Hereditary hemochromatosis (HH), also termed “genetic hemochromatosis”, is a genetic autosomal recessive disorder which occurs as a result of genetic mutations of certain genes (HFE gene) involved in the metabolism of iron, resulting in increased intestinal iron absorption. Common initial symptoms comprise abdominal pain, paleness, lethargy, and weight loss. The start of symptoms is between 30 to 50 years in males and afterward menopause in females. If left untreated, hemochromatosis could cause serious disease and early death. The keystone of screening is the level of serum transferrin saturation as well as the serum ferritin level. Definition, risk factors, pathophysiology, clinical features, investigations and treatment of hemochromatosis will be discussed in this article.
Hereditary Hemochromatosis

Image: “Grade 3 hepatocyte iron accumulation with an acinar distribution pattern consistent with homozygous genetic hemochromatosis.” by Joseph Mathew, May Y Leong, Nick Morley and Alastair D Burt. License: CC BY 2.0


Hereditary hemochromatosis (HH) is an inherited disorder caused by unusually high absorption of iron by the colonic tract, resulting in extreme storage of iron, mainly in the liver, skin, pancreas, heart, joints, in addition to testes.

The additional iron provides the skin a bronze color, in addition to harms the liver, beginning liver damaging (fibrosis) or else cirrhosis, typically after age 40. Diabetes similarly occurs because of harm to the pancreas. Congestive heart failure & arrhythmias, arthritis and hypogonadism also may occur.

Risk Factors

Populations affected by hereditary hemochromatosis

Haemochromatosis is one of the most common congenital (genetic) sicknesses in the United States. Almost 1 million persons in the United States have the pair of hemochromatosis genetic factor. Haemochromatosis is greatest communal in Caucasians of north European ancestry. It is rare in African Americans and more communal in men than in females.

Older persons are more probable to improve the illness than younger persons. Actually, signs and symptoms do not typically appear in men till ages 40 to 60. In females, signs and indications do not typically appear until afterward the age of 50 (after menopause). Young kids infrequently develop hemochromatosis.

Main risk factors of hereditary hemochromatosis

  1. Having a pair of irregular HFE genetic factor (one from each parental) is the main risk factor for haemochromatosis. Though, numerous people with two copies of the irregular gene do not grow signs or else symptoms of the disease.
  2. Alcoholism is a risk factor for haemochromatosis.
  3. A family past of certain illnesses also designates an advanced risk for haemochromatosis. Several of these illnesses are heart attack, diabetes, arthritis, liver disease, and erectile dysfunction.


There are two kinds of hemochromatosis:

Primary hemochromatosis

It is a genetic complaint passed down over families and happens at birth. Persons with this state absorb too much iron throughout their peptic tract. Iron shapes up in the body, particularly the liver. The Patient is more probable to get this sickness if somebody else in his family has or else had the condition.

Secondary (acquired) hemochromatosis

It occurs as a result of other blood-related complaints (such as thalassemia or certain anemias) or else many blood transfusions. Occasionally it occurs in persons with long-term alcoholism in addition to other health conditions. 


Genetic study of hemochromatosis has controlled to the discovery of a quantity of genes whose mutations disturb iron homeostasis in addition to lead to iron overload. In a mainstream of patients (> 85 %) with hemochromatosis, mutations in the iron-controlling gene HFE are the reason. Iron, while present in extra, is an inducer of oxidative stress and suppresses mitochondrial purpose. Patients with hemochromatosis demonstrate evidence of colonic irritation. Additional, certain studies have revealed increased jeopardy for colon cancer-related with genetic alterations recognized to cause hemochromatosis.

Normally, the entire body iron content is around 2.5 g in women as well as 3.5 g in men. Because symptoms might be delayed until iron buildup is extreme (eg, > 10 to 20 g), hemochromatosis might not be familiar until late in life, even however it is inherited irregularity. In women, clinical appearances are uncommon before menopause since iron loss because of menses (and occasionally pregnancy and childbirth) inclines to offset iron buildup.

