(Iron overload)

Hemochromatosis (Iron overload): Overview

Hereditary Hemochromatosis (HHC) is characterized by increased iron absorption in the gastrointestinal tract that may cause lifelong excessive iron absorption and accumulation and serious health effects including arthritis, cirrhosis, diabetes, impotence, myocardial infarction, and death.

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Incidence; Causes and Development

HHC is one of the most common genetic disorders in the United States, affecting approximately 1.5 million persons.

HHC is commonly underdiagnosed in white patients.  In other ethnic groups, such as African Americans and Hispanics, it may not even be considered despite the presentation of signs and symptoms strongly suggestive of iron overload.  The prevalence of iron overload among Hispanic persons is estimated to be as high as 5 in 1,000 persons.

HHC, an autosomal recessive disorder previously considered to be rare, is now known to be the most prevalent genetic disease in individuals of northern European descent.  The hemochromatosis gene is responsible for most cases of HHC.  The prevalence of the homozygous genotype is estimated to be 1 in 250 persons; the prevalence of the heterozygous genotype is approximately 1 in 8 persons.

Evidence suggests that primary iron overload may be common in African Americans.  Hepatic iron excess was observed in 1.5% of African Americans during a recent autopsy series and in 10.4% of African Americans who underwent liver biopsy during medical care delivery.  In a large nutrition survey among the general African American population aged 3 to 45 years, hyperferritinemia consistent with iron overload was more common among African Americans than whites.

HHC was first recognized more than a century ago as an iron overload condition presenting as a clinical triad – type 2 diabetes mellitus, skin bronzing, and cirrhosis of the liver.  Several causes for iron overload exist, the primary ones being genetically based.  Secondary iron overload may be the result of excessive transfusion therapy, poorly responding anemia being treated with iron supplementation, or chronic liver disease due to alcohol abuse.

Persons with normal hemoglobin levels and iron stores absorb just enough iron to meet their daily needs and balance losses (1mg per day).  No internal mechanism exists for excreting excess iron absorbed from the diet.  The amount of iron absorbed is influenced by the amount of iron stored in the body, the rate and effectiveness of red blood cell creation, the amount and form of iron in the diet, and the presence of iron absorption enhancers and inhibitors in the diet.  However, patients with HHC continue to absorb high amounts of dietary iron even when their bodies have enough or too much iron.

HHC patients can chronically absorb a small excess of iron each day, resulting in iron stores 10 times the normal amount by the time they are middle-aged.  The body is unable to adequately chelate and store this amount of iron.  Therefore, unbound iron accumulates and generates free radicals, leading to cellular injury of the liver and other organs.

Signs and Symptoms

The first symptoms associated with iron overload are often nonspecific and the disorder may not be considered in the differential diagnosis.  Consequently, the underlying cause may not be recognized and treated and organ damage may continue.  At least 50% of men and 25% of women with both genes for HHC are likely to develop potentially life-threatening disease complications, especially in countries where there is high dietary intake of iron.

The clinical manifestations of HHC usually do not appear until a person is aged 40 to 60 years, when sufficient iron has accumulated to cause organ damage.  Some persons have clinical manifestations by 20 years of age, but others with both genes for the disease may never have clinical signs.  Depending on which study one reads, an estimated 67% to 94% of men and 41% of women with HHC show signs and symptoms of the disease after 40 years of age.

Diagnosis and Tests

The use of supplementary iron and vitamin C (which increases iron absorption) may lead to earlier laboratory abnormalities and iron deposition.  Conversely, blood donation, physiologic blood loss (through menstruation and pregnancy), and pathologic blood loss (for example, through peptic ulceration or inflammatory bowel disease) may decrease the amount of iron stored in the liver.  However, the belief that premenopausal women cannot develop symptomatic or even life-threatening HHC is a misconception.

Liver biopsy continues to be the gold standard for diagnosis and staging of HHC because it can detect the level of iron overload and identify hepatic fibrosis and cirrhosis.  Many specialists prefer liver biopsy to quantitative phlebotomy, particularly when clinical or laboratory evidence of hepatic involvement is present.  In patients younger than 40 years who have an serum ferritin concentration of less than 750 ng/mL and normal liver enzyme levels, phlebotomy therapy can be started without a liver biopsy.  In all other cases, biopsy remains essential for diagnosis and optimal management.

