Hemosiderosis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hemosiderosis is a condition whenever there is an overload of iron which results in the deposition of hemosiderin in many organs and tissues. Hemosiderosis occurs in the setting of genetic disorders (ie hemochromatosis occurs due to excessive iron absorption), transfusional, abnormal clearance/use, increase absorption, abnormal hepcidin, hemolytic anemia, or homeotropic parasites. Although hemosiderosis implies iron overload without tissue damage, often an early stage of iron accumulation, there are three types of hemosiderosis: Transfusion hemosiderosis, Idiopathic pulmonary hemosiderosis, Transfusional diabetes. 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. 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 patient 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.
• The findings were first to the clinical symptoms by 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

• IPH may be grouped into three categories based on disease characteristic:

• Group 1 pulmonary hemosiderosis involves PH with circulating anti-GMB antibodies.
• Group 2 pulmonary hemosiderosis involves PH with an immune complex disease such as systemic lupus erythematosus, SLE.
• Group 3 pulmonary hemosiderosis involves no demonstrable immune system involvement.

Pathophysiology

• Recurrent episodes of intra-alveolar hemorrhage attract macrophages to the alveoli, which digest the hemosiderin (iron component) found in hemoglobin, leading to an abnormal accumulation of hemosiderin-laden macrophages. This attracts more pro-inflammatory cytokines and causes chronic inflammation and thickening of the alveolar basement membrane. Ultimately this causes interstitial lung fibrosis with a restrictive picture on spirometry.
• In infants, the disease is poorly understood.

Causes

• There are no established causes for IPH, 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 the pathophysiology of the condition include allergy, due to its frequent association with Cow's milk protein allergy, genetic, due to the rare finding of familial clustering (but without any identified genes yet), and environmental due to the now refuted claim of its association with the fungi Stachybotrys atra exposure, toxic insecticides (based on epidemiological studies in rural Greece), premature birth.

Differentiating IPH from other Diseases

• IPH must be differentiated from other diseases that cause alveolar hemorrhage, such as those include infectious etiologies( ARDS, streptococcus pneumoniae, staphylococcus aureus, and legionella, influenza A and pneumocystis jirovecii), rheumatic disease such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic, and granulomatous polyangiitis, and mixed cryoglobulinemias, drug-induced injury in medications such as medication such as amiodarone, nitrofurantoin, and infliximab. Penicillamine, thromboembolic disease, bleeding disorders, and neoplasms

Epidemiology and Demographics

• The prevalence and incidence of IPH are relatively unknown because of the rare nature.

Age

• IPH is more commonly observed among children. ( approximately 80% of cases are seen in children who are diagnosed in the first decade of life.)
• 205 of cases are adult-onset IPH.

Gender

• IPH affects males and females equally in childhood-onset IPH
• Adult-onset IPH are almost twice as many males as females.
• Males are more commonly affected with IPH than females in adult-onset IPH.

Race

• There is no racial predilection for IPH.

Risk Factors

• There are no established risk factors for IPH.

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

Diagnostic Criteria

• The diagnosis of acute IPH is made clinically, after other known causes of pulmonary and systemic or visceral hemorrhage have been excluded.
• 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.

Symptoms

The clinical features of idiopathic pulmonary hemorrhage depend on whether it is acute or chronic Symptoms of IPH in the acute phase may include the following:

• Severe dyspnea
• Cough
• Hemoptysis
• Worsening anemia
• Rapid asphyxiation due to massive pulmonary hemorrhage

patients who present in the chronic phase of the disease may have:

• Weight loss
• Failure to thrive
• Hypoxemic respiratory failure in severe cases,

Physical Examination

Physical examination findings vary depending on whether it is an acute or chronic presentation.

• In the acute phase, the physical examination may be completely normal or include respiratory signs such as tachypnea.
• In the chronic phase, there may be:
• Pallor
• Failure to thrive
• Weight loss
• Hepatosplenomegaly
• Digital clubbing and other signs of chronic hypoxia in the setting of pulmonary fibrosis

Laboratory Findings

• Reduced hemoglobin counts and hematocrit, leucocytosis, and elevated erythrocyte sedimentation rate may be seen in patients with IPH.

Imaging Findings

• Chest x-ray taken during an acute phase of IPH exacerbation may show diffuse alveolar infiltrates greatest at the lung bases.
• CT scans taken during an acute phase of IPH exacerbation may show ground-glass attenuation in the lung bases.
• Chromium and technetium based perfusion scans show intra-alveolar bleeding. Scans with abnormal pulmonary uptake 12-24 hours after the injection have been observed in patients with pulmonary hemorrhage.

Other Diagnostic Studies

• Erythrocytes and hemosiderin-laden macrophages may be seen in sputum testing with hematoxylin-eosin and Prussian blue stains, indicating intra-alveolar bleeding. Stains and cultures for mycobacteria, bacteria, and fungus are done to rule out the infective cause.
• Alveolar macrophages filled with hemosiderin and intact erythrocytes and occasionally neutrophils in Bronchoalveolar lavage (BAL) has a higher diagnostic yield than sputum testing.
• Pulmonary function testing generally shows a restrictive pattern of varying severity. The carbon monoxide diffusing capacity (DLCO) can be elevated during the acute phase.

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.
• Blood should be transfused to correct severe anemia and shock during the acute phase.
• Patients with acute IPH and respiratory failure secondary to alveolar hemorrhage may require invasive ventilation support. In these patients, it is also recommended to consider immunosuppressive therapy in addition to high dose systemic corticosteroids.
• Immuno-suppressants such as hydroxychloroquine, azathioprine, cyclophosphamide, and 6-mercaptopurine are sometimes used in combination with steroids for severe cases, or when steroids are contraindicated or not tolerated.
• Other treatment options with unknown efficacies include intravenous immunoglobulin (IVIG), plasmapheresis, liposteroids, and dietary modification (gluten-free diet in those with celiac disease and IPH has been shown to improve symptoms).

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