The apparatus for iron overload in together HFE as well as non-HFE hemochromatosis is augmented iron immersion from the GI tract, prominent to chronic statement of iron in the muscles. Hepcidin, a liver-derived peptide, is the serious control device for iron absorption. Hepcidin is usually up-regulated while iron stores are raised and, over its inhibitory effect on ferroportin (which participates in iron absorption), it stops extreme iron absorption in addition to storage in usual people. Hemochromatosis types 1 over 4 share the similar pathogenic basis (eg, lack of hepcidin synthesis or else activity), as well as key clinical features.

Generally, tissue wound appears to outcome from sensitive free hydroxyl radicals producedwhile iron deposition in matters catalyzes their creation. Other devices might affect specific organs (eg, skin hyperpigmentation) could result from augmented melanin in addition to iron accumulation.

Clinical Features

heterozygous genetic Hemochromatosis

Image: “Perl’s Prussian Blue stain for iron shows a typical pattern of iron accumulation seen in heterozygous genetic Hemochromatosis” by Mathew, J et al.. License: CC BY 3.0

The accumulated iron is retained mainly in the parenchymal cells, then lately in the reticuloendothelial cells. Hemochromatosis could affect numerous parts of the body causing numerous signs and symptoms, which might be similar to other diseases. The clinical manifestations of hereditary hemochromatosis include:

  • Liver function abnormalities
  • Lethargy and weakness
  • Skin hyperpigmentation
  • Diabetes mellitus
  • Arthralgia
  • Impotence in males
  • Electrocardiographic abnormalities

Signs and symptoms of hemochromatosis typically don’t happen until middle age. Women are more probable to have over-all symptoms first, for example, fatigue (tiredness). In men, problems such as diabetes or else cirrhosis (damaging of the liver) often are the first symptoms of the disease.

Signs and symptoms furthermore differ based on the strictness of the disease. Common signs as well as indicators of hemochromatosis comprise joint pain, fatigue, general faintness, weight loss, in addition to stomach pain.

Not everybody who has hemochromatosis has signs of the disease. Estimations of how numerous persons develop signs plus symptoms vary significantly. Several estimates propose that as numerous as half of all persons who have the sickness do not have signs or symptoms.

Liver disease

Deposition of excessive iron in the liver may result in hepatomegaly with increased liver enzymes, and progressive fibrosis which eventually ends up with cirrhosis. Excessive iron deposition in the liver may result in hepatocellular carcinoma, a serious fatal complication of hemochromatosis.

Diabetes mellitus

Diabetes mellitus occurs in about 50 % of cases with hereditary hemochromatosis due to excessive deposition of iron in the pancreases. The triad of diabetes mellitus, liver cirrhosis, and skin pigmentation is termed “bronze diabetes” which occurs in the advanced disease when the total iron content increases 5 times its normal level.


Hereditary hemochromatosis can be associated pseudogout, chondrocalcinosis, and chronic arthropathy.

Heart disease

Excessive deposition of iron in the myocardium can lead to dilated cardiomyopathy with subsequent heart failure, conduction disturbances, and sick sinus syndrome.


Excessive deposition of iron in the pituitary cells may reduce the trophic hormones levels causing decreased libido & impotence in men. Amenorrhea may also occur in women.

Excessive skin pigmentation

The characteristic metallic “bronzing” color of the skin occurs in the advanced disease due to increased iron and melanin in the skin.

Investigations and Diagnosis

Haemochromatosis could be difficult to diagnose as numerous of the distinctive symptoms can furthermore result from other circumstances, or excessive iron overload may present without early symptoms. It is vital to diagnose hemochromatosis before hepatic cirrhosis occurs since phlebotomy therapy can prevent severe chronic disease and could even lead to normal life expectation. The degree of excess of iron in the body can be assessed by:

Blood tests

Haemochromatosis is typically identified using blood tests, which might include:

Transferrin saturation

It’s a blood test that designates how much iron is willingly accessible for use in the body. It’s elevated early in the course of the disease but has significant false positive and negative rates.

Serum ferritin concentration

It’s a blood test that designates the quantity of iron stored in the body. Although serum ferritin level >1000 mg/L is a strong indicator of hemochromatosis, it still can be elevated in patients with hepatocellular necrosis. Therefore, repeating the ferritin level is mandatory after resolving of any acute hepatic damage (e.g. alcoholic liver disease).

Genetic testing

If tests notice high levels of iron in your body you would be referred for a more thorough blood test, wherever a sample of your DNA is checked for the HFE change. This genetic test would usually confirm or else rule out the diagnosis to also control whether a person is a carrier of the HFE alteration.

Liver biopsy

A liver biopsy might be suggested if tests disclose high stages of iron or else there are enzymes present that designate liver damage (liver fibrosis). After the availability of genetic testing for the C282Y mutation which is usually done if the two blood tests are abnormal, the role of liver biopsy has declined significantly.

MRI of the liver

Excessive iron deposition in the liver can be revealed as increased density of the liver by the MRI. MRI becomes very accurate in determining the concentration of the iron in the liver.


If a diagnosis of hemochromatosis was established in a patient, it’s very important to screen for other family members. Both symptomatic and asymptomatic patients with hemochromatosis have:

  • High transferring saturation
  • High serum-ferritin concentration

Patient’s first-degree relatives should be tested for C282Y and H63D mutations.


Treatments for hemochromatosis comprise iron chelation therapy, therapeutic phlebotomy, in addition to treatment for complications. Persons with hemochromatosis do not requisite to follow a distinct diet. Iron supplements in addition to vitamin C supplements must be avoided. Drinking alcohol infrequently (one or else two drinks per week) is perhaps safe unless the individual has liver disease (cirrhosis or else hepatitis).

Therapeutic phlebotomy

Therapeutic phlebotomy is a process that eliminates excess iron from the body. A needle is introduced into a vein, in addition to patient’s blood flows over an airtight tube into a sterile container or else bag. Removal of the iron from the body is best done by removal of 500 mL of blood once or else twice a week. Thereafter, phlebotomy might be needed less frequently —usually every 2–4 months, to maintain serum ferritin levels around 50 and 100 mg/L.

During therapy, the transferrin saturation keeps in high levels till the whole available iron stores are depleted, in contrast to the plasma ferritin concentration which decreases gradually over time indicating the gradual decrease of the body iron stores.

Iron chelation therapy

This therapy uses certain drugs to eliminate additional iron from your body. Chelating agents such as deferoxamine is given parenterally and can remove 10–20 mg iron per day. This amount is less than what can be removed by phlebotomy. Although phlebotomy is less expensive and safer for most patients with hemochromatosis, iron chelating therapy is indicated:

  1. When there is severe anemia or hypoproteinemia.    
  2. In persons who cannot have routine blood elimination.

Treatment for complications

People with hemochromatosis are more probable to have heart diseases, type 2 diabetes, and hepatic failure. Without treatment, the iron overload may lead to damage of these organs and death. The management of these diseased organs is similar to their conventional therapy.

Hemochromatosis also may result in hormonal disturbances due to hemochromatosis-induced hypogonadism, which should be managed with testosterone replacement or gonadotropin therapyEnd-stage liver disease should be treated with liver transplantation. Evidence has shown that the main metabolic abnormality in HH can be corrected and reversed with transplantation of the liver.

Popular Exam Questions

The correct answers can be found below the references.

1. What is the type of genetic inheritance of hereditary hemochromatosis?

  1. Autosomal recessive
  2. Autosomal dominant
  3. X-linked
  4. Non-inheritance disease

2. Iron-chelating therapy is used in treatment of hereditary hemochromatosis if there is…

  1. …severe anemia.
  2. …hypoproteinemia.
  3. …heart failure.
  4. A & B.                     

3. The characteristic blood tests abnormality in hereditary hemochromatosis are what?

  1. High transferring saturation and low ferritin level
  2. High transferring saturation and high ferritin level
  3. Low transferring saturation and high ferritin level
  4. Low transferring saturation and low ferritin level
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