Secondary Iron Overload

Secondary iron overload typically occurs in patients who have

Iron overload results from the following mechanisms:

Increased iron absorption in patients with ineffective erythropoiesis may be partly due to the secretion, by erythroid precursors, of erythroferrone (ERFE), which suppresses hepcidin (an inhibitor of iron absorption).

Patients with hemoglobinopathies and congenital hemolytic anemias now typically live into adulthood, so complications of iron overload are now common and clinically important. In such patients, iron overload involving the heart, the liver, and endocrine organs has become a common cause of death, but survival can be prolonged by iron removal.

The clinical consequences of iron overload are the same regardless of the etiology and pathophysiology of the overload.

Historically, experts believed that symptoms did not develop until significant organ damage had occurred. However, organ damage is slow and subtle, and fatigue and nonspecific systemic symptoms often occur early.

Glucose intolerance or diabetes mellitus Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more is another common initial manifestation. Some patients present with hypothyroidism Hypothyroidism Hypothyroidism is thyroid hormone deficiency. Symptoms include cold intolerance, fatigue, and weight gain. Signs may include a typical facial appearance, hoarse slow speech, and dry skin. Diagnosis... read more . In men, the initial symptoms may be hypogonadism and erectile dysfunction Erectile Dysfunction Erectile dysfunction is the inability to attain or sustain an erection satisfactory for sexual intercourse. Most erectile dysfunction is related to vascular, neurologic, psychologic, and hormonal... read more caused by gonadal iron deposition.

Liver disease is the most common complication and may progress to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more . Patients who develop cirrhosis are at increased risk of hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more . The liver disease can present insidiously with nonspecific symptoms and signs, such as fatigue, and with right upper quadrant abdominal pain and hepatomegaly. Laboratory abnormalities of iron overload and hepatitis typically will be present well before clinical symptoms develop. Liver disease is the most common cause of death. Cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more with heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more is the 2nd most common fatal complication. Hyperpigmentation (bronze diabetes) and porphyria cutanea tarda Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is a comparatively common hepatic porphyria affecting mainly the skin. Liver disease is also common. PCT is due to an acquired or inherited deficiency in the activity... read more are common, as is symptomatic arthropathy.

Patients with ineffective erythropoiesis should be evaluated for secondary iron overload, which is diagnosed by measuring serum ferritin, serum iron, and transferrin saturation. Serum ferritin measurement is the simplest and most direct initial test. Elevated levels (> 200 ng/mL [> 200 mcg/L] in women or > 250 ng/mL [> 250 mcg/L] in men) are usually present in secondary iron overload but can result from other abnormalities, such as hereditary hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more , inflammatory liver disorders (eg, chronic viral hepatitis, nonalcoholic fatty liver disease Metabolic Dysfunction–Associated Liver Disease (MASLD) Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more , alcoholic liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more ), cancer, certain systemic inflammatory disorders (eg, rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more , hemophagocytic lymphohistiocytosis Hemophagocytic Lymphohistiocytosis (HLH) Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder causing immune dysfunction in infants and young children. Many patients have an underlying immune disorder, although in some... read more ), or obesity.

Further testing is done if ferritin level is abnormal; testing includes fasting serum iron (usually > 300 mg/dL [> 53.7 millimole/L]) and iron binding capacity (transferrin saturation; levels usually > 50%). Hereditary hemochromatosis should be ruled out by history and genetic testing. A transferrin saturation < 45% has a negative predictive value of 97% for iron overload.

Some patients can be treated with phlebotomy and given erythropoietin to maintain erythropoiesis. However, because it worsens anemia, phlebotomy is not recommended for many patients (eg, those with hemoglobin level < 10 g/dL [< 100 g/L], those who are transfusion dependent, and those who develop symptoms of anemia after phlebotomy). Treatment in these patients is iron chelation. The goal of treatment is a transferrin saturation of < 50%.

Deferoxamine is the drug traditionally used for iron chelation therapy. Dose is 40 to 50 mg/kg/day (maximum: 60 mg/kg/day) given by a slow subcutaneous infusion overnight over 8 to 12 hours through a portable pump for 5 to 7 nights/week. Dose for children > 3 years and growing adolescents is 20 to 40 mg/kg/day IV infusion over 8 to 12 hours, 5 to 7 days per week, usual maximum daily dose is 40 mg/kg/day. However, this therapy is complex to administer and requires an unusual time commitment from patients, resulting in a high rate of nonadherence. Important adverse effects include hypotension, gastrointestinal disturbances, and anaphylaxis (acutely) and vision and hearing loss (with chronic use).

Deferasirox, an oral chelating agent, is an effective and increasingly used alternative to deferoxamine. Deferasirox reduces iron levels and prevents or delays onset of complications of iron overload. Initial dose is 20 mg/kg orally once a day. Patients are monitored monthly with dose increases up to 30 mg/kg once a day if needed. Maximum dose is 40 mg/kg/day. If deferasirox oral granules are used, the initial dose is 14 mg/kg/day and the maximum dose is 28 mg/kg/day. Treatment can be interrupted when serum ferritin is < 500 ng/mL (< 500 mcg/L). Adverse effects (which occur in about 10% of patients) can include nausea, abdominal pain, diarrhea, and rash. Liver and kidney function may become abnormal; liver and kidney blood tests should be done periodically (eg, monthly, sometimes more frequently for high-risk patients).

Deferiprone, another oral iron chelator, is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes Thalassemias Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people with African, Mediterranean... read more when chelation therapy with deferasirox or deferoxamine is inadequate. Deferiprone can also be used in combination with deferasirox because they have different mechanisms of action. Initial dosing is 25 mg/kg orally 3 times a day. The maximum dose is 33 mg/kg orally 3 times a day. Absolute neutrophil counts are obtained weekly to look for neutropenia (precedes agranulocytosis). Serum ferritin is measured every 2 to 3 months; treatment is temporarily interrupted when levels are consistently < 500 ng/mL (< 500 mcg/L).

Diabetes mellitus Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more , cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more , erectile dysfunction Erectile Dysfunction Erectile dysfunction is the inability to attain or sustain an erection satisfactory for sexual intercourse. Most erectile dysfunction is related to vascular, neurologic, psychologic, and hormonal... read more , and other secondary manifestations are treated as indicated. Patients with advanced fibrosis or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more due to iron overload should be screened for hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more every 6 months with a liver ultrasound.

Patients should follow a balanced diet; it is not necessary to restrict consumption of iron-containing foods (eg, red meat, liver). Alcohol should be consumed only in moderation because it can increase iron absorption and, in high amounts, increases the risk of cirrhosis. Vitamin C supplements should be avoided because they increase the absorption of iron in the duodenum.