Mechanisms involved in the development of Hereditary Haemochromatosis

Worldwide one of the most common inherited disease is hereditary haemochromatosis it is an autosomal recessive genetic disorder which is known for causing severe iron overload. It varies from type 1 up to type 4 the most common is type 1 which is caused by a mutation in the HFE gene responsible for encoding non classical MHC class 1 protein. The other types are not as common as type 1 and are usually caused by altered functions of different proteins which are important for regulating iron homeostasis. While they all differ in severity most patient with (HH) hereditary haemochromatosis are unable to regulate iron absorption effectively, the increase in iron builds up in the parenchymal organs until it exceeds the body’s storage capacity and then begins to cause damage to tissue and organs throughout the body such as the heart, liver and pancreas. These can lead to the development of liver fibrosis, arthritis, heart disease, diabetes, cirrhosis and premature death. This essay will discuss the mechanism involved in the development of hereditary haemochromatosis, pathways involved in iron absorption, and transport to the liver, mechanisms involved in liver Iron toxicity and current biochemical and molecular diagnostic tests.
Pathways involved in iron absorption, and transport to the liver
Iron is essential for life it is an important growth factor for the differentiation and proliferation of almost every living cell throughout the human body. Most eukaryotic cells need iron for metabolic pathways and are vital for enzyme functions (L.POWELL 2002). Iron is absorbed across the epithelial cells from the proximal small intestine also known as the duodenum in a heme or non heme form however most iron from food is ferric (Fe3+) which is not easily absorbed so needs to first be reduced to ferrous (Fe2+), a ferric reductase enzyme, (Dcytb) duodenal cytochrome b reduces (Fe3+) to (Fe2+) and then transported into the cells by DMT1 a protein also known as divalent metal transporter. Iron can then be stored in the cytoplasm of the villus as ferritin or transported through the basolateral membrane by IREG1 a membrane protein also known as ferroprotein, hephaestin (Heph) is also important in this process as it functions as a ferroxidase by oxidizing Fe2+ to Fe3+ (L. M. Fletcher and J. W. Halliday 2002).
Plasma transferrin can then bind to iron present on the surface of the basolateral body tissue primarily reticulocytes and also the liver with the help of TfR transferrin receptor. In the liver hepatocytes gain iron in a number of ways such as receptor mediated endocytosis through TfR transfrerrin receptors, iron is then released by acidification within the endosome and then transported by DMT1 throughout the endosomal membrane where it is stored as ferritin until it is needed or used in the metabolic process. Iron released from hepatocyte would usually involve cerplasmin and Ireg1 which oxidizes Fe2+ to Fe3+ (L. M. Fletcher and J. W. Halliday 2002).
Hereditary Haemochromatosis and the HFE Gene
Iron overload tends to occur when the regulatory process above begins to malfunction, if its stores are full the body begins to absorb less iron however iron toxicity occurs due to an increase in iron absorption which results in damage to tissues and organs around the body like the liver. Hereditary haemochromatosis is caused by a gene mutation in HFE that enhances iron absorption. The HFE gene is responsible for encoding HFE proteins and is located on the short arm of chromosome 6 at 6p21.3 (L. M. Fletcher and J. W. Halliday 2002).
However this is only for the main type of HH hereditary haemochromatosis, according to online mendelian inheritance there are 5 types of HH, type 2 hemochromatosis also known as juvenile hemochromatosis JH which comes in two forms, 2B JH which is caused from a mutation in the HAMP gene and 2A JH which results from a mutation in HJV gene on chromosome 1q21. HH types 3 and 4 are resultants from a mutation in SLC4OA1 and TFR2 genes located on chromosome 2q32 and 7q22 for type 3 HH (P.Santos, J.Krieger, A.Pereira 2012).
The main type of HH is a class I MHC histocompatibility complex related gene. MHC class I type proteins associate with beta2M B2 microglobulin which assists in the transportation of proteins towards the cell surface. A single G A transition from nucleotide point 845 is known for causing most HH cases. This mutation occurs when amino acid cysteine is substituted for tyrosine at position 282 of the gene which causes a mutation C282 (L. M. Fletcher and J. W. Halliday 2002). This results in a disulphide bond being unable to form which is needed in maintaining protein conformation, because of this HFE proteins can no longer associate with B2 microglobulin which is needed for the transportation of HFE proteins to the cell surface.
It is also important to remember that HFE is highly expressed in intestinal crypt cells but not that strongly in the hepatocytes or villus, in the liver however it is expressed in kupffer cells. It seems as though the role of HFE in iron metabolism is to sense the controlling signals that stimulate intestinal cells to increase iron absorption (L. M. Fletcher and J. W. Halliday 2002). Recent studies have shown that iron concentration in the crypt cells is important in trying to determine the amount of iron that is absorbed by the villus when the crypt cells begin to migrate and differentiate to the villus (L. M. Fletcher and J. W. Halliday 2002).
The C282Y mutation in HFE gene is due to HFE protein accumulating inside the endoplasmic reticulum and its inability to reach the cell surface which impairs transferrin HFE mediated iron uptake. Studies have shown that HFE probably effects transferrin bound iron entry the crypt (P.Santos, J.Krieger, A.Pereira 2012). A decrease in iron intake in the crypt can result in incorrect signals for increase in iron absorption. As soon as these programmed cells enter the villus the movement of iron through DMT1 is increased and more iron can know enter the intestinal cell where it can then move throughout the basolateral surface.
Mechanisms involved in liver Iron toxicity and Hepcidin
It’s important to note that a normal individual absorbs 1-2mg of iron which is balanced by equivalent loss there is no mechanism in regulating iron loss from the body so it is important that iron absorption is carefully regulated. Most of the iron used throughout the body is recycled senescent erythrocytes by macrophages which is then returned to the bone marrow to be integrated in erythroid precursors. The major storage of iron is in the liver and the reticuloendothelial cells. Iron metabolism and absorption are adjusted according to the body requirements and response to iron deficiency or iron overload conditions for example expression of duodenal NRAMP2 and SIC40A1 is increased during iron deficiency (G.Weiss 2009). While this seems to be upregulated in the macrophages and duodenum it is downregulated in the liver which is due to a systemic iron regulator. This master regulator helps to control iron homeostasis and is a peptide hormone encoded in the liver known as hepcidin which is encoded by the HAMP gene.

