National Hemochromatosis Awareness Month
WHAT IS HEMOCHROMATOSIS?
Hereditary Hemochromatosis – A Genetic, Metabolic Disorder
Hereditary hemochromatosis is a genetic, metabolic disorder that results in iron overload; the body absorbs and retains too much dietary iron. It is a primary disorder of iron metabolism that can affect many organ systems including the liver, pancreas, heart, endocrine glands and joints. It is potentially fatal, but
easily treated if diagnosed early, before the excess iron causes irreversible damage.
‘Normal’ Iron Levels
Iron is an essential nutrient for the human body. Too little can compromise many important functions and lead to various diseases. Similarly, too much can cause severe damage to organs and tissues, leading to disease and early death.
A normal diet provides between 10-20 mg of iron daily, of which the body absorbs only 1.0 to 1.5 mg through the intestinal tract. The rest of the iron not absorbed during digestion is excreted in the stool. Iron metabolism is a complex process. The body responds to increased or decreased demand by adjusting the amount it absorbs. Once iron is absorbed into the body, it is difficult to eliminate, and can only be lost in small amounts through blood loss, sweat, urine and the sloughing of skin and gut cells. Therefore, our body maintains a strict regulation of iron absorption.
Normally, the body has about 4,000 mg of iron, of which about 3,000 mg is contained in hemoglobin in the red blood cells. About 500 mg is bound to the storage protein ferritin, and 300 mg is stored in the liver. Transferrin, the protein that carries the iron from organ to organ around the body, helps regulate how and when iron is stored and transferred to bone marrow and other cells when needed for body processes.
Broken Iron Feedback System
In hereditary hemochromatosis (HHC), the feedback signal within this complex system is not working properly. The gut continues to absorb iron at 2-4 times the normal rate, despite the body already being overloaded with iron. In response, the level of ferritin, the protein that stores unused iron in body cells, increases in an attempt to contain excess iron. As the transferrin protein gets saturated with iron, other proteins not usually involved in iron metabolism bind the excess iron.
Unfortunately, these other proteins readily enter cells to deposit the iron in organs and tissues where it causes damage from free radical activity leading to specific organ dysfunction, disease and death. The liver and heart are particularly vulnerable, but the pancreas, endocrine glands, testes and ovaries, joints and skin can also be affected.
Excess iron accumulation in HHC is chronic and ongoing, and while a normal body contains about 4 grams (4,000 mg) of iron, a hemochromatosis patient typically has at least 15-60 grams of iron upon diagnosis.
Development of Symptoms
It takes time for iron overload to reach a level that will cause organ damage and failure. Men typically develop disease between 40 and 60 years of age, and women after menopause. Diet, vitamin pills with iron, and alcohol consumption all can have an effect.
HOW COMMON IS IT?
The Most Common Genetic Disorder in the Western World
Hemochromatosis is the most common genetic disorder in the western world, affecting an estimated 1 in 300 Canadians of Northern European descent. That means about 100,000 Canadians have Type I hemochromatosis, the most common form of hereditary hemochromatosis (HHC).
Hereditary hemochromatosis is an autosomal recessive disorder, meaning that a person needs to inherit two defective copies of the gene, one from each parent, in order to be affected. Men and women are affected equally. People with just one copy of the mutated gene and one normal copy are referred to as carriers, or heterozygotes. While carriers only rarely develop hemochromatosis, children of two carriers may inherit the defective genes from both and develop the disorder. Current research estimates that 1 in 9 Canadians are carriers, making the above scenario a very real possibility.
Genetics
The most common gene related to iron metabolism is called HFE (Human + Fe, the symbol for iron). In 1996, genetic researchers, searching for genes responsible for hemochromatosis, identified HFE as essential to iron metabolism and that mutations of this gene were responsible for Type I Hemochromatosis. The two most common mutations of this gene, named C282Y and H63D, account for 85% of all cases of hemochromatosis.
