Iron Overload

Etiology

Primary iron overload is most 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, which encodes the hereditary hemochromatosis protein (HFE protein) and plays a role in hepcidin regulation. Less common genetic mutations are found in HAMP, HJV, TFR2, and SLC40A1. These gene mutations are grouped as non-HFE hemochromatosis.[3]

The previous classification of hemochromatosis consisted of four types. Type 1 is classic hemochromatosis resulting from HFE gene mutation (C282Y or H63D). The remaining types are non-classical. Type 2A results from HAMP mutation. Type 2B results from HJV mutation. Type 3 is due to a mutation in TFR2, and Type 4 is due to SLC40A1.[4] A newer system that classifies hemochromatosis as HFE-related, non-HFE-related, and digenic has been proposed. The classification places type 1 into the HFE-related group. This also includes the heterozygosity of C282Y with other rare HFE variants. Groups Type 2, 3, and 4 fall into the non-HFE-related group. Digenic consists of double heterozygosity and/or double homozygosity/heterozygosity for mutations in two different genes, which can be HFE or non-HFE-related.[5]

The introduction of excess iron into the body causes secondary iron overload. This occurs most commonly through blood transfusion and also can be due to hemolysis or excessive parenteral and/or dietary consumption.[6]

Epidemiology

An estimated 16 million Americans have some degree of iron overload, either inherited or acquired. Hereditary hemochromatosis is found more commonly in the white population of European backgrounds. One study found a rate of C282Y homozygosity of 0.4% and heterozygosity of 9.2% in European countries and 0.5% and 9% in North America.[7] It is estimated that 1 in every 200 US white patients is positive for iron overload, and 10% to 14% are genetic mutation carriers.[8] 

The HEIRS study, investigating the prevalence of homozygous C282Y in the US and Canada, revealed a predominant occurrence among non-Hispanic whites (0.44%), Native and indigenous Americans (0.11%), and Hispanics (0.027%). In contrast, a study conducted in Ireland reported a higher rate, with 1.2% of individuals identified as homozygous for the C282Y mutation.[9] 

Pathophysiology

Iron homeostasis is mainly dependent on controlling iron absorption from the diet. Normal plasma levels of iron range between 12 to 25 μM/L. Plasma iron depends on iron absorbed from enterocytes and macrophages. The export of iron into the serum is regulated by ferroportin. Hepcidin is a protein synthesized in the liver and regulates ferroportin activity. Increased levels of hepcidin decrease ferroportin activity by inducing its internalization. This results in a decrease in plasma iron concentrations.[10] Conversely, low levels of hepcidin increase plasma iron. Upon initial entry into the serum, iron undergoes oxidation facilitated by ceruloplasmin and is then bound by transferrin, giving rise to the formation of holotransferrin. Holotransferrin then transports the iron to all cell types in the body. High levels of holotransferrin increase the release of hepcidin into the serum.[11] 

Hepcidin production is regulated by the hereditary hemochromatosis protein (HFE protein). This protein functions based on whether it binds to transferrin receptor 1 (TFR1). When TFR1 is bound, hepcidin production decreases; when it is not bound to TFR1, hepcidin production increases. As overall serum iron levels increase, transferrin becomes saturated, and non-transferrin-bound iron (NTBI) will begin to appear in the plasma, which can go on to cause cell toxicity.[12] 

The most common mutation, C282Y, a mutation to HFE, disrupts this protein binding interactions with various other proteins, ultimately leading to decreased hepcidin levels. HAMP mutations are homozygous recessive and lead to the absence of normal hepcidin, disrupting the regulation of plasma iron concentrations. HJV mutations are homozygous recessive and lead to the disruption of upregulation of HAMP transcription, leading to decreased levels of hepcidin. The TFR2 gene is involved in the uptake of transferrin-bound iron. Mutation in this gene disrupts iron uptake into cells, increasing plasma iron.[12] 

Excess NTBI leads to reactive oxygen species (ROS) forming via the Fenton-Haber-Weiss reaction. Iron cycles between its ferrous (Fe2+) and ferric (Fe3+) states, generating hydroxide ions, hydroperoxyl, and hydroxyl radicals. ROS oxidize lipids, proteins, and nucleic acids in this reaction, leading to cellular apoptosis and eventual organ damage.[13]

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 and 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.[14]

Histopathology

Microscopic examination of involved tissues reveals iron deposition. Microscopic pancreatic islet beta-cell examination can reveal iron deposition. A liver biopsy can show hemosiderosis on iron staining (Prussian blue or Perls' iron stain) and cirrhosis if the 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.[15]

History and Physical

Patients will often be asymptomatic for many years, and diagnosis of HFE-related hemochromatosis may not occur until adulthood, often later than 30 years of age. In non-HFE-related hemochromatosis, patients often manifest symptoms when they are younger, typically 20 to 30 years of age.[16]

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.[17] Men with primary hemochromatosis are more likely to experience symptoms than women due to a lack of menses.

Evaluation

Iron overload suspected after a history and physical can generally be diagnosed with low-cost, non-invasive blood tests. Serum iron levels are not indicated. Serum ferritin >300 ng/ml in males and greater than 150 to 200 ng/ml in menstruating females can indicate iron overload. However, serum ferritin levels can also be elevated for various reasons, including inflammation, infection, and liver disease. Ferritin is known as an acute-phase reactant.[18] Total binding iron capacity (TIBC) may be normal as well. Fasting and elevated serum transferrin saturation percentage >45% can assist in further diagnosis. In classic hemochromatosis, both serum ferritin and transferrin iron saturation percentages will most often be elevated.

