Hereditary Hemochromatosis: What Is It?

Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders, cardiomyopathy, diabetes, erectile dysfunction, and arthropathy.

Diagnosis is by elevated serum ferritin, iron, and transferrin saturation levels and confirmed by a gene assay. Treatment is usually with serial phlebotomies. If it’s not treated, hemochromatosis can make your organs stop working.

Hereditary Hemochromatosis
Hereditary Hemochromatosis – Hematology and Oncology – (Merck Manuals)

What is Hemochromatosis?

Hemochromatosis is a disorder where too much iron builds up in your body. Sometimes it’s called “iron overload.” Normally, your intestines absorb just the right amount of iron from the foods you eat.

But in hemochromatosis, your body absorbs too much, and it has no way to get rid of it. So, your body stores the excess iron in your joints and in organs like your liverheart, and pancreas. This damages them. As can be seen, from the examples below, there are two types of hemochromatosis conditions.

Primary and Secondary Hemochromatosis

Whereby, Primary Hemochromatosis is hereditary, meaning it runs in families.

If you get two of the genes that cause it, one from your mother and one from your father, you’ll have a higher risk of getting the disorder.

And by the same fashion, Secondary Hemochromatosis happens because of other conditions you have. These include:

Having said that, there are 4 types of hereditary hemochromatosis, types 1 through 4.

Types of Hereditary Hemochromatosis

For example, anemia in hypotransferrinemia or atransferrinemia, or neurologic defects in aceruloplasminemia. Although these types vary markedly in the age of onset, clinical consequences of iron overload are the same in all.

The general types of Hereditary Hemochromatosis include;

  1. Mutations of the HFE gene (Type 1)
  2. Juvenile hemochromatosis (Type 2): Mutations in the HJV and HAMP genes
  3. Mutations in the TFR2 gene (Type 3)
  4. Ferroportin disease (Type 4): Mutations in the SLC40A1 gene

Important to realize, other much rarer genetic disorders can cause hepatic iron overload. But, the clinical picture is usually dominated by symptoms and signs due to the failure of other organs.

Hereditary Hemochromatosis
Did you know DNA changes cause Hemochromatosis? – (didyouknowdna)

How does Hereditary Hemochromatosis occur?

Normal total body iron content is about 2.5 g in women and 3.5 g in men. Because symptoms may be delayed until iron accumulation is excessive (eg, > 10 to 20 g), hemochromatosis may not be recognized until later in life. And, even though it is an inherited abnormality.

In women, clinical manifestations are uncommon before menopause because iron loss due to menses (and sometimes pregnancy and childbirth) tends to offset iron accumulation.

The general Iron intake in the Body

The mechanism for iron overload in both HFE and non-HFE hemochromatosis is increased iron absorption from the GI tract. Generally, leading to chronic deposition of iron in the tissues. Hepcidin, a liver-derived peptide, is the critical control mechanism for iron absorption.

Equally, Hepcidin is normally up-regulated when iron stores are elevated and, through its inhibitory effect on ferroportin (which participates in iron absorption). Not forgetting, it prevents excessive iron absorption and storage in normal people.

Feature-based Hereditary Hemochromatosis 

Hemochromatosis types 1 through 4 share the same pathogenic basis (eg, lack of hepcidin synthesis or activity) and key clinical features. In general, tissue injury appears to result from reactive free hydroxyl radicals. Generated when iron deposition in tissues catalyzes their formation.

Other mechanisms may affect particular organs (eg, skin hyperpigmentation can result from increased melanin as well as iron accumulation). In the liver, iron-associated lipid peroxidation induces hepatocyte apoptosis. Again, which stimulates Kupffer cell activation and the release of pro-inflammatory cytokines.

These cytokines activate hepatic stellate cells to produce collagen, resulting in pathologic accumulation of liver fibrosis.

Symptoms and Signs 

The clinical consequences of iron overload are the same regardless of the etiology and pathophysiology of the overload. Historically, experts believed that symptoms did not develop until significant organ damage had occurred.

However, organ damage is slow and subtle, and fatigue and nonspecific systemic symptoms and signs often occur early. For example, liver dysfunction can manifest insidiously with fatigue, right upper quadrant abdominal pain, and hepatomegaly.

General Symptoms and Signs include;

Important to realize, laboratory abnormalities of iron overload and hepatitis usually precede symptoms. For instance, in type 1 hereditary (HFE) hemochromatosis, symptoms relate to the organs with the largest iron deposits (see table Common Manifestations of Hereditary Hemochromatosis).

In men, the initial symptoms may be hypogonadism and erectile dysfunction caused by gonadal iron deposition. Glucose intolerance or diabetes mellitus is another common initial presentation. Some patients present with hypothyroidism.

Symptoms associated with Liver

Liver disease is the most common complication and may progress to cirrhosis; 20 to 30% of patients with cirrhosis develop hepatocellular carcinoma. Liver disease is the most common cause of death.

Cardiomyopathy with heart failure is the 2nd most common fatal complication. Hyperpigmentation (bronze diabetes) and porphyria cutanea tarda are common, as is symptomatic arthropathy in the hands.

