Hemosiderosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Roghayeh Marandi
Overview
Idiopathic pulmonary hemosiderosis (IPH) is a rare disease of unknown etiology characterized by repeated episodes of a diffuse alveolar hemorrhage which cause periodic attack of tachycardia, pyrexia, pallor, fatigue, cyanosis, increasing dyspnea, signs of congestive cardiac failure, severe anamia and hemoptysis. The repeated alveolar hemorrhage causes the accumulation of hemosiderin, a by-product of hemoglobin breakdown, in the alveoli. Alveolar macrophages take up these hemosiderin molecules, usually within 36 - 72 hours, and can remain in the lungs for up to 8 weeks. Between attacks, patients may remain well but commonly there is chronic ill-health. Over the time, It can lead to multiple respiratory complications and permanent lung damage. It is not familial and is found primarily in children from a few months to 16 years of age and rarely be seen in adults.
Historical Perspective
IPH was first described as "brown lung induration" by Rudolf Virchow in 1864 in patients after their death. Wilhelm Ceelen gave a more detailed description of the condition after autopsies revealed large amounts of hemosiderin in 2 children in 1931. In 1944, the antemortem diagnosis was made by Waldenstrom.
Classification
Based on the duration of symptoms, pulmonary hemosiderosis may be classified as either acute or chronic phase.Pulmonary hemosiderosis may be classified into three groups based on disease characteristic: first group with circulating anti-glomerular basement membrane (anti-GBM) antibodies, second group, with immune complex disease, and the third group without known immunologic association or (Idiopathic pulmonary hemosiderosis).
Pathophysiology
After the repeated episodes of a diffuse alveolar hemorrhage, the alveolar macrophages are responsible for the repeated clean up of excess blood. As the macrophages degrade the erythrocytes, the excess iron from heme degradation within the alveolar macrophages stimulates intracellular ferritin molecules. Further processing of the ferritin leads to hemosiderin complexes.(see below for more information). In the early stages of pulmonary hemosiderosis, interstitial and intra-alveolar hemorrhage predominate, with collections of both free hemosiderin and hemosiderin-filled macrophages found in the alveolar spaces and the interstitium. When the disease progresses, interstitial fibrosis ensues. Pulmonary hemosiderosis can occur either as a primary lung disorder (Idiopathic pulmonary hemosiderosis) or as the sequela to other pulmonary, cardiovascular, or immune system disorder.
Causes
There are no established causes for idiopathic pulmonary hemosiderosis, but it is likely to be multifactorial. Some consider it to be an autoimmune condition. The evidence is backed by the fact that the disease responds to immunosuppressants. Other hypotheses for this condition include allergy, due to this frequent association with Cow's milk protein allergy, or genetic cause, due to the rare finding of familial clustering (but without any identified genes yet), and environmental factors such as its association with the fungi (Stachybotrys atra) exposure, or toxic insecticides (based on epidemiological studies in rural Greece), and premature birth.
Differentiating IPH from other Diseases
Idiopathic pulmonary hemosiderosis must be differentiated from other diseases that cause alveolar hemorrhage, such as those include infectious etiologies( ARDS, Streptococcus pneumonia, Staphylococcus aureus, and legionella, influenza A and Pneumocystis jirovecii), rheumatic diseases such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic granulomatous polyangiitis, and mixed cryoglobulinemias, drug-induced injury in medications such as amiodarone, nitrofurantoin, and infliximab, Penicillamine, or from thromboembolic disease, bleeding disorders, and neoplasms.
Epidemiology and Demographics
The prevalence and incidence of idiopathic pulmonary hemosiderosis are relatively unknown because of the rare nature. IPH is more commonly observed among children. 20% of cases are adult-onset IPH.IPH affects males and females equally in childhood-onset IPH. Males are more commonly affected by IPH than females in adult-onset IPH.
Risk Factors
There are no established risk factors for Idipathic pulmonary hemosiderosis.
Natural History, Complications and Prognosis
The clinical spectrum of IPH ranges from asymptomatic cases to a chronic cough and dyspnea to repetitive hemoptysis with fatigue, anemia, and slowly progressive dyspnea and life-threatening acute respiratory failure. Common complications of IPH include Iron deficiency anemia and pulmonary fibrosis. Prognosis is generally variable, and the mean survival rate of patients with IPH is 2.5 to 5 years after diagnosis. Deaths can occur from acute massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.
Diagnosis
There are no established criteria for the diagnosis of idiopathic pulmonary hemosiderosis. Lung biopsy is the gold standard for the diagnosis of IPH, where the hemosiderin-laden macrophages can be visualized. However, it is an invasive procedure and is often not practicable in children.
History and Symptoms
The most common symptoms of IPH in the acute phase include severe dyspnea, cough, hemoptysis. when the disease progress, weight loss, Failure to thrive, and respiratory failure occurs in severe cases.
Physical Examination
Common physical examination findings of IPH include tachypnea, pallor during the acute phase, and hepatosplenomegaly, failure to thrive and weight loss, and signs of respiratory failure such as digital clubbing in the chronic phase in severe cases.
Laboratory Findings
The laboratory findings consistent with IPH include reduced hemoglobin counts and hematocrit, leucocytosis, and elevated erythrocyte sedimentation rate.
Imaging Findings
A chest x-ray taken during an acute phase of IPH exacerbation may show diffuse alveolar infiltrates greatest at the base of the lungs. Lungs CT scans may be helpful in the diagnosis of IPH. Findings on CT scan suggestive of IPH include ground-glass attenuation in the base of lungs during the acute phase of IPH. Chromium and technetium based perfusion scans may be helpful in the diagnosis of IPH. Findings on these perfusion scans suggestive of IPH include: abnormal pulmonary uptake 12-24 hours after the injection in patients with pulmonary hemorrhage.
Other Diagnostic Studies
Other diagnostic studies for IPH include sputum testing and bronchoalveolar lavage (BAL) for intact erythrocytes and hemosiderin-laden macrophages, which demonstrate pulmonary hemorrhage, and pulmonary function tests, which generally shows a restrictive pattern of varying severity and decreased DLCO.
Treatment
Medical Therapy
There is no treatment for IPH; the mainstay of therapy is supportive care based on the presentation and acute vs. chronic nature of the patient. Immuno-suppressants in combination with steroids is used for severe cases. Supportive therapy for IPH includes blood transfusion to correct severe anemia, and invasive ventilation support for respiratory failure secondary to alveolar hemorrhage.
Surgery
Surgical intervention is not recommended for the management of IPH.
Prevention
Preventive measures for the secondary prevention of IPH include: maintenance doses of prednisone or prednisolone of 10 to 15 mg/kg/day
Future or investigational therapies
More researches should be done in order to investigate the cause of idiopathic pulmonary hemosiderosis so that selective and directed therapeutic approaches can be undertaken.