Iron overload is defined as excess stores of iron in the body. Excess iron is deposited in organs throughout the body. The most notable organs with iron deposition are the liver, heart, and endocrine glands. Resulting symptoms and disease are related to specific organ damage.
Primary iron overload is often inherited. Hereditary hemochromatosis is the leading case of iron overload disease. In 1996, 2 gene mutations (C282Y and H63D) of the HFE gene were discovered and linked to primary iron overload. The most common is C282Y. The introduction of excess iron into the body causes secondary iron overload. This occurs most commonly through blood transfusion, but also can be due to hemolysis or excessive parenteral and/or dietary consumption.
An estimated 16 million Americans have some degree of iron overload, either inherited or acquired. Hereditary hemochromatosis is found more commonly in the Caucasian population of European background. It is estimated that one in every 200 US Caucasians are positive for iron overload, and 10% to 14% is genetic mutation carriers. Men with primary hemochromatosis are more likely to experience symptoms than women due to lack of menses.
The functional changes in the human body that result from iron overload are numerous. Excess iron deposits mainly in the liver, heart and endocrine organs. Damage to the liver can result in chronic liver disease, cirrhosis and lead to hepatocellular carcinoma. Damage to the heart muscle can lead to heart failure and irregular heart rhythms. Damage to the pancreas can lead to elevated blood glucose levels and "bronze" diabetes. Hypothyroidism and hypogonadism can result in fatigue, hair loss, infertility, and decreased libido. Joint involvement leads to arthritis. Neurological involvement can accelerate neurodegenerative diseases such as Alzheimer disease.
Microscopic examination of involved tissues reveals iron deposition. Liver biopsy can show hemosiderosis on iron staining (Prussian blue or Perls' iron stain) as well as cirrhosis if liver disease is advanced. Liver biopsy is also useful for patients with cirrhosis and liver lesions suspected to be hepatocellular carcinoma. Liver biopsy with a Hepatic Iron Index (HII) has been the standard of diagnosis. With the advent of genetic testing, liver biopsy is utilized less frequently. Microscopic pancreatic islet beta cell examination can reveal iron deposition.
Patients with iron overload are asymptomatic in 3 out of 4 cases. When signs and symptoms occur, they are generally related to specific organ involvement. These include chronic fatigue, arthralgia, abdominal pain, hepatomegaly, irregular heart rhythm, hypogonadism, decreased libido, elevated blood glucose levels, hyperpigmentation (bronze skin), and depression.
Iron overload suspected after a history and physical can generally be diagnosed with low costs, non-invasive blood tests. Serum iron levels are not indicated. Serum ferritin greater than 300 ng/ml in males and greater than 150 to 200 ng/ml in menstruating females can be indicative of iron overload. However, serum ferritin levels can also be elevated to a variety of reasons, including inflammation, infection and liver disease; it is known as an acute phase reactant. Total binding iron capacity (TIBC) may be normal as well. Fasting, elevated, serum transferrin saturation percentage greater than 45% can assist in further diagnosis. In classic hemochromatosis, both serum ferritin and transferrin iron saturation percentage will most often be elevated.
Genetic testing is now available for the HFE gene associated with hemochromatosis. Mutations in this gene can occur in many different patterns. Patients with the C282Y/C282Y, H63D/H63D or C282Y/H63D pattern are most at risk for the disease. It is estimated that one million Caucasian Americans have the C282Y/C282Y inheritance pattern.
Hepatic iron index on percutaneous liver biopsy can give be utilized in difficult to diagnose cases but carries greater procedural risk than blood testing. Liver biopsy has been the standard of diagnosis, but with the introduction of genetic testing is reserved for more complicated cases.
Once the diagnosis of iron overload is established, more specific testing is directed depending on suspected organ involvement.
The treatment for iron overload is reduction therapy. This is most commonly achieved through therapeutic phlebotomy. In patients with an acceptable hemoglobin level, phlebotomy can initially be prescribed every 1 to 2 weeks until serum ferritin is brought within acceptable levels. Then a schedule of periodic phlebotomy can be maintained, generally every 2 to 3 months, according to achieved serum ferritin levels. When serum ferritin remains above 1000 ng/ml, the risk of liver damage and decreased life expectancy increase dramatically. Often, patients with mildly elevated serum ferritin levels are advised to donate blood on a regular basis. Donating more frequently than every 8 weeks usually necessitates physician approval.
In patients with hemoglobin levels that do not tolerate therapeutic phlebotomy, iron chelation therapy becomes an option. Deferoxamine is an iron chelation therapy currently in use. A conundrum occurs in patients who must receive regular blood donations, such as the patient with thalassemia. In these specific situations, blood transfusion must occur but is accompanied by chelation therapy with deferasirox or deferiprone.
The differential diagnosis for hemochromatosis includes elevated iron levels due to multiple transfusions, over-consumption, alcoholic liver disease, ineffective erythropoiesis with hyperplastic erythroid marrow, elevated iron with chronic anemia, and porphyria cutanea tarda. Genetic testing of the HFE gene can help illuminate the diagnosis.
When hemochromatosis has advanced to liver cirrhosis, liver biopsy is indicated to determine the severity of the disease. This is especially the case if liver transplant in part of the management plan.
The prognosis of patients with iron overload is extremely positive when diagnosed early and when treatment effectively reduces iron levels to acceptable levels. A normal lifespan and extremely low rates of liver damage are reported in patients who maintain serum ferritin levels within an acceptable range.
Complications of iron overload include liver damage, liver cirrhosis, pancreatic islet cell damage, diabetes, hypothyroidism, and hypogonadism.
Consulting a gastroenterologist or hepatologist may be necessary if the patient develops cirrhosis and its sequelae.
There are many resources for patients with hereditary hemochromatosis. Patient compliance with therapy is key to maintaining a normal lifespan.
A long-term study of patients with hemochromatosis has shown that overall longevity was related to the presence of liver cirrhosis. In patients with hemochromatosis and no liver cirrhosis, long-term survival was unaffected. This reiterates the need for early diagnosis and treatment before cirrhosis develops. Frontline healthcare providers, including physicians, physician assistants, and nurses should be knowledgeable on this topic to help identify cases at an early stage and initiate prompt, coordinated treatment.