Magnetic resonance imaging (MRI) can be useful to quantify body iron overload. MRI should be used to evaluate the iron burden in the liver and spleen. Significant liver iron excess and absence of spleen iron excess are highly suggestive of hepcidin deficiency.[19]

Additional genetic testing is indicated in those patients who are found to have iron overload. After other mechanisms have been ruled out, such as hypotransferrinemia, nephrotic syndrome, or malnutrition, genetic testing for the HFE gene associated with hemochromatosis should be performed. 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 1 million white Americans have the C282Y/C282Y inheritance pattern.[20][21]. If this is negative, genetic testing for non-HFE mutations should be pursued. Genetic testing is generally not widely available as it requires specialized laboratories. Therefore, treatment is not dependent on the specific genetic mutation and should not be delayed once a clinical diagnosis has been obtained. 

Hepatic iron index on percutaneous liver biopsy can be utilized in difficult-to-diagnose cases but carries greater procedural risk than blood testing. Liver biopsy was previously the standard for diagnosis, but with less invasive testing, it is reserved for more complicated cases.[22]

Once the diagnosis of iron overload is established, more specific testing is directed depending on the suspected organ involvement.

Treatment / Management

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 (approximately 50ug/L). Then, a schedule of periodic phlebotomy can be maintained, generally every 2 to 3 months, according to the serum ferritin levels achieved. When serum ferritin remains >1000 ng/ml, the risk of liver damage increases, and life expectancy decreases dramatically. Patients with mildly elevated serum ferritin levels are often advised to donate blood regularly. Donating more frequently than every 8 weeks usually necessitates physician approval.[23][24]

In patients with hemoglobin levels that do not tolerate therapeutic phlebotomy, iron chelation therapy becomes an option. Potential agents include parental deferoxamine and oral agents deferasirox and deferiprone. Deferoxamine is a parental treatment that requires prolonged infusions of up to 8 to 12 hours with multiple administrations per week to be effective. Subcutaneous infusion is preferred for treating chronic overload, whereas intravenous infusion is reserved for acute toxicity.[25] It is also associated with many adverse effects, including hypotension, dizziness, and rash, as well as an increased risk of Yersinia sepsis and the development of acute respiratory distress syndrome. Deferasirox and deferiprone are relatively newer oral agents that are less cumbersome in dosing and are as effective in treatment as deferoxamine.[26][27](A1)

Proton pump inhibitors, such as pantoprazole, may be a useful adjunct for patients with hemochromatosis. In a randomized control trial, pantoprazole significantly reduced the need for phlebotomy in patients with C282Y mutation.[28](A1)

Ongoing research is exploring the potential of hepcidin-based therapies as adjunctive treatments to phlebotomy.[29](A1)

Patients should be encouraged to avoid iron supplementation, iron-containing multivitamins, and vitamin C. Vitamin C, in particular, can increase iron absorption in the GI tract, resulting in an increased body burden of iron.

Differential Diagnosis

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 or other related mutations can help illuminate the diagnosis.

Another iron overload disorder that presents with neurologic findings is neuroferritinopathy. This disorder results from an autosomal dominant mutation in the FTL gene, resulting in iron deposition in the basal ganglia. Patients can present with chorea, dystonia, and speech and swallowing difficulties. Over time, behavioral and cognitive deficits also develop.[30]

Staging

When hemochromatosis has advanced to liver cirrhosis, a liver biopsy is indicated to determine the severity of the disease. This holds particularly true when a liver transplant is included in the management strategy.

Prognosis

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.[31]

Patients who are not treated or inadequately treated have lower survival rates than those who are adequately treated. Patients who are inadequately treated develop liver cirrhosis, hepatocellular carcinoma, pancreatic fibrosis, and diabetes at higher rates. The ferritin level at the time of diagnosis also has prognostic significance. Patients with a ferritin level >2000 ug/L have higher mortality rates when compared to those with a ferritin level <1000 ug/L.[32]

Patients with severe liver damage due to inadequately treated hemochromatosis can receive a liver transplant. This effectively can "cure" the patient, as the transplanted liver will contain the normal wild-type HFE genotype. As a result, hepcidin production is normal after transplantation.[33] Patients with severe HFE-associated cardiomyopathy may also benefit from heart transplantation.[34]

Complications

Iron overload poses various complications that can significantly impact an individual's health. The excessive accumulation of iron in vital organs, particularly the liver, heart, and endocrine glands, can lead to organ damage due to the formation of reactive oxygen species. Complications may manifest as liver diseases, including cirrhosis and hepatocellular carcinoma, cardiomyopathies affecting the heart, and endocrine disorders such as diabetes and hypothyroidism. Additionally, iron overload has been linked to increased susceptibility to infections and impaired immune response. Recognizing and managing these complications is crucial in preventing further deterioration of organ function and improving overall patient outcomes. Regular monitoring, intervention strategies, and interdisciplinary collaboration are essential to mitigating the complications associated with excessive iron accumulation.