Once a diagnosis of HHC is confirmed, the patient should have the excess iron removed and family members should be screened for the disorder.  Iron overload is treated with successive phlebotomies in patients with or without clinical manifestations.  The total amount of blood that must be removed to produce iron deficiency provides an estimate of total body iron load.

Diagnosis of HHC is commonly delayed until clinical manifestations have appeared and irreparable organ damage has occurred.  Therefore, basic and continuing medical education about the disease is urgently needed.  Simple screening tests, such as serum transferrin saturation and ferritin concentrations, can be helpful in discovering asymptomatic patients with iron overload.

Performing iron studies on routine screening chemistry panels has become more commonplace as demonstrated by a study of 40 patients with newly diagnosed HHC prospectively referred to a tertiary university-based hepatology clinic.  Clinical information, serum and liver iron studies, liver histology, and phlebotomy requirements were evaluated to see what features were most helpful in making the diagnosis.

The study documented that 83% of patients came to the attention of the medical staff as a result of routine blood screening.  Of these patients, 73% were asymptomatic and 78% had normal physical examinations.  Only 3 patients had cirrhosis from HHC alone, 2 patients were diabetic, and 2 patients had increased skin pigmentation.  With the use of iron screening studies on routine serum chemistry panels, patients with HHC can be identified and subsequently treated before symptoms or organ damage occurs.

Prognosis; Complications

The causes of death in untreated patients include cardiac failure (30%), liver failure or portal hypertension (25%), and hepatocellular carcinoma (30%).  The degree of iron overload at the time of diagnosis, as well as organ dysfunction, have prognostic implications.  The 5-year survival rate increases with treatment from 33% to 89%.  However, discovering HHC prior to the onset of tissue or organ damage is very important.  When HHC is found early and properly managed, long-term prognosis, including life expectancy, should not differ from that of persons without the disorder.

Deposition of iron within tissues causes inflammation and subsequent fibrosis and destruction of major organs leading to organ failure and chronic disease.  HHC often goes undetected and untreated until symptoms of permanent organ damage become apparent.

Type 2 diabetes mellitus develops in about 65% of patients and is more commonly a complication in patients with a positive family history for diabetes.  Hypogonadism is common in both sexes and can lead to loss of libido, impotence, amenorrhea, testicular atrophy, and loss of body hair.

Arthropathy is present in up to 50% of symptomatic patients.  Occasionally, acute episodes of an inflammatory arthritis occur; some of these episodes are caused by deposits of calcium.

Signs, symptoms & indicators of Hemochromatosis (Iron overload):

Lab Values - Cells

Lab Values - Chemistries

(Very) low TIBC

While low TIBC is commonly explained by the presence of hemochromatosis, it can also be caused by hypoproteinemia from malnutrition, anemia with infection and chronic disease, and nephrosis.

Elevated liver enzymes

A common early sign of progressive iron overload is symptom-free elevation of liver enzymes, which can be accompanied by recurrent right-sided abdominal pain and liver enlargement.  Liver disease, which is present in as many as 95% of patients with iron overload, is the most common complication.

Elevated/normal TIBC

While low TIBC is commonly explained by the presence of hemochromatosis, it can also be caused by hypoproteinemia from malnutrition, anemia with infection and chronic disease, and nephrosis.

Symptoms - Abdomen

Symptoms - General

Symptoms - Hair

Symptoms - Mind - Emotional

Symptoms - Skeletal

Symptoms - Skin - General

Darker/redder skin color

Excessive skin pigmentation (bronzing) is present in more than 90% of symptomatic patients at the time of diagnosis.  Deposition of iron within the skin causes inflammation and enhances melanin production by melanocytes.  Patients usually notice a generalized increased pigmentation and occasionally notice that they tan very easily.  This is due to ultraviolet light exposure and iron acting synergistically to induce skin pigmentation.  Fair-skinned persons, who usually tan poorly, may never develop hyperpigmentation despite large iron burdens.  Ethnically dark-complexioned patients (for example, people of Mediterranean descent) can develop a striking almond-colored hue.  With particularly heavy iron overload, visible iron deposits sometimes appear in the skin as a grayish discoloration.

