Hemochromatosis and Laboratory Testing

Hemochromatosis is a blood disorder that causes the body to accumulate more iron than it needs. This is an iron metabolism disorder that may be acquired or inherited. Because the human body does not have the ability to excrete excess iron, a progressive build-up of iron occurs in the tissues and organs. Eventually, this causes an iron overload that can lead to life-threatening conditions that cause the dysfunction and failure of vital organs in the body, notably the liver, heart, and the endocrine portion of the pancreas. 

Complications of hemochromatosis include: 

  • Arthritis 
  • Liver cirrhosis 
  • Diabetes 
  • Heart arrhythmias 
  • Heart failure 
  • Increased skin pigmentation (bronzing) 

Types of Hemochromatosis

There are two types of hemochromatosis: Primary or Inherited Hemochromatosis, that is passed on from generation to generation; Secondary Hemochromatosis that is caused by another disease or underlying condition in the body. 

  • Primary or Inherited Hemochromatosis (HH) 

Inherited hemochromatosis is thought to be caused by a mutation in the HFE gene that controls the amount of iron absorbed by the body from food and is passed on from parents to children. Each person inherits 2 copies of this gene – one from their father and one from their mother.  

These mutations cause changes to occur in the building blocks of proteins called amino acids and are commonly referred to according to the amino acid changes they induce. There are 2 common mutations in the HFE gene – C282Y and H63D. For example, C282Y is one of the most common mutations that involve the change of the amino acid cysteine (C) into tyrosine (Y) that occurs in the 282nd amino acid of the protein created by the HFE gene. This is the most common type of hemochromatosis. 

In the United States, it is one of the most common genetic disorders that affect more than one million people, mostly Caucasians. The probability of iron overload in the body will depend on the combination of inherited genes. Genetic testing can be done to find out whether you have mutations in your HFE gene that can increase your risk of hemochromatosis. 

  • Secondary or Acquired Hemochromatosis 

This type of hemochromatosis is caused by an acquired iron overload due to certain other diseases and conditions that include the following: 

  • Alcohol abuse 
  • Excessive oral iron supplementation (rarely) 
  • Multiple blood transfusions 

Signs and Symptoms 

Not everyone who has the disorder will have signs and symptoms and, though estimates vary, according to the National Heart, Lung & Blood Institute, as many as half of those may not have any initial symptoms. Symptoms tend to be like those of other conditions and take a long time before they emerge and increase in severity. 

Inherited hemochromatosis is present at birth, but symptoms often only appear later in life, usually after the age of 60 in women and 40 in men. Symptoms in women are more likely to appear after menopause when the body no longer loses iron due to menstruation and pregnancy. Early symptoms of hereditary hemochromatosis can be difficult to diagnose as stiff joints and fatigue may be caused by other underlying conditions. 

The severity of signs and symptoms of hemochromatosis may vary from person to person but usually include: 

-Weakness and fatigue 

  • Joint pain 
  • Abdominal pain 
  • Liver dysfunction or abnormal liver blood tests 
  • Increased blood glucose levels 
  • Lack of menstruation in women 
  • Decreased sex drive or erectile dysfunction in men 
  • Hypothyroidism (low thyroid hormone levels) 
  • Changes in skin color e.g., turning bronze or grey 

Testing for Hemochromatosis 

Tests can be carried out to evaluate the severity of iron overload in body organs and to detect and diagnose hemochromatosis. Genetic testing can be used to confirm a diagnosis; however, since most people never develop any symptoms, the most reliable method of diagnosis is blood tests. 

Laboratory tests usually include the following: 

  • Serum iron testing to determine iron levels in the blood 
  • TIBC (total iron-binding capacity) testing to measure the total amount of iron that can bond to proteins in the blood; this is a good indirect measurement of the availability of the primary iron-building protein transferrin. 
  • Transferrin saturation is a calculation derived from the results of the iron and TIBC tests that represent the percentage of transferrin in the body saturated with iron. Transferrin saturation is elevated in people with HH (hereditary hemochromatosis) but is not specific to it. 
  • Ferritin testing is used to evaluate the iron stores in the body; ferritin levels may be elevated in hereditary hemochromatosis but not specific to it. Normal levels of ferritin in those with HH gene mutations indicate a low risk that organ damage will develop. 
  • Liver Panel is a group of tests that evaluates liver function. 
  • Liver Biopsy is done to determine the extent of damage to the liver; the examination of a liver biopsy specimen is not usually needed to confirm a diagnosis for iron accumulation but is useful in determining damage. 
  • Genetic testing can help to confirm an HH diagnosis. In most cases, HH is caused by 2 copies of a C292Y mutation. The presence of 2 copies of this mutation in the HFE gene can mean an increased risk of the disorder but does not necessarily indicate that the person will develop HH.  

The largest population study in the U.S. has found that men are more likely to be affected with a risk of 25% compared to 1% of women. Sometimes HH may be caused by 2 copies of H63D or S65C mutations or by paired combinations of the 3. On rare occasions, HH can be attributed to another genetic abnormality. 

Possible Gene Combinations for the HFE gene 

  • 2 copies of C282Y or a copy of C282Y together with a copy of H63D/S65C mutant genes will place a person is at the highest risk for HH. 
  • 2 copies each of H63D; S65C; or 1 copy each of H63D, and S65C is rarely associated with HH and will place a person in a low-risk category. Although carriers will not develop HH, they may pass it on to children they have with someone else who is also a carrier. 

Because other genes can affect the ability of a person to metabolize iron, no combination of genes can guarantee that a person will or will not develop HH. As mentioned before, only an estimated 25% of men and 1% of women with 2 copies of C282Y mutations will ever be at risk of developing organ damage that is related to excess iron. 

Two other forms of HH occur in young children and teens – neonatal and juvenile hemochromatosis. These two disorders are caused by mutations that occur in a different gene called HJV.  HJV causes changes in the protein hemojuvelin that affects iron metabolism.  

A small percentage of HH is due to mutations in the gene coding for other proteins, apart from HJV, which also affects iron metabolism. These include hemojuvelin, hepcidin, and transferrin receptor 2. However, tests are not widely available for these mutations.