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Classic Hemochromatosis


Classic or Type 1 hemochromatosis Note that in scientific journals the type is identified with the Roman numeral. Type 1 (I) ,
Type I which is also called classic hemochromatosis, is the most common form of hemochromatosis. This type is caused by mutations (sometimes called variations) of HFE, a gene located on the short arm of chromosome number 6. There are more than 20 known mutations of HFE, but the ones most responsible for abnormal iron loading are C282Y and H63D. These two mutations along with one other S65C are the only mutations of HFE for which patients can be tested. Other mutations and other genes can only be determined in a research setting.
C282Y and H63D genetic mutations are common among Americans; more than 30% of the population has one or two copies of either the C282Y or H63D mutation.  When any two of these variations are inherited, the risk for iron overload disease and its consequences increases, but inheriting 2 copies of the C282Y mutation appears to present the greatest risk. Type I hemochromatosis is seen mostly in whites (Caucasians), although cases have been documented of black persons who are homozygous for C282Y (two copies of C282Y). In Type I HHC, iron overload builds slowly, usually taking 25-30 years before symptoms appear, but organ damage can be underway long before symptoms are present.  In clinical practice, iron overload is more often seen in males in their mid to late fifties. For this reason HHC has acquired the mistaken identity of an older male's disease. HHC can also present in females, especially those who no longer menstruate.  Iron loading from HHC can result in heart and liver disease, bone and joint disease, hormone imbalances, and can contribute to other diseases, particularly infections and cancers.

HFE, the gene for classic hemochromatosis, was discovered by a team of scientists in California 1996. Two major mutations of HFE attributable to iron loading are C282Y and H63D. Numerous prevalence studies support that the C282Y mutation of HFE is common among whites. In this population, one in 200-250 are homozygous (have two mutated copies). One in 50 are compound heterozygotes (have one C282Y mutation and one H63D mutation). One in 8-10 are simple heterozygotes or carriers of one C282Y mutation.  

Prior to the gene discovery patients with hemochromatosis had to undergo liver biopsy to confirm the diagnosis. With better evidence such as how serum ferritin levels correlate with organ disease along with the discovery of HFE, patients whose serum ferritin is less than 1,000ng/mL at the time of diagnosis can opt for genetic testing.  Of course the genetic test results provides no information about liver iron or body iron levels. Also as many as 15% of the people who have excessive levels of body iron do not have the typical genetic makeup for classic—type 1 hemochromatosis.

Genetic testing can be a very good tool for identifying family members of a person with genetic hemochromatosis. Early detection offers an excellent opportunity to seek early treatment and prevent disease.

Most At Risk for classic—Type 1 Hemochromatosis :
•    Scottish
•    Irish
•    British
•    Dutch
•    Scandinavian
•    German
•    French
•    Spanish (mainly northern regions)Italian (mainly northern regions)
•    Northern Western European descent
•    Northern Western European males
•    Females who no longer menstruate
•    Blood relatives of people diagnosed with Hemochromatosis

One’s family history of disease can offer clues that hemochromatosis may be present. A simple iron panel should be performed on anyone with a family history of any of the following:
•    a premature death by heart attack or liver cancer
•    diabetes mellitus
•    skin color changes—bronze colored skin (year-round tan without being in the sun)
•    osteoarthritis or complaint of pain the first two knuckles of the hands (iron fist)osteoporosis (especially joint replacement)
•    hypothyroidism
•    infertility
•    impotence or depression

Sufficient evidence warrants routine monitoring iron levels in heterozygotes (carriers), especially when there is a family history of disease.
According to Finnish studies, the mean age of death by heart attack for males with untreated hemochromatosis is 58. Females with hemochromatosis die at the same rate as men, but death may occur twenty years after menopause or cessation of menstrual cycle. For women, monthly blood loss due to period appears to serve as a preventive means of excess iron accumulation.
For this reason, men might realize the same benefit by donating blood. According to University of Kansas Medical Center cardiologist David Meyers, MD, Iron Disorders Institute Medical & Scientific Advisory Board member "males can reduce risk of heart attack by 50% with one blood donation a year."