Although the vast majority of hemochromatosis patients have a combination of the 2 common mutations (C282Y and H63D) in the HFE gene, other genes associated with iron metabolism have been discovered. Mutations in these other genes have been linked to more rare types of hereditary hemochromatosis, including Juvenile Hemochromatosis, Hemochromatosis Type III and Type IV that account for iron overload in other race and age groups. In addition, more mutations of the original (HFE) gene have been identified, making the genetics of hemochromatosis a complex topic.
Complexity
Research into the various genes involved in the metabolism of iron has led to a better understanding of other disorders that may involve malfunctions of iron absorption, such as Alzheimer’s and Parkinson’s disease. The complexity of iron metabolism and the interrelation of several genes, some known, some yet to be discovered, may account for the fact that some carriers develop hemochromatosis, and some people with two defective genes do not. It also may explain why such a wide range of severity and expression of disease exists among individuals with hemochromatosis.
NOTE: Mutations of the HFE gene are found to cause hemochromatosis primarily in people of Northern European descent. These mutations are not typically found in African, Asian or Middle Eastern populations. Although uncommon, iron overload conditions do exist in these populations but are undoubtedly caused by other genes or environmental factors.
SYMPTOMS
Early Symptoms Often Go Unnoticed
In spite of being the most common genetic disorder among persons of Northern European descent, hemochromatosis remains relatively unknown. Until recently, physicians were taught that HHC was extremely rare, so symptoms were attributed to other causes. Many early symptoms go unnoticed so individuals with hemochromatosis go undiagnosed until irreversible damage has occurred. Even post mortem, hemochromatosis is often overlooked as a possible cause of death. That is why hereditary hemochromatosis has been called “the silent killer”.
Symptoms of HHC do not necessarily appear in a particular order, and importantly, not all hemochromatosis sufferers will have every symptom. The following symptoms have been associated with hemochromatosis, and any combination of two or more should prompt further investigation:
•chronic fatigue
•joint pain
•arthritis, especially of the knuckles of the first and second finger, and thumb
•a change in skin colour, either bronzing like a tan that never fades or a slate gray
•abdominal pain and distention
•menstrual irregularities and premature menopause
•loss of body hair
•loss of libido or sexual drive
•impotence
•sudden weight loss
•thyroid problems
•mood swings and other personality changes such as severe depression or anger
•elevated liver enzyme levels, such as AST, ALT, GGT or alk phos, on routine blood work
•elevated triglyceride levels
•increased glucose levels (blood sugars)
•diabetes (adult onset or Type II)
•enlarged liver, cirrhosis or other liver conditions
•irregular heartbeat (arrhythmia)
•congestive heart failure or cardiomyopathy, a disease of the heart muscle
Preventing Life Threatening Complications
Without any kind of intervention, damage to organs from too much iron can eventually result in life threatening significant diseases, such as:
•cirrhosis, with all its complications such as liver cancer and internal hemorrhage
•congestive heart failure
•diabetes
Diagnosing the disorder before symptoms occur, while still in the early stages before irreversible damage is done, is extremely important. Many complications can be treated or prevented, but early diagnosis and therapy is the key.
DIAGNOSING & TESTING
Transferrin Saturation and Serum Ferritin Tests
Currently, tests for hemochromatosis are not part of a general medical checkup. They must be specifically ordered on a blood lab requisition form. A doctor can order an iron series profile and, depending on the lab, may include serum iron, ferritin, transferrin, and transferrin saturation or total iron binding capacity. Of particular importance in this profile is serum ferritin (SF) and transferrin saturation (TS). These tests should ideally be performed in the morning after the patient has fasted overnight for a more accurate reading.
Serum ferritin and transferrin saturation measurements reflect how much iron is in the body and how much is being transported and stored.
Biochemical Blood Screening Tests
Serum Ferritin (SF)
A normal serum ferritin result varies with gender and age. An abnormally high ferritin will be highlighted on the lab test result as out of range. Ferritin is a non-specific test and can be elevated for reasons other than hemochromatosis. Subsequent tests may be necessary to see if elevations continue over time. A level of more than 200 ng/ml for women and 300 ng/ml for men is considered out of range, but it is rare for organ damage to occur with ferritin levels below 1000 ng/ml.
