of isolated pulmonary hemosiderosis, the use of corticosteroids has been shown to be effective. However, in a failed regimen due to single use of only corticosteroids or contraindications associated with corticosteroid use, other drugs may be used including immunosuppressive drugs such as, azathioprine, chloroquine or cyclophosphamide. The use of chloroquine in managing children having idiopathic pulmonary hemosiderosis was previously mentioned in a report and significant improvement following the treatment was observed. In addition, combination therapy of both azathioprine and corticosteroids has been used in treating acute exacerbation associated with idiopathic pulmonary hemosiderosis in an affected child. Studies supporting the choice of these drugs are limited and mostly case reports [9]. 

Prognosis

The prognosis of hemosiderosis depends on the affected body part. For example, in pulmonary hemosiderosis, death of the affected patient may occur rapidly following acute, excessive pulmonary bleeding, pulmonary failure or heart failure.

Etiology

Hemosiderosis is a broad term which involves accumulation of hemosiderin in the body mainly in the reticuloendothelial system (RES) with little or no organ damage. There are different etiological factors which are responsible for hemosiderosis by causing accumulation of iron or iron overload in the body. These etiologies include hemochromatosis, a genetic disease which causes abnormal increase in iron absorption, frequent blood transfusions, prolonged intake of iron supplements or medications and increased hemolysis. Repeated blood transfusions may lead to depositional siderosis in the reticuloendothelial system. However, if the blood units transfused exceed 40, it may result into deposition of iron in other parts of the body other than the RES causing hemochromatosis.

Conditions marked by increased hemolysis such as hemolytic anemia and myelodysplasia usually lead to hemosiderosis. A rare disorder known as bantu siderosis resulting from the intake of iron-rich beer brewed locally, has also been reported in some parts of Africa. Hemosiderosis may also be caused by chronic infections and diseases related to the cardiac and immune system. 

Epidemiology

Globally, the prevalence rate of hemosiderosis is not known. One of the commonest forms of hemosiderosis is the idiopathic pulmonary hemosiderosis (IPH). It results from the deposition of the iron in the lungs. IPH is an uncommon clinical disorder worldwide, with varying incidence. In the United States, idiopathic pulmonary hemosiderosis is a rare but known clinical condition. The incidence of IPH has been reported in countries such as Sweden and Japan with a value of 0.24 and 1.23 in about 1 million children. The survival rate of idiopathic pulmonary hemosiderosis after the detection is between 2.5 to 5 years. Death usually occurs as a result of excessive bleeding or following gradual pulmonary insufficiency and right heart failure. In countries such as the United States, Sweden, and Greece, the report of idiopathic pulmonary hemosiderosis among children particularly those below 10 years of age, revealed an even distribution of the condition in males and females. Among older patients, above 10 years, a ratio of 2:1 is observed in male and female respectively. 

Other forms of hemosiderosis may be seen in conditions such as Goodpasture syndrome, which is usually observed among young adult males and rarely in children. Also, Heiner syndrome is commonly diagnosed among children between 24 weeks to 2 years of birth. Also, higher risk of hemosiderosis has been reported in men, especially among the 30 and 50 years age groups. Histopathological examination of liver tissue of chronic viral hepatitis may show features of iron deposition in the liver among 10-73% of the affected patients [6].

Sex distribution
Age distribution

Pathophysiology

Iron is an important constituent of red blood cells (i.e the hem part of the hemoglobin molecule). Hemoglobin is involved in the transportation of oxygen in the blood vessel and to the various cells of the body. This oxygen transport is important for specific cell activities such as cellular respiration and metabolic activity for life sustenance.

Pulmonary hemosiderosis is a rare clinical disorder, which may cause severe complications following pulmonary bleeding. Hemosiderosis may develop either primarily as a lung disease, or following cardiovascular or immune system diseases. Pulmonary hemosiderosis 1 is associated with circulating anti-GMBH antibodies, while pulmonary hemosiderosis 2 usually involves both pulmonary and immune complex disorders such as systemic lupus erythematosus (SLE). Pulmonary hemosiderosis 3 on the other hand does not involve any observable immune system affection. Different pulmonary diseases show symptoms similar to the clinical features observed in hemosiderosis and are not associated with the deposition of iron in the lungs. These pulmonary diseases may develop individually or in combination with hemosiderosis. These conditions include pulmonary fibrosis (PF), intra-alveolar bleeding (IAB), adult respiratory distress syndrome (ARDS) and immune complex disease. The distinguishing features of pulmonary hemosiderosis is the detection of iron deposit in the lungs.

Prevention

Hemosiderosis can be prevented by various means. For example, patients diagnosed with Heiner syndrome are discouraged from consuming milk or dairy products. Also, it is important that individuals do periodic medical check ups including laboratory investigations to estimate iron body levels in order to detect conditions such as hemochromatosis.