Chronic fatigue and joint pain are among the first and most common symptoms reported by patients with hemochromatosis.
Later when iron overload is present, symptoms and signs can include:
•    Abdominal pain (upper right quadrant in the location of the liver)
•    Liver disease (cirrhosis, liver cancer)
•    Irregular heart rhythm
•    Heart failure
•    Diabetes mellitus
•    Osteoarthritis
•    Osteoporosis
•    Hypopituitarism
•    Hypothyroidism
•    Hypogonadism
•    Loss of period (premature stoppage of menstruation)
•    Loss of interest in sex
•    Depression
•    Impotence
•    Hair loss (other than “normal” male balding)
•    Skin color changes (bronze, ashen gray green, having a tan without being in the sun)
•    Skin surface changes: blisters
According to the Centers for Disease Control and Prevention (CDC), people with HHC are often misdiagnosed and on average see three doctors over almost 10 years before obtaining a successful diagnosis. This remains a critical health concern, because hemochromatosis is common and early detection with proper treatment can save lives and improve quality of life.


Hemochromatosis can be confirmed in several ways: blood chemistries, genetic testing, liver biopsy, or quantitative phlebotomy.
Blood chemistries (lab tests) that can detect excess levels of body iron include: serum ferritin, fasting serum iron and total iron binding capacity (TIBC). Serum iron divided by TIBC X 100% provides the transferrin-iron saturation percentage (TS%).  In classic HHC both TS% and serum ferritin are above normal. TS% values greater than 45% warn of potential iron overload and should be investigated. A test that is less commonly used, but is also helpful, is UIBC (unsaturated iron binding capacity).
If a person with hemochromatosis is diagnosed with serum ferritin less than 1,000ng/mL, the chances of finding undetected cirrhosis, the most common life-threatening disease caused by iron overload, are minimal, as low as 1%. If however serum ferritin is allowed to rise above 1,000ng/mL, the risk of cirrhosis or liver cancer increase 20-200 fold.
Ideally, and for the greatest testing accuracy, serum iron should be tested when fasting; patients should take nothing by mouth past midnight or prior to blood work and should avoid vitamin C supplements three days prior to tests and reduce consumption of Vitamin C rich juices during this same period. In general, the best time for blood work is in the morning. Hemoglobin or hematocrit are performed to assure levels are sufficient enough to perform blood removal with therapeutic phlebotomy (TP), which is the same as a blood donation except, a doctor’s order is required.

Genetic tests or DNA analysis or molecular analysis can confirm the presence of mutations C282Y, H63D or S65C. The genetic test does not provide any information about body iron levels but genetic testing can provide a diagnosis and expose a potential risk for symptoms and disease.
Genetic testing can be done by two methods: cheek brush or whole blood sample.
Cheek brush collection involves scraping cells from inside the mouth using a mascara-like wand with tiny bristles on the end or a cotton swab. Whole blood collection requires a needle to be inserted into the arm (same place where blood is removed during donation or phlebotomy) and a vial of blood removed. According to John Longshore, Ph D., Iron Disorders Institute Advisory Board member and expert in laboratory diagnostics, both methods are reliable. One should take care to protect the sample, which might include using an overnight mailing service, as extreme cold or heat may destroy tissue sample.
Genetic testing is available through most health care providers or a test kit can be ordered online. Before getting genetically tested it is important to be fully informed of the potential for employment or insurance discrimination, including the likelihood of policy denial or cancellation. Genetic testing, when used correctly, can be helpful and can help prevent unnecessary suffering or death. Parents who are planning a family to determine if they are carriers and have the potential to pass mutated copies of hemochromatosis genes to their children.

Recommended Reading, Forms and Educational materials:
•    Hemochromatosis Newbie’s Starter Kit
•    Personal Health Profile
•    Phlebotomy Described
•    Iron Content in Foods
•    Newsletter
•    Reading Room

Our Books

Guide To Hemochromatosis is a comprehensive look at the very common disorder, Hemochromatosis. As many as 4 Million Americans have Hemochromatosis and it is genetic. Purchase Guide To Hemochromatosis for you and for your family.
Hemochromatosis Cookbook contains a basic introduction, great for beginners and recipes, eating plan, checklists, forms and charts.