Hereditary hemochromatosis (HHC) is a genetic disorder that causes the body to absorb too much iron from the diet.  All of the problems associated with iron overload – from the benign bronzing of the skin to the life-threatening liver cancer – can be traced back to one crucial protein called HFE. The HFE gene on chromosome 6 encodes the HFE protein. The HFE protein is normally found in the cell membrane.  However, in most people with hereditary hemochromatosis, HFE is missing from the cell membrane. Some people with HHC have less serious complications because they make a mutated HFE protein that still works, though not as well as the normal HFE. Because researchers have not figured out exactly how the protein works, why this missing HFE leads to iron overload is still somewhat mysterious.  What is known, however, is that HFE regulates iron in two different systems.  The most important system is located in the small intestine, where the body first encounters iron from the food we eat. Here, in the fingerlike projections of the intestine known as villi, HFE is thought to help cells sense the amount of iron already present in the body.  If iron is needed, the villi cells are signaled and iron receptors are made and placed at both ends of the cells. Here, in the fingerlike projections of the intestine known as villi, HFE is thought to help cells sense the amount of iron already present in the body.  If iron is needed, the villi cells are signaled and iron receptors are made and placed at both ends of the cells. Iron transport begins when the villi cells migrate from the valley to the tip of the villi. Receptors at the intestinal side of the cell first grab the iron molecules and then draw them inside the cell.  They pass through the cell’s cytoplasm and exit the other side through additional iron channels that deliver the iron directly to the bloodstream. In hemochromatosis, HFE is absent, and the sensory ability of cells in the valleys fails.  The villi cells are tricked into sensing an iron deficit.  Twice as much iron is transported into the bloodstream. Once the iron is in the bloodstream, it binds to a "transferrin" molecule that ferries iron to the organs and tissues that need it.  

Many transferrins are present in the bloodstream waiting to bind iron.  Usually there isn’t enough iron to fill them up, leaving about 70% of the iron-binding spots free. In a person with hemochromatosis, because so much iron is present, the transferrins become saturated, leaving 50, 40, and even 0 percent of the iron-binding spots free. Transferrin delivers most of the iron to the bone marrow, where the iron is incorporated into hemoglobin molecules in newly formed red blood cells. Much of the rest is delivered to the liver, the primary storage area for excess iron.  Here, and in other tissues and organs that store iron, HFE plays a second role in iron uptake. To get iron inside a liver cell, transferrin docks to a receptor on the outside.  HFE is usually attached to this receptor, controlling its ability to deliver iron to the interior of the liver cell.  If HFE remains attached, iron is not delivered into the cell. If HFE is absent, as for most people with HHC, the whole complex of receptor, transferrin, and iron is engulfed, and the iron is released into the cytoplasm of the liver cell. The iron that’s not immediately used by the cell is encased within an aggregation of molecules called ferritin.  In people with HHC, more and more iron is encased within ferritin and other storage systems inside the cell until the storage systems are full. At this point, which may take 30 years or so, excess iron is left unguarded and it unleashes its toxicity by creating hydroxyl radicals.  The hydroxyl radicals react with other structures in the cell – proteins, fats and DNA – damaging and even killing the cells. The type of cellular damage in the liver, pancreas, heart and other tissues can lead to the failure of these organs and degradation of the tissues. It’s hard to believe that all the cellular damage from hemochromatosis can arise from the absence of a single protein, HFE, made by our bodies.  It may be even harder to believe that the reason for the HFE’s absence is a change in a single letter of genetic code out of the 3.2 billion letters that make up the human genome. This small change occurs within the gene for the HFE protein.  The gene encodes instructions for making HFE in a sequence of chemicals called bases (or letters).  Most people with hemochromatosis have inherited, from both their mother and their father, a version of the gene that contains an ‘A’ where a ‘G’ usually resides.  (This gene version is called C282Y). The consequence of this change is seemingly minor.  Instead of inserting a cysteine molecule into the growing HFE protein, the cell’s protein-production machine inserts a tyrosine. Only one of the protein’s 343 individual molecules differs from the norm, but the change has huge consequences.