In type 2 disease, symptoms and signs include progressive hepatomegaly and hypogonadotropic hypogonadism.

In type 3 disease, symptoms and signs are similar to type 1 hereditary (HFE) hemochromatosis.

Type 4 disease manifests in the first decade of life as increased serum ferritin levels with low or normal transferrin saturation; progressive saturation of transferrin occurs when patients are in their 20s and 30s.

Clinical manifestations are milder than in type 1 disease, with modest liver disease and mild anemia.

Hemochromatosis or Iron Overload
Hemochromatosis or Iron Overload? – (epainassist)

Hereditary Hemochromatosis Diagnosis

Symptoms and signs may be nonspecific, subtle, and of gradual onset so that the index of suspicion should be high.

Primary hemochromatosis should be suspected when typical manifestations, particularly combinations of such manifestations, remain unexplained after routine evaluation.

A family history of hemochromatosis, cirrhosis, or hepatocellular carcinoma is a more specific clue. All patients with chronic liver disease should be evaluated for iron overload.

Methods of Hereditary Hemochromatosis diagnosis;

  • Sometimes liver biopsy
  • Genetic testing
  • Serum ferritin,
  • Fasting serum iron, and
  • Transferrin saturation

Serum Ferritin

Serum ferritin measurement is the simplest and most direct initial test. Elevated levels (> 200 ng/mL [> 200 mcg/L] in women or >250 ng/mL [> 250 mcg/L] in men) are usually present in hereditary hemochromatosis.

But, it can result from other abnormalities, such as inflammatory liver disorders (eg, chronic viral hepatitis, nonalcoholic steatohepatitisalcoholic liver disease), cancer, certain systemic inflammatory disorders (eg, rheumatoid arthritishemophagocytic lymphohistiocytosis), or obesity.

Further tests are done when ferritin level is abnormal; testing includes fasting serum iron (usually > 300 mg/dL [> 53.7 mcmol/L]) and iron-binding capacity (transferrin saturation; levels usually > 50%).

A transferrin saturation of < 45% has a negative predictive value of 97% for iron overload. In type 2 disease, ferritin levels are >1000 ng/mL (> 1000 mcg/L), and transferrin saturation is >90%.

In transferrin or ceruloplasmin deficiency, serum transferrin (ie, iron-binding capacity) and ceruloplasmin levels are profoundly low or undetectable.

Genetic Testing

Gene assay is a diagnostic of hereditary hemochromatosis caused by HFE gene mutations. About 70% of patients with C282Y homozygous mutations of the HFE gene have an elevated ferritin level. But, only about 10% of these patients have evidence of organ dysfunction.

Clinically, significant iron overload is even less common in patients with heterozygous mutations of the HFE gene (ie, C282Y/H63D).

In which ferritin and iron blood tests indicate iron overload and genetic testing is negative for the HFE gene mutation. Particularly, in younger patients. Confirmation of these diagnoses is evolving.

Liver Biopsy

Up to 80% of patients with cirrhosis and a homozygous C282Y mutation will have a ferritin of > 1000 ng/mL, elevated AST and ALT, and platelet count < 200 x 103 /mcL (< 200 × 109/L).

Because the presence of cirrhosis affects prognosis, when the ferritin is > 1000 ng/mL, liver biopsy is commonly done and tissue iron content is measured (when available).

Iron Screening

But, a negative genetic evaluation. MRI with non-contrast MR elastography (MRE), a noninvasive alternative for estimating hepatic iron content and hepatic fibrosis, is becoming increasingly accurate.

Screening is required for first-degree relatives of people with hereditary hemochromatosis by measuring serum ferritin levels and testing for the C282Y and H63D mutations in the HFE gene.

Hereditary Hemochromatosis Treatment

Treatment is indicated for patients with clinical manifestations, elevated serum ferritin levels (particularly levels > 1000 ng/mL), or elevated transferrin saturation.

Asymptomatic patients need only periodic (eg, yearly) clinical evaluation and measurement of serum iron, ferritin, transferrin saturation, and liver enzymes.


Phlebotomy is the simplest and most effective method to remove excess iron. It delays the progression of fibrosis to cirrhosis, sometimes even reversing cirrhotic changes, and prolongs survival. But, it does not prevent hepatocellular carcinoma.

When iron levels are normal, phlebotomies can be intermittent to maintain ferritin between 50 and 100 ng/mL.

Screening & Ultrasound

Diabetes mellituscardiomyopathyerectile dysfunction, and other secondary manifestations are treated as indicated. Patients with advanced fibrosis or cirrhosis due to iron overload should be screened for hepatocellular carcinoma every 6 months with a liver ultrasound.

Patients should follow a balanced diet; it is not necessary to restrict the consumption of iron-containing foods (eg, red meat, liver). Alcohol should be taken moderately. Because it can increase iron absorption and, in high amounts, increases the risk of cirrhosis.

In patients with type 4 disease, tolerance to vigorous phlebotomy is poor. Not to mention, treatment of transferrin deficiency and ceruloplasmin deficiency is experimental.

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