Brief History

Hereditary hemochromatosis is a congenital disorder that affects iron transport and metabolism. In 1865, the disease was first described by the French doctor Trousseau who examined the autopsy of a patient that showed bronze pigmentation in the skin, which was associated with diabetes and liver cirrhosis (Ulvik et. al., 2011).

Later in 1889, the German pathologist Friedrich Daniel von Recklinghausen demonstrated that the liver contained excess iron and linked the syndrome to iron metabolism (Hollerer et. al., 2017). He was the first to stain liver autopsies from patients, demonstrating that the bronze pigmentation seen in the skin was caused by the massive iron deposition (Ulvik et. al., 2011). At this point in time, these discoveries led to the belief that there was a connection between diabetes and liver cirrhosis and hemochromatosis.

However, in 1935, the English doctor Sheldon provided an analysis of 311 patient case reports and concluded that the disease was a unique inborn error of metabolism resulting in increased iron absorption and deposition in the body rather than the manifestation of diabetes or liver cirrhosis (Ulvik et. al., 2011).

The conclusions drawn by Sheldon were questioned over time and a genetic basis was determined in 1996 by Feder et. al. Initially, Feder et. al. identified two mutations on the chromosome 6p21.3 in the HFE gene, a member of the MHC class I-like family. The first identified mutation was Cys-282 → Tyr (C282Y), which prevents the altered HFE protein from associating with β2-microglobulin and reaching the cell surface for expression (Feder et. al., 1996). The second mutation they identified was His-63 → Asp (H63D), which alters the three-dimensional shape of the protein. Further experimentation showed that the mutated HFE gene encodes for a 348-residue type I transmembrane glycoprotein, HFE. Based on their previous work, in 1998, Feder et. al. showed that the HFE protein forms a stable complex with the transferrin receptor 1 (TfR1), which is the molecule that regulates receptor-mediated endocytosis of iron-bound transferrin (Feder et. al., 1998). The authors found that this interaction between the HFE protein and TfR leads to a lower affinity for transferrin, allowing them to conclude that there may a molecular link between HFE and iron metabolism and suggest how the mutations may contribute to the disease (Feder et. al., 1998).

At the protein level, Bennett et. al, reported the first crystal structure of the HFE protein complexed with transferrin receptor 1 at a 2.8 Å resolution in 2000 (Bennett et. al., 2000). Previous crystal structures of the HFE protein and TfR allowed Bennett et. al. to describe the way the two structures interact. The manner in which both molecules are oriented indicated that HFE and TfR1 associate on the same membrane, as they are both membrane bound, rather than between opposing membranes (Bennett et. al., 2000). A breakdown of the specific interactions between HFE and TfR1 is shown in Figure 1.

Figure 1. Adapted from Bennett et. al. 2000. a) Transferrin receptor 1 (TfR1) monomer and HFE protein platform b) HFE-TfR1 interaction with specific interactive regions highlighted; portion of HFE in gold and TfR1 in aqua. Side chains of residues on TfR1 in cyan and residues on HFE in red c) HFE-TfR1 complex highlighting interaction at three-helix bundle of HFE (gold) and helical domain helices 1 and 3 of TfR1 (green) d) Similarities between HFE-TfR1 and MHC class I-TCR interactions. Abbreviations: HFE, HFE protein; TfR, transferrin receptor.

The primary interaction between HFE and TfR1 is seen by the two helices within the helical domain of TfR1 and the α1 and α2 domain helices of HFE. Figure 1a shows cut away views of TfR1, and Figure 1b shows the regions that are in contact within the HFE (gold) and TfR1 (aqua) interaction (Bennett et. al., 2000). Portrayed in Figure 1c is the core of the interface complex. The figure shows a three-helix bundle consisting of the α1 helix from HFE (gold) and helical domain helices 1 and 3 (green) from TfR1 (Bennett et. al., 2000). The HFE-TfR1 interaction is known to be similar to the MHC class I interactions with TCR. Figure 1d shows that both TCRs and TfR1 bind across the α1–α2 domain helices, whereas TCRs do not bind at the high points (red arrows) of the α1–α2 helices (Bennett et. al., 2000). Two homologs of TfR exist, each playing a crucial role in iron regulation. TfR1 is a key mediator of iron uptake, and TfR2 plays a regulatory role in whole-body iron homeostasis (Goswami et. al, 2006).

Hepcidin is a peptide hormone produced by the liver that is essential for regulating the absorption of dietary iron, the release of hemoglobin iron of macrophages, and the movement of iron stored by hepatocytes (Nemeh et. al., 2004). Iron homeostasis is regulated by the interaction of hepcidin and the iron exporter, ferroportin (De Domenico et. al., 2011). Typical HFE protein function leads to the production of hepcidin. However, the C282Y and H63D mutations of HFE impair the signal transduction of the HFE-TrF2 interaction that leads to hepcidin production, resulting in low levels of hepcidin production (Muckenthaler et. al., 2014).

Diagnosis and Symptoms

Hereditary hemochromatosis is characterized by an increase in dietary iron absorption. Two key blood tests can be used for iron overload detection in order to diagnose the disease. A serum transferrin saturation measures the amount of iron that is bound to transferrin, which carries iron in the blood. Transferrin saturation values greater than 45% are too high (Bacon et. al., 2011). Along with a serum transferrin saturation, serum ferritin measures the amount of iron stored in the liver. If the levels of serum transferrin saturation are high, then serum ferritin is tested because elevated levels of both signify the presence of hemochromatosis. If these tests provide abnormal results, then genetic testing of the HFE gene can be used to confirm the diagnosis.

Figure 2. Adapted from Bacon et. al. 2011. An algorithm of steps providing tests and treatment options for hereditary hemochromatosis.

As seen in Figure 2, gene testing can be followed up with a liver biopsy or phlebotomy to step in the direction of treatment. The disease can be detected while patients are still asymptomatic. However, people who have a family history of hemochromatosis or abnormal liver function are more susceptible.

Iron overload in hereditary hemochromatosis can manifest with a range of signs and symptoms. Table 1 provides an overview of possible symptoms from a range of patients.

Table 1. Adapted from Bacon et. al. 2011. Range of typical symptoms seen in hereditary hemochromatosis patients.

Hemochromatosis patients tend to present with complaints of fatigue, right upper quadrant abdominal pain, arthalgias, chondrocalcinosis, impotence, decreased libido, and symptoms of heart failure or diabetes (Bacon et. al., 2011). Individuals may require clinical attention at varying stages of iron overload.

Early iron deposition is indicative of liver and synovial tissue joint damage. With a prolonged iron overload state, organ damage can occur in the pancreas, skin, anterior pituitary gland, and heart (Murphree et. al., 2020). Cirrhosis, pancreatic endocrine and exocrine insufficiency, hypothyroidism, and heart failure can be findings related to tissue damage (Murphree et. al., 2020). Hemochromatosis patients are at a higher risk of hepatocellular carcinoma and other sequelae of cirrhosis (Murphree et. al., 2020).


Table of Contents

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Effects, Detection, and Treatments



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