History

Hemochromatosis is a disorder in which excess iron accumulates in the body, potentially leading to multiple organ dysfunction.1 Parts of the body that may be affected by hemochromatosis include the liver, thyroid, heart, pancreas, skin, joints, pituitary gland, and gonads.1

Hemochromatosis was first described in medical literature in 1865 by Armand Trousseau within French pathology literature but was not given its name until many years later. In 1889, German pathologist Friedrich Daniel Von Recklinghausen also observed this disease and concluded that pigmentation in the liver was caused by iron.

This led to the disease’s official name as the Latin roots of the word are linked to the English words “blood” and “color.” It was Von Recklinghausen who posited that internal bleeding was the source of this liver coloration.2 While hemochromatosis can cause serious health problems and death, it is a common disease that is highly treatable, especially when diagnosed early.3

Epidemiology

There are two main types of hemochromatosis — primary (also known as hereditary or classical hemochromatosis) and secondary.3

  • The most common type is primary, which is an inherited variation of the disease. The hereditary hemochromatosis carrier is a mutation in the HFE gene, known to some as the hemochromatosis gene, that is typically passed down in an autosomal recessive fashion.1
  • Secondary hemochromatosis refers to any other condition that could lead to an iron overload, such as anemia, blood transfusions, iron supplementation, long-term kidney dialysis, or liver disease.3

Within hereditary hemochromatosis, there are four distinct types. 

Type 1. Affects about 1 million Americans and is one of the most common genetic disorders in the United States.4 It mostly affects people with a lineage from northern Europe, and White populations have a six times greater risk of developing the disease than Black populations.1 

The other 3 types are based on mutations:

Type 2. An autosomal recessive disorder, which is divided into 2 parts, with 2a caused by mutations of hemojuvelin gene and 2b is caused by mutations of the hepcidin gene.

Type 3. Autosomal recessive, caused by mutations of transferrin receptor-2 gene

Type 4. Autosomal dominant, caused by mutations of the ferroportin gene

Types 2 to 4 are considered rare.4 Men are also two to three times more likely to be affected by hemochromatosis than women.1

Hemochromatosis Diagnosis & Presentation

Symptoms of hemochromatosis present in a wide variety of ways and to varying degrees. Some people will not develop symptoms at all, while others may experience very serious symptoms and complications from the disease.3 As hemochromatosis can lead to organ dysfunction in multiple organs, clinical signs of the condition depend on the organ system(s) that is most affected.

Patients are typically asymptomatic until middle age, and the diagnosis often comes only after multiple systems are affected. Women with hemochromatosis usually present later in life due to the blood loss and iron excretion associated with menstruation.1 One symptom that almost all patients complain of is severe fatigue.1 Other symptoms may include:3

  • General weakness
  • Lethargy
  • Joint pain
  • Abdominal pain
  • Heart flutters or irregular heartbeat
  • Pain in the knuckles of the pointer and middle fingers, sometimes known as “iron fist”
  • Bronze or gray skin color5
  • Unexplained weight loss

Hemochromatosis can be difficult to diagnose, with most patients presenting with symptoms for 10 years before diagnosis.1 When hemochromatosis is suspected based on symptoms and family history, there are many tests that can be utilized to confirm the diagnosis.

Diagnostic Workup

There is no single hemochromatosis test.

  • Serum ferritin concentration6 and serum transferrin saturation. These are the two key tests to begin diagnosis. In hemochromatosis, ferritin levels are often above 200 mcg/L in women or 300 mcg/L in men, while transferrin saturation is typically higher than 40% in women or 50% in men.1 Either of these results should lead to further testing.
    • Serum ferritin levels more than 1000 mcg/L or elevated liver enzymes in a diagnosed case of hemochromatosis indicate the need for a liver biopsy.1 
  • Genetic testing for mutations in the HFE gene will confirm the diagnosis in over 90% of cases.1 

After diagnosis, organ involvement or damage should be assessed using the following tests:

  • Echocardiography can evaluate for cardiomyopathy, while a chest radiograph can indicate increased pulmonary vascular markings or cardiomegaly
  • An MRI of the liver can measure liver iron concentration in a non-invasive manner
  • A liver biopsy can assess for liver damage1
  • Fasting blood glucose levels should be checked for diabetes
  • Bone densitometry to evaluate for osteoporosis
  • Hormone levels to evaluate hypogonadism

Due to the hereditary prevalence of the condition, first-degree relatives of hemochromatosis patients should undergo screening and genetic testing as well.1

Differential Diagnosis

Since hemochromatosis often leads