Conditions that suggest Hemochromatosis (Iron overload):


Congestive Heart Failure

Congestive heart failure occurs in about 7% of symptomatic patients with hemochromatosis.  If untreated, patients may develop an acute onset of severe congestive heart failure with rapid progression to death.


Cardiac arrhythmia occurs in about 7% of symptomatic hemochromatosis patients.


Yeast / Candida Infection

Genetic disorders such as celiac disease or hemochromatosis can cause Candida overgrowth.


Organ Health

Cirrhosis of the Liver

Cirrhosis is the most common severe consequence of hemochromatosis.

Diabetes Type II

Iron deposits in the pancreas decrease insulin production which can lead to insulin dependent diabetes mellitusHemochromatosis is also called bronze diabetes because those sufferers with diabetes can express a bronze-colored tint to their skin.

Patients with hemochromatosis can also be diagnosed with liver disease, diabetes, heart disease and arthritis without the physician realizing that these diseases are the result of iron-overload.  Thus, the hemochromatosis might itself go undiagnosed and untreated.

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Risk factors for Hemochromatosis (Iron overload):


Alcohol-related Problems

Use of alcohol and other hepatotoxic drugs lowers the ability of the liver to safely store iron and may accelerate the development of the liver changes seen with hemochromatosis.

Symptoms - Skeletal

Hemochromatosis (Iron overload) can lead to:



According to a study published in Neurology, high iron levels in stroke patients may prompt more severe neurological symptoms and possibly increase brain damage.  Elevations of iron may intensify post-stroke neurological problems such as increased weakness, speech and orientation difficulties, and decreased levels of consciousness.  Stroke patients with high ferritin concentrations may also have larger areas of the brain damaged due to stroke.  High body iron stores may increase free radical production in brain cells, thus prompting stroke progression.

Coronary Disease / Heart Attack

Male carriers of the common hemochromatosis gene mutation are at 2-fold risk of a first heart attack compared with noncarriers.  Some 10% to 20% of the population carry at least one gene for hemochromatosis.  Full-blown hemochromatosis affects about 0.5% and gene carriers usually do not know that they are at increased risk.  They have almost no increase in iron stores over those without the mutation [Circulation: Journal of the American Heart Association September 21, 1999;100].

Giving blood is the best way to lower iron stores, but a more recent study found no protective effect against heart attack among men who donated blood regularly. [Circulation January 2, 2001]


Lab Values



Tumors, Malignant

Liver Cancer

Once a person's liver iron concentration reaches 400 mmol/gm (dry weight), cirrhosis is common and the risk of liver cancer and death is increased.

Recommendations for Hemochromatosis (Iron overload):

Laboratory Testing

Transferrin Saturation Test

The first step in working up a patient with suspected iron overload is the transferrin saturation measurement in a fasting blood draw.  Pathologic blood loss or a history of frequent blood donations should be considered reasons for normal iron status in patients who nevertheless have symptoms consistent with hemochromatosis.

Test Iron Stores (Ferritin)

Patients with elevated transferrin saturation test values should proceed with serum ferritin testing and additional workup as warranted.



Manganese can protect against the free radical damage from excess iron. [Free Radical Biology and Medicine, 1992; 13: pp.115-20]

Not recommended


Not recommended
Vitamin C (Ascorbic Acid)

One study has indicated that excessive vitamin C intake may be a contributing factor in hemochromatosis.  Vitamin C increases intestinal iron absorption while at the same time it seems to have an effect in decreasing copper.  This copper decreasing effect could be the direct result of increasing iron absorption or it could be an independent effect. [Int J Vitam Nutr Res 1999 Mar; 69(2): pp.67-82]

As a result, some suggest that one doesn't take vitamin C supplements at all, while others recommend limiting vitamin C supplementation to 500mg per day.  Eating natural (unfortified and unprocessed) foods which contain vitamin C is fine.

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