Summary

Hemosiderosis, characterized by deposition of hemosiderin, may affect various parts of the body. A specific feature of hemochromatosis is the deposition of hemosiderin in the liver. Iron deposition in pancreatic beta cells may lead to diabetes mellitus [1] [2] [3], in the skin it may cause hyperpigmentation. Most often, accumulation of hemosiderin in the skin gradually disappears following bruising. However, in other conditions such as stasis dermatitis, hemosiderin may persist.

An accumulation of hemosiderin in the lungs is usually observed following alveolar hemorrhage commonly seen in diseases which include Goodpasture syndrome (GPS), Wegener granulomatosis (Granulomatosis with polyangiitis), and idiopathic pulmonary hemosiderosis (IPH). Mitral valve stenosis may also result in pulmonary hemosiderosis.

The deposition of hemosiderin in the brain usually occurs following bleeding from chronic subdural hemorrhage (SDH), cerebral arteriovenous malformations (AVM), and cavernous hemangiomata (cavernous angioma). In the kidney, accumulation of hemosiderin is related to significant hemolysis and paroxysmal nocturnal hemoglobinuria.

Clinical conditions associated with iron overload in the body usually cause hemosiderin accumulation. Hemosiderosis often results from disorders requiring blood transfusions following chronic blood loss. These include sickle cell anemia and thalassemia. Deposition of hemosiderin in the liver has been observed in beta thalassemia minor particularly among patient with non-alcoholic fatty liver disease without relation to transfusions [4] [5].

Patient Information

Hemosiderosis is an uncommon clinical condition caused by accumulation of iron in the blood and other parts of the body such as the lungs. Iron is stored in the blood in the form of hemosiderin, which appears as a pigment in the blood. Although hemosiderosis is not transmissible, the underlying diseases which lead to the condition may be an infection which is transmissible in nature. Hemosiderosis is usually associated with anemia and could also result from heart diseases or the immune disorders. In children particularly those below 10 years, pulmonary hemosiderosis is the most common form of hemosiderosis. 

Hemosiderosis is diagnosed by various techniques. These may include taking previous history of the patient as well as the physical examination. Other diagnostic techniques which may be required include laboratory investigations such as hematological analysis (full blood count), liver function test, sputum culture and biopsies. Radiography examination such as chest X-ray, abdominal and chest ultrasound may be necessary. Patient with hemosiderosis should be properly managed because chronic cases may result into conditions such as glomerulonephritis or gradual deterioration of the glomerular filtration system, liver cirrhosis (causing persistent liver scarring and reduction in liver function), diabetes mellitus, cardiac diseases (e.g congestive heart failure) and death.

Patient diagnosed with hemosiderosis are treated by various means depending on the etiological agent and the clinician's observations. Low blood levels resulting from blood loss may be regulated by blood transfusions and shortage of blood oxygen may require supplemental oxygen. Also, medications such as corticosteroids may be administered to reduce immune system hyperactivity. Milk-free diet is usually recommended for patient with hemosiderosis caused by reactions to milk or dairy product intake. 

References

Article

  1. Lu JP, Hayashi K. Transferrin receptor distribution and iron deposition in the hepatic lobule of iron-overloaded rats. Pathol Int. 1995; 45(3): 202-6. 
  2. Lu JP, Hayashi K. Selective iron deposition in pancreatic islet B cells of transfusional iron-overloaded autopsy cases. Pathol Int. 1994; 44(3): 194-9. 
  3. Lu JP, Hayashi K, Okada S, Awai M. Transferrin receptors and selective iron deposition in pancreatic B cells of iron-overloaded rats. Acta Pathol Jpn. 1991; 41(9): 647-52. 
  4. Valenti L, Canavesi E, Galmozzi E et al. Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease. Journal of Hepatology. 2010; 53 (5): 927–33.
  5. Stickel F, Hampe J. Dissecting the evolutionary genetics of iron overload in non-alcoholic fatty liver disease. Journal of Hepatology. 2010; 53(5): 793–4.
  6. Cojocariu C, Trifan A, Mihailovici MS, Danciu M, Stanciu C. [Liver hemosiderosis study in chronic viral hepatitis]. Rev Med Chir Soc Med Nat Iasi. 2008; 112(4):914-21.
  7. St. Pierre T. G, Clark PR, Chua-Anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005; 105 (2): 855–61.
  8. Sethi GR, Singhal KK, Puri AS, Mantan M. Benefit of gluten-free diet in idiopathic pulmonary hemosiderosis in association with celiac disease. Pediatr Pulmonol. 2010; 21. 
  9. Kahraman H, Köksal N, Ozkan F. Eight Years Follow-up of a Case with Idiopathic Pulmonary Hemosiderosis After Corticosteroid Therapy. N Am J Med Sci. 2012 Jan. 4(1):49-51. 
  10. Bhatia S, Tullu MS, Vaideeswar P, Lahiri KR. Idiopathic pulmonary hemosiderosis: alveoli are an answer to anemia. J Postgrad Med. 2011; 57(1):57-60.

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Last updated: 2018-06-22 12:22