Transferrin Saturation (TS)
A normal result is typically 25-40% saturation. Anything greater than 45% saturation requires further investigation. Transferrin saturation is more specific to hemochromatosis but is still considered a screening test and on its own does not confirm hemochromatosis.
If both serum ferritin and transferrin saturation come back abnormally high, or even high normal, these screening blood tests may be repeated for accuracy. If the results continue to be elevated, then further medical work-up is required. Additional diagnostic testing can be done to confirm the presence of hemochromatosis. This includes genetic testing for the HFE gene.
Elevated levels of serum ferritin and transferrin saturation can be detected even before symptoms are noticeable. Continued abnormally high results of serum ferritin and transferrin saturation are called biochemical iron overload and is considered the first sign of hemochromatosis.
Genetic Diagnostic Test
Genetic testing of the HFE gene will confirm the diagnosis of hemochromatosis. A blood sample is taken for the genetic test which checks the HFE gene for the mutations C282Y and H63D, the ones abnormal in Type I HFE-Hemochromatosis.
Possible positive combinations resulting from the HFE genetic test:
C282Y / C282Y – homozygous for HFE Type I Hemochromatosis. The majority of hemochromatosis individuals have this combination, with severe biochemical iron overload occurring in most if not all of the individuals.
C282Y / H63D – compound heterozygous for HFE Type I Hemochromatosis. Significant iron overload occurs in only 15% of these individuals. In the other 85%, the iron overload is generally much less severe.
H63D / H63D – homozygous for HFE Type I Hemochromatosis. Iron overload is unusual, with not much chance of organ damage, although other (genetic and environmental) factors may play a role.
A positive HFE genetic test will implicate other family members who should also be tested. First-degree relatives (parents, siblings, and children) are at risk of being carriers of the HFE gene, or inheriting both abnormal copies of the HFE gene and developing hemochromatosis. Spouses should be tested if there are minor children, so as to assess their risk. Genetic counseling may be helpful, especially for those found to be positive who are contemplating starting a family.
See Genetic Inheritance for graphical representations of possible inheritance.
If the genetic test is negative because mutations (C282Y and H63D) were not detected in the HFE gene, then there may be another reason for iron overload, such as another disease, or another form of hemochromatosis caused by a different gene. Further medical investigation will be required. Hepatitis C, chronic alcoholism and those with a fatty liver are all at risk of developing mild to moderate secondary iron overload.
Other Possible Tests
In addition to the biochemical blood screening tests (ferritin and transferrin saturation) and the genetic HFE test, there are other tests that can be ordered to help assess risk of, and monitor, injury to particular organs:
A liver enzymes test is often performed to analyze ongoing liver injury. Liver enzyme measurements are typically followed to see that they return to normal with de-ironing. If not, they must be explained. For example, cirrhosis may already be present, or the patient may have another liver disease.
A liver biopsy, to establish the degree of damage to the liver, may occasionally be done, but is not necessary for establishing the diagnosis in the majority of patients with hemochromatosis. It is not helpful for ongoing monitoring.
Radiological imaging of the liver is usually required; it gives a structural picture of the liver and may be useful in finding cirrhosis and some of its complications. Most importantly, in patients with cirrhosis, it is used to screen for primary liver cancer (hepatoma / HCC), a complication that occurs in about 25 per cent of patients with cirrhosis resulting from hemochromatosis. Most patients should be enrolled in a program for hepatoma screening consisting of an alpha-fetoprotein (a blood test) and a radiological procedure, usually an ultrasound or triphasic CT scan, every six to twelve months.
Additionally, all patients should be screened for other causes of hepatitis, and those without protection should be vaccinated for hepatitis A and B.
TREATMENT
Aggressive De-Ironing
Treatment for hemochromatosis involves management of complications, screening for liver cancer, avoidance of supplemental iron and appropriate vaccinations for hepatitis A and B; however, an aggressive de-ironing protocol is most important. Excess iron is removed by a procedure known as phlebotomy, which is the drawing off of a unit of blood, using the same technique as a blood donation, but with a much higher frequency.
