History and Metabolic Context

Timeline

1865- Trousseau first documented a patients autopsy with the constellation of bronze pigmentation in the skin associated with diabetes and liver pigmentation (Trousseau 1865)

1871- However, Trosier a french physician is given the credit of the first diagnosis is (Troisier 1871). At this time it was known as ‘bronze diabetes’ or cirrhose pigmentaire. (Troisier 1871)

1921- Prior to the development of insulin the majority of patients died shortly after diagnosis. However, following the development of insulin to treat diabetic manifestations patients had a longer lifespan (Finch 1955)

1935- Dr. Sheldon analyzed a series of over 300 cases from medical literature and concluded that the disease was not a manifestation of diabetes or cirrhosis but a unique inborn error of metabolism resulting in increased iron absorption and deposition in the body (Sheldon 1935). This was a controversial topic in medicine with debates going into the sixties and seventies.

1955- Doctors Finch and Finch demonstrated that phlebotomy, or therapeutic removal of blood, can serve as a suitable treatment of disease by reducing iron stores (Finch 1955). They came to this conclusion as they saw how large numbers of transfusions could cause hemochromatosis to develop (Finch 1955)

1962- Liver biopsy tests were first used to diagnose hemochromatosis. Staining was performed using Prussian blue, a technique developed by Perl’s in the 1800’s. The amount of iron was graded from 0-5 to indicate severity of disease (Scheuler 1962)

1975- A linkage between prevalence of hereditary hemochromatosis and the HLA-3 antigen was shown. (Simon 1975).

1996- The theory of genetic basis was confirmed when in 1996 a mutation was identified in a novel HLA-like gene region that was strongly correlated with development of hereditary hemochromatosis (Feder 1996) This gene is now known as HFE.

1998- A crystal structure of the HFE protein was solved and the most common mutation was analyzed displaying the causative interaction changes mediating HFE-hemochromatosis (Lebron 1998). The structure was also shown bound to the transferrin receptor (Lebron 1998).

2001- The peptide now known as hepcidin, a 25amino acid protein with four disulfide bonds was found in the liver and heart and was identified as an antimicrobial peptide (Krause 2001)

2002- The recently discovered peptide, hepcidin, was implicated in one form of hemochromatosis indicating its role in iron homeostasis (Roetto 2002)

2004– Hepcidin was shown to bind to ferroportin, inducing its internallization thus controling iron absorbtion (Nemeth 2004)

2006-HFE was shown to bind to TFR2 when levels of Tf-fe are high, indicating a possible role in sensing iron levels (Goswami 2006).

Diagnosis

The disease is often first diagnosed based on routine laboratory serum testing while patients are asymptomatic. These test use blood samples to check levels of iron indirectly by measuring Transferrin iron saturation index (TS) and serum ferritin. TS looks at the total binding capacity and the amount of serum iron, a value of >45% is indicative of iron overload. Ferritin measures the amount of stored iron, standard levels are based on age and gender. Having either a TS >45% or elevated ferritin is indicative of iron overload and requires additional testing (Bacon 2011)

Previously confirmation of hemochromatosis was done through analysis of a liver biopsy. This test is still used to determine the degree of liver cirrhosis and iron deposition in patients, however, is less common due to the advent of genetic screening. Since the regions encoding the most commonly mutated genes resulting in hemochromatosis have been identified, genetic testing can confirm the diagnosis. Genetic testing is also performed on the family members of a patient in order to diagnose disease before damage occurs (Bacon 2011).

Symptoms

symptoms
A) Bronzing or hyperpigmentation of the skin (left) as compared to normal skin tone (right) B) The most commonly affected arthritic joints are highlighted C) Prussian blue staining of liver tissue reveals hemosiderin iron deposits sources A) B) C)
  • Hyperpigmentation (‘Bronzing’ of the skin)
  • Hair loss
  • Fatigue, weakness, lethargy
  • Arthritis—specifically in fingers and hands
  • Liver disease
    • Cancer
    • Cirrhosis
    • Hepatomegaly
  • Hypogonadism
    • Loss of libido
  • Cardiomyopathy and cardiac arrhythmias
  • Hair loss
  • Fatigue, weakness, lethargy
  • Hypothyroidism
  • Diabetes

(Allen 2008) 

Iron Regulation in the Body

Iron is an important metal in the body serving as a key component in heme, forming iron sulfur clusters and acting as an oxidant in cellular reactions. Thus regulating iron in the body is crucial for the maintenance of homeostasis. When iron is improperly controlled it can result in disease, anemia in the case of iron deficiency and hemochromatosis in the case of iron overload.

 

Slide1
Figure 2: The path of iron absorption through enterocytes to the blood stream EMG
Slide2
Figure 3: Receptor mediated endocytosis facilitates iron uptake by cells EMG

We absorb approximately 1-2mg/day of dietary iron, and macrophages recycle approximately 20-25mg iron per day. Once freed ferric (Fe+3) iron is first reduced, by the Duodenal Cytochrome B (DcytB), utilizing a vitamin C cofactor, prior to absorption as ferrous iron (Fe+2) (Hentze 2010). Ferrous ion is then transported across the intestinal cells by the Divalent Metal Transporter (DMT1) (Hentze 2010). Heme iron uses a specialized heme channel protein (HCP) to cross the membrane due to its large porphryn ring (Hentze 2010). Once in the cytoplasm free ferrous iron can be bound by the iron storage protein ferritin (Zhang 2009). It can also be transported out of the duodenal cells or macrophage cells into the blood stream using ferroportin (FPN) (Zhang 2009). It is then oxidized back to ferric iron by either hephaestin, on the membrane, or ceruloplasmin, which circulates in the blood stream (Zhang 2009). The ferric iron is bound to transferrin proteins, which then circulate in the blood stream (Zhang 2009)

The transferrin receptors are dimeric receptors found on the extracellular surface of cells (Lawrence 1999). When transferrin binds it causes receptor mediated endocytosis to take the iron into the cell (Lawrence 1999). Iron is released from transferrin by a change in pH due to proton pumping into the vesicle (Anderson 2009). The Trf-transferrin complex is then recycled back to the cellular surface (Lawrence 1999). The free iron is incorporated into either ferritin for storage or used is used to make proteins such as those in the electron transport chain in the mitochondria or in hemoglobin(Anderson 2009). When there is excess iron it can also be stored in the form of Hemosiderin (Anderson 2009). Hemosiderin consists of aggregates from degraded ferritin proteins and ferrous clusters and is found mainly found in the liver (Anderson 2009).

Loss of iron occurs due to the loss of mucosal and epithelial cells and through sweat or blood loss (Zhang 2009). This is not a regulated process and there is not a mechanism in which to excrete excess iron thus the absorption pathway is tightly regulated. One of the main regulating agents of iron absorption is hepcidin, a small protein produced in the liver (Nemeth 2004). It functions to regulate the iron levels by binding ferroprotin and inducing its internalization (Nemeth 2004). Additionally, DMT1, ferritin, TfR1 have iron responsive elements (IRE’s) in their mRNA , so iron status controls the expression of these proteins to regulate the amount of iron in the body.

A comprehensive, visual and interactive representation of the iron regulatory pathway in the body can be found at: http://www.ironatlas.com/en/online.html

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