Hepcidin is an acute phase protein, the protein applies its regulatory effects on iron homeostasis by binding to SIC40A1, this results in degradation, ubiquitinylation and internalization of transporter proteins which reduces the exportation of iron from cells (G.Weiss 2009). People with HH hereditary haemochromatosis produce a reduced amount of the master regulator hepcidin which in turn causes an increase dietary iron absorption and build up in tissues. The reduction of hepcidin production is due to induction of SIC40A1 expression and an increase of iron transfer from res and gut into the circulation (G.Weiss 2009). People with an abnormal iron regulator gene are not able to reduce absorption of iron despite an increase in iron levels in the body and with a reduction of hepcidin, the iron stores of the body increase, the iron that was stored as ferritin then begins to deposit in organs like the liver, heart and pancreases which can cause organ fibrosis, it is released as haemosiderin which is very toxic to tissue

Biochemical and molecular diagnostic tests
Serum transferrin and transferrin saturation
There are a variety of diagnostic methods to determine whether a patient has haemochromatosis most of the time they are detected from a routine blood screening, however the most common test are serum transferrin and transferrin saturation. Transferrin binds iron is needed to transport iron in the blood. By measuring transferrin we are able to gain a crude measurement of iron stores in the body. Normal values range between 15-40% about 300ng/L in males and 200 in females. Values indicating overload are 60% in men and 50% in women, a transferrin saturation greater than 62% may indicate homozygosity for a mutation in the HFE gene. Serum ferritin is another method in diagnosing haemochromatosis, by measuring ferritin we can get a rough estimation of whole body iron stores. Normal values range from 12-150 ng/ml in females and 12-300 ng/ml in males, anything above 1000 nano grams per millilitre of blood is strongly due to haemochromatosis. Although serum ferritin is a sensitive test for iron overload in hereditary haemochromatosis it is also low specificity making it elevated in a variety of inflammatory conditions such as diabetes, liver damage and alcohol consumption.
Liver biopsies and Genetic testing
Liver biopsies involve the extraction of liver tissue using a needle, the amount of iron in the tissue sample is then measured and then compared to a normal standard and evidence of liver damage. This is measured microscopically and by atomic absorption spectrophotometry of the hepatic parenchymal cells. However this method does come with risks such as bruising, infection and bleeding. Another useful diagnostic method is genetic testing this can be done with a blood test to identify HFE hemochromatosis gene which results in hereditary hemochromatosis an inherited disorder. HFE testing is useful in determining if a person will have hemochromatosis, the test locates and identifies the mutation in the HFE gene known as C282Y and H63D.
Once identified with haemochromatosis the treatment is simple and effective using phlebotomies which involves removing the excess iron by extracting 500ml of blood weekly until haemoglobin concentration is lower than the reference range about 120 -130g per L, iron depletion is confirmed with serum ferritin and transferrin saturation. Once treatment is done patients require a periodic phlebotomy typically 4- 8 times per year to prevent re- accumulation.

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