This treatment is effective because phlebotomies remove red blood cells that contain iron. Each unit of blood contains approximately 225 mg of iron in hemoglobin, the main component of red blood cells. In the process of making new red blood cells, a signal is sent for the stored iron in the tissues and organs to be pulled out and transported to the bone marrow where red blood cells are produced. This repeated procedure gradually depletes the stores of excess iron and eventually the iron levels fall back to normal.
In the initial phase of de-ironing, depending on the amount of stored iron, phlebotomies may need to occur once a week or even twice a week for one year. These phlebotomies can take place at a doctor’s office or a local hospital outpatient clinic.
Monitoring Progress
Some doctors use hemoglobin exclusively during this phase to monitor progress and establish frequency. It is checked at each treatment and de-ironing is deemed complete when the hemoglobin level falls to 10.5 – 11 g/dL and a mild anemia develops. Patients may become quite fatigued when they are finally iron deficient. In addition to monitoring hemoglobin levels, some doctors monitor ferritin levels periodically during this phase as well and may move to the maintenance phase of treatment when ferritin levels drop below 50 ng/ml.
During the maintenance phase of treatment, the goal is to keep transferrin saturation between 30-40% while maintaining a normal hemoglobin (normal hemoglobin range is 13-18 g/dL for men and 12-16 g/dL for women). It depends on the individual, but typically this could be achieved with one phlebotomy every 3-4 months. The treatment is ongoing for life.
Becoming a Regular Blood Donor
If a person with hemochromatosis is otherwise eligible, he / she can become a regular donor at Canadian Blood Services (CBS). Many healthy hemochromatosis patients find the CBS a much more comfortable environment for lifetime maintenance phlebotomy treatment; not only is it therapy, but also it provides much needed blood for other Canadians. Blood donations can be made every 56 days, provided the hemoglobin is normal and the patient is not on insulin.
Phlebotomies can be inconvenient, invasive, and painful for some, and it is a life-long commitment, but they work! Studies clearly show that both survival rates and quality of life are significantly improved with phlebotomy therapy, even for patients who have already sustained organ damage. For those diagnosed early, before clinical symptoms manifest, and before there is evidence of liver dysfunction or cirrhosis, longevity is statistically the same as for the average person without hemochromatosis, in the absence of other risk factors for liver disease, such as alcoholism or hepatitis.
Improvement Over Time
Depending on the timing of diagnosis and treatment, many of the disease symptoms will disappear after iron levels are back to normal. Fatigue and depression seem to improve. Some liver function can be improved, but not cirrhosis. As such, those patients require life-long screening for hepatomas. There is a mild improvement in diabetes and heart function. Improvement in the joint symptoms is variable but there seems to be no improvement in some of the hormonal complications, such as impotence. Even if there is no improvement, preventing progression of the disease process in damaged organs makes phlebotomy treatment worthwhile.
Diet
Despite that hemochromatosis is caused by inappropriate iron absorption from dietary iron and resulting iron overload, reducing dietary iron to a below-normal level does not significantly affect treatment of the disease. However, it is important to modify lifestyle and diet in order to not take in more-than-normal amounts of iron through the diet such as in certain vitamin pills or fortified foods.
See “Treatment of Iron Overload: A Hemochromatosis Primer” in the Fall 2005 issue of Iron Filings (PDF), the CHS newsletter, for more on lifestyle and diet issues.
Chelating Agents
For those patients who cannot tolerate phlebotomies, there are chelating agents that will also reduce body iron stores. However, toxicity is a concern, they are not as efficient, and they are inconvenient to administer because they must be injected subcutaneously over several hours. Because of all these factors, they are prescribed only as a last resort. Research with newer versions of chelators and other forms of oral drugs is ongoing. In the future, patients with hemochromatosis may have other options for the type of treatment that is best for them, but for now, phlebotomy is the gold standard.
Click here to learn more about hemochromatosis
Source: Canadian Hemochromatosis Society
