Hemochromatosis and its Web of Illnesses

Most of the health problems today are the results of a lifestyle of excess.

Obesity rates are at an all-time high due to poor diet habits across the world. With this, comes diabetes, a disease that results from insulin resistance caused by too much blood sugar.

Heart diseases and hypertension risk increases with a more sedentary way of life coupled with a poor diet. High blood pressure puts anyone at risk of various diseases: stroke, atherosclerosis, just to name a few.

Too much salt also causes the diseases mentioned, and may even hurt the kidneys in the process.

Again, these are from a lifestyle of excess, something humans can actually control through proper diet and regular exercise.

The proper diet entails we get all the vital nutrients we need in the right amounts. Sugars and carbs are the body’s fuel after all, although too much of it causes diabetes. Salt regulates the balance of fluids in the body but going beyond recommended amounts has its setbacks.

The saying goes: too much of a good thing can be bad. However, there is a rare disease that weaponizes one of the body’s building blocks against the very own structure it tries to sustain.

DNA-derived Illnesses
Some diseases are built in the DNA. Genetic diseases, like hemophilia and sickle-cell anemia, are illnesses beyond the control of patients because these are written in their genetic code.

A hereditary hemochromatosis is a group of diseases that is characterized by the body’s ability to absorb too much iron from one’s food intake.

Iron, in the right amounts, is essential to keep bodily functions running. It is most needed to keep the blood in your veins and arteries functional and flowing. Hemoglobin, a compound found in blood, is mostly made up of iron. This is where the oxygen from the lungs latch on to, to be delivered throughout the body.

Iron is also vital during pregnancy. During this time, the volume of blood and red blood cell production increases dramatically to accommodate the oxygen and nutrient needs of a growing fetus. It is due to this that demand for iron increases. Risks arising from iron deficiency balloons during gestation.

Iron and Hemochromatosis

Low iron intake increases the risk of premature birth and low birth weight. Furthermore, the lack of iron during pregnancy may adversely affect cognitive and behavioral development in infants. There is also evidence that low iron levels may leave a woman susceptible to infection, as the nutrient is also responsible for keeping the immune system running.

Iron is also needed to maintain the health of cells, skin, hair, and nails.

The said nutrient is essential to athletic performance. For athletes, iron deficiency may spell the difference between winning and losing. Lack of hemoglobin greatly affects the performance of the muscles, as the compound, as mentioned before, is required for oxygen transportation inside the body.

A study found out that female endurance athletes are more at risk for iron deficiency due to their menstruation and intense activities from the sport.

While iron may be beneficial for health, it is not recommended that people take too much of it. Supplements should be limited to 45mg for adults, says WebMD. Anything more than that should be taken under a doctor’s supervision. Children are most vulnerable to iron poisoning as their still-developing bodies do not need that much iron in them. Ingestion of excessive amounts of iron may cause severe vomiting, diarrhea, abdominal pain, dehydration, and bloody stool in children.

WebMD says that the human body typically absorbs 10 percent of the iron it ingests. However, some people absorb up to 30 percent, a level considered to be medically dangerous. These people have a genetic disorder called hemochromatosis.

While adult humans have built-in systems in place to regulate iron, a genetic mutation in those with hemochromatosis causes the body to over-absorb said nutrient. Thus, hemochromatosis is called iron overload disorder.

Types of Hemochromatosis

The disease has four known types, all with different genetic mutations causing them.

Type 1 is caused by mutations in the HFE gene. It is the most common type of four. HFE is a gene that provides instructions for producing a protein found on the surface of the liver and intestinal cells, and some immune cells as well. The HFE protein interacts with numerous proteins, however, its job in regulating iron absorption can be examined through its relationship with a protein called transferrin receptor 1.

Once HFE is attached to this receptor, it can not bind to a protein called transferrin. If transferrin is attached to its respective receptor, iron enters liver cells. Hence, the HFE proteins regulate iron levels in the liver by hijacking the attachment between transferrin and its receptor.