  The mutant protein can not fold into its proper shape.  Normally, the HFE protein binds to a shipping protein that carries HFE to its place in the cell membrane.  The C282Y HFE protein is a different shape.  The shipping protein can no longer bind to the mutated HFE, and thus no HFE is present in the cell membrane. The C282Y HFE stays in the cell interior and is eventually degraded. A few percent of people with HHC carry a different version of the HFE gene  – called H63D – which also differs from the norm by a single base change. This shape change does not affect HFE's presentation to the cell membrane like C282Y.  However, H63D proteins do not work as well as normal HFE to control iron absorption, but since it does work somewhat, HHC in someone with the H63D version is usually less severe. Both copies of chromosome 6 can have the H63D version.  Alternatively,  one copy may have the H63D and the other the C282Y version.  While most people with two C282Y versions are likely to develop HHC, less than 2 percent of people with one or two H63D versions will develop HHC. Why some people with H63D genes develop HHC and why some don’t is still unknown, but other genetic differences and environmental differences may be at work.  Finally, there are still some versions of the gene, and possibly completely other genes, that can cause HHC that have not been deciphered. Hereditary hemochromatosis is caused by a mutation on chromosome 6 in the HFE gene. In this example, the parents are heterozygous for the HFE gene. This means that each parent has two different versions of the HFE gene; one on each chromosome. When the father and mother produce sperm and eggs, only one of their two HFE genes enter each cell.  About half the cells get the C282Y type, and half get the normal type. When a sperm carrying the C282Y type fertilizes an egg carrying the C282Y type, the resulting child inherits both genes and usually develops hemochromatosis.  (The exact percent of people with two C282Y's that have HHC is very high but not 100%).The child in this example is homozygous for the HFE gene.  He has the same version of the HFE gene on both chromosomes. Everybody has two HFE genes, but a person with hereditary hemochromatosis has inherited two mutated HFE genes, one gene from each parent. For this to happen, each parent must have at least one of the mutations, which is usually the C282Y type (shown as the red chromosome). In this example, the parents are heterozygous for the HFE gene. This means that each parent has two different versions of the HFE gene; one on each chromosome. When the father and mother produce sperm and eggs, only one of their two HFE genes enter each cell.  About half the cells get the C282Y type, and half get the normal type. If one parent has hemochromatosis and two C282Y genes, the chance of having a child with 

HHC depends on the genes of the other parent.  If the other parent has one C282Y gene, the chance is 50%, or 1-in-2.  To see why, we'll construct a Punnett square. To set up the square, we first arrange each parent's genes on the outer edges, as shown.  (The + symbols represent "normal" HFE genes). Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes HHC (C282Y/C282Y). Two out of four boxes contain this pair, so each child of this couple has a 1-in-2 (50%) chance of inheriting both genes and getting hemochromatosis. If one parent has hemochromatosis and two C282Y genes, the chance of having a child with HHC depends on the genes of the other parent.  If the other parent has one C282Y gene, the chance is 50%, or 1-in-2.  To see why, we'll construct a Punnett square. To set up the square, we first arrange each parent's genes on the outer edges, as shown.  (The + symbols represent "normal" HFE genes). Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes HHC (C282Y/C282Y). Two out of four boxes contain this pair, so each child of this couple has a 1-in-2 (50%) chance of inheriting both genes and getting hemochromatosis. If one parent has hemochromatosis and two C282Y genes, the chance of having a child with HHC depends on the genes of the other parent.  If the other parent has one C282Y gene, the chance is 50%, or 1-in-2.  To see why, we'll construct a Punnett square. When the father and mother produce sperm and eggs, half the sperm get the H63D mutation, and half the eggs get the C282Y mutation. When a sperm carrying H63D fertilizes an egg carrying C282Y, the resulting child will inherit both genes.  However, only 1 to 2 percent of people with these two genes show clinical signs of iron overload. This risk, though small, should not be ignored.  Children in these situations should be closely monitored especially if there is a history of hemochromatosis in the family. The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 50% chance of inheriting hemochromatosis. In this family, one in four children inherited HHC.  Other couples with the mutation may have two, three, four, or even no children with the disorder. If, on the other hand, the other parent does not carry any HFE mutation, none of this couple's children will inherit hemochromatosis.  Again, we'll construct a Punnett square to see why. If, on the other hand, the other parent does not carry any HFE mutation, none of this couple's children will inherit hemochromatosis.  Again, we'll construct a Punnett square to see why. None of the four boxes contain the C282Y/C282Y pair, so each child of this couple has a zero chance of inheriting both genes and getting hemochromatosis. When neither parent has HHC, their child can still inherit hemochromatosis IF both parents carry a C282Y gene.  To see why, we'll construct a Punnett square.  First, we place the parents' genes on the outside of the square, as shown in the animation.  (The + symbol represents the "normal" HFE gene). When neither parent has HHC, their child can still inherit hemochromatosis IF both parents carry a C282Y gene.  To see why, we'll construct a Punnett square.  First, we place the parents' genes on the outside of the square, as shown in the animation.  (The + symbol represents the "normal" HFE gene). Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes hemochromatosis (C282Y/C282Y).  Out of four boxes, only one contains this pair, so each child of this couple has a 1-in-4 (25%) chance of getting HHC. What is it? What causes it? How is it inherited? How is it diagnosed? How is it treated? What is it like to have it? For more information… Acknowledgments When Symptoms Arise Dr. Victor Herbert discusses when hemochromatosis symptoms will arise in makes and females. A Cautionary Tale Dr. Herbert talks about the fate of undiagnosed people. 