This type affects one million people in the United States of America and is considered one of the most common genetic disorders in the country. It mostly affects people of Northern European descent.

Type 2 is caused by mutations in either the HJV or HAMP gene. This type manifests during early childhood that is why it is a juvenile-onset disorder.

Hemojuvelin is the protein that the HJV gene makes. This protein is made in the liver, heart, and skeletal muscles. It regulates iron levels in the body by controlling the amount of another protein, hepcidin. Hepcidin is necessary for maintaining iron balance, or homeostasis, in the body.

The mutations in the gene make an altered hemojuvelin protein that can not do its job. Without the proper hemojuvelin protein, hepcidin levels go down, thus breaking the balance of iron in the body. This causes over-absorption of iron during digestion.

The HAMP gene is also involved with the production of hepcidin in the body. Hepcidin is mainly made in the liver. As mentioned, it is vital in keeping the balance of iron in the body. Once blood iron levels are too high, the liver releases the protein. This then stops iron absorption in the small intestine. Mutations in the HAMP gene causes the production of abnormal hepcidin that is unable to fulfill its duty to stop iron absorption.

The symptoms of Type 2 hemochromatosis manifest in the decreased or absent secretion of sex hormones upon reaching the age of 20. This is, again, caused by iron accumulation in the body. Females with the affliction menstruate normally but then their periods will stop after a few years. Affected males experience delayed puberty. If untreated, Type 2 can lead to fatal heart disease once the patient reaches 30 years of age.

Type 3 hemochromatosis is caused by an abnormality in the TFR2 gene. It is mainly concerned with making the protein transferrin receptor 2, which helps iron enter hepatocytes or liver cells. The receptor binds with transferrin on the surface of liver cells. This aids in the transportation of iron throughout the body through the blood.

Transferrin receptor 2 can also help regulate iron storage levels in the body by controlling hepcidin as well.

Mutations in the TFR2 gene manifest in different ways. Some prevent the production of transferrin receptor 2, while others make abnormal amino acid sequences in proteins. These mutations make transferrin binding impossible thus blocking iron from entering liver cells. Some mutations are thought to hamper hepcidin production in the body, throwing iron balance into chaos.

Mutations in the SLC40A1 gene cause Type 4 hemochromatosis. The SLC40A1 gene helps in the making of a protein called ferroportin, a compound involved in the absorption of iron from the food eaten. This type is also called ferroportin disease.

This protein transfers the iron absorbed through the small intestine to the bloodstream. Iron is then carried by the blood throughout the body. Ferroportin also takes out iron from specialized immune system cells called reticuloendothelial cells found in the liver, spleen, and bone marrow.

The amount of ferroportin in the body is controlled by hepcidin as well. Hepcidin binds to ferroportin and causes it to break down once iron supply in the body is normal. When iron levels are low, hepcidin levels decrease thus increasing ferroportin to facilitate iron transport to the blood.

Almost all SLC40A1 gene mutations change the amino acid sequence in ferroportin. This abnormal ferroportin cannot transport and release iron like it is supposed to do, thus resulting in an impaired iron balance in the body.

Type 4 is further subdivided into 4A and 4B. Type 4A might not exhibit the usual symptoms, but it is associated with liver disease later in life. The other type, 4B, is associated with the more classical symptoms of the disease such as fatigue, weakness, and joint pain.

Type 1 and 4A develop upon adulthood, while 4B may start anytime from childhood to adulthood. Type 2 starts in childhood, while symptoms of Type 3 start around 30 years of age.

Types 1, 2 and 3 are passed on through an autosomal recessive pattern, meaning both copies of the gene in each cell must bear the mutation before any symptoms arise. This means that both parents of a person afflicted with any of these three types of hemochromatosis have at least one copy of the mutation. However, they do not exhibit any signs or symptoms of the disease.

Type 4 is passed on through an autosomal dominant inheritance pattern. Just one copy of the mutation of the gene in one of the parents is enough for the disease to manifest.

The proteins mentioned above, HFE, hemojuvelin, hepcidin, ferroportin, play important roles in regulating iron levels in the body. Mutations and abnormalities impair the balance and absorption of iron from the food people eat, hence leading to excessive levels of iron in the blood.

Iron Overload

High levels of iron in the body then cause the build-up of said element in the different organs, such as the skin, heart, liver, pancreas, and joints. This leads to illnesses associated with these body parts, such as skin discoloration, cirrhosis, heart failure, diabetes, and arthritis.

Iron overload in the body is usually characterized by the feeling of fatigue, malaise and other nonspecific symptoms. Genetic testing is needed to accurately diagnose hereditary hemochromatosis. This may also include other procedures such as a magnetic resonance imaging (MRI) scan and liver biopsy.

The Fight Against Hemochromatosis

Treatment options include therapeutic phlebotomy, iron chelation therapy, dietary changes, and other treatments relevant to complications.

Phlebotomy would mean removing blood and iron from the body, like a routine blood donation. Iron chelation therapy is an option for those who can not undergo blood removal. This can be done through injection at the doctor’s office or orally at home.

Dietary changes may include stopping the intake of iron supplements and vitamin C. This makes the body absorb iron from the food you eat. There could also be restrictions on the intake of uncooked fish and shellfish. Alcohol is not allowed as well since iron overload mainly affects the liver.

Treatment may prevent further damage to organs if any. However, it can not reverse the damage already done by the disease, which is also sometimes called bronze diabetes.

But, it pays to ask what are the actual risks of hemochromatosis.

Studies have shown that women who exhibit the mutation are at risk of developing ovarian cancer. Scientists from Canada have shown that women who have the Type 1 mutation C282Y have a higher chance of developing ovarian cancer. Furthermore, the presence of the said mutation is linked to poorer outcomes in ovarian cancer patients.

Cancer cells usually need more nutrient resources, like iron, for them to proliferate. Thus, people with hemochromatosis provide iron-rich resources to these malignant tumors.

Other studies show that the risk for any type of cancer increases with iron overload, whether owing to hemochromatosis or not. A research team from Denmark in 2011 used elevated transferrin levels as a proxy for iron overload and found the risk for any type of cancer increases with higher iron levels in the body. Specifically, they found out that once transferrin saturation levels go beyond 50 percent, cancer risk rises significantly, even more than the effect of smoking. This led researchers to recommend cancer screening to anyone whose transferrin saturation level breaches 50 percent.

A 2004 study in Tennessee drew a connection between breast cancer and iron overload. The researchers found out that women who have the Type 1 mutation C282Y tend to develop breast cancer, with or without risk features. This suggests that altered iron metabolism may cause an aggressive form of breast cancer to manifest.

In 2010, a research team in Australia also made a connection between the presence of the Type 1 mutation C282Y and increased risk of breast and colorectal cancer, comparing those who do not possess the said mutation.

A team from Denmark in 2007 found out that the presence of Type 1 mutation H63D increases the risk of ischemic cerebrovascular disease (ICVD) and ischemic stroke by two- to three-fold.

Another team in Denmark in 2010 also made a connection between iron overload and hypertension. The study found out that the presence of the mutation, with or without the high level of transferrin saturation, is associated with the use of anti-hypertensive medication.

Postoperative patients of gastric bypass surgeries, who have high transferrin saturation levels, tend to have more complications and longer lengths of stay in the hospital. The presence of two or more HFE mutations means increased cases of overall and wound complications for patients following gastric bypass surgery.

Different studies also prove the effects of high iron levels in the bones of the body. Research from Germany in 2010 has shown that people with hemochromatosis tend to have joint replacement surgeries earlier in life. Furthermore, people with this genetic disorder tend to have more joint replacement surgeries in life than those who do not.

Another study from Australia in 2012 found out that people with Type 1 mutation C282Y are found to have increased risk for single and bilateral total hip replacement, secondary to osteoarthritis. Arthritis can be remembered as one of the symptoms of hereditary hemochromatosis.