Blood Tests Dr. Herbert talks about the serum transferring saturation test, a blood test done to detect hemochromatosis. Test Results Dr. Herbert explains the results from blood tests as they apply to iron overload. Organ Damage Dr. Herbert describes the various effects that hereditary emochromatosis can have on the body, especially organ damage. Importance of Screening Dr. Herbert discusses the importance of including the iron overload test as part of the routine screening procedures. Chris Reilly discusses the various tests needed for hereditary hemochromatosis. Phlebotomy Dr. Herbert talks about the treatment for iron overload. Iron Damage Dr. Herbert talks about the damage caused by hemochromatosis and the possible therapies. An HHC Diet Dr. Herbert recommends a diet for those with hereditary hemochromatosis. Phlebotomy Frequency Dr. Herbert talks about how much and how often. Phlebotomy Aftermath Dr. Herbert talks about what can happen after a phlebotomy. Crushed Bone Marrow Dr. Herbert talks about patients with crushed bone marrow, and what has been done about those situations. Chelators Dr. Herbert discusses the cases in which chelators may be more appropriate than phlebotomies. Diagnosis Chris Reilly talks about how he was diagnosed for hemochromatosis. Iron Levels Chris explains how to maintain low iron levels in the body by keeping a careful diet and having phlebotomies. Common Signs Chris lists common signs of hereditary hemochromatosis. He also talks about the misconception that women do not get the disease. Letters Chris talks about how he sent letters to family members after his diagnosis, asking them to get tested for hemochromatosis. Phlebotomies Chris describes how a phlebotomy works and the side effects of this process. Ferritin Levels Chris discusses how often he has to go in for a phlebotomy based on his level of ferritin. Organ Damage Chris talks about organ damage and how his risk of level has decreased. Liver Biopsy Chris describes his own experience with having a liver biopsy. Awareness Chris talks about how hemochromatosis is the most common hereditary disease in the United States, and how the disease changed his awareness. Hereditary hemochromatosis (HHC) is an inherited recessive disorder and is not contagious.  A person must inherit two copies of the mutated "hemochromatosis" gene (one from each parent) to develop severe symptoms.  Consequently, every child of a person with HHC has a 50% chance of inheriting the disease ONLY if the other parent also carries the mutated gene. Early signs of hemochromatosis include abdominal pain, arthritis, and chronic fatigue.  

Later signs include diabetes, liver disease and other organ damage.  Hemochromatosis is frequently underdiagnosed because other diseases share the same symptoms. Hemochromatosis is the most common genetic disorder in the United States, affecting about 1 in every 200 to 400 people.  It is even more common in people of Celtic origin where 1 in every 4 people carry a gene for the disease. Simple blood tests can easily detect the iron overload caused by hemochromatosis.  High transferrin saturation and serum ferritin levels are  indicative of iron overload.  Liver function tests can also help with diagnosis.  A DNA test can sometimes confirm the diagnosis, as will a liver biopsy. Simple blood tests can easily detect the iron overload caused by hemochromatosis.  High transferrin saturation and serum ferritin levels are  indicative of iron overload.  Liver function tests can also help with diagnosis.  A DNA test can sometimes confirm the diagnosis, as will a liver biopsy. If diagnosed early, hemochromatosis is easily treated by blood donation sessions (also known as phlebotomies).  Phlebotomies decrease the amount of iron stored in the liver and other organs.  If diagnosed after organ damage is irreversible, other treatments for diabetes, liver disease and heart disease caused by long-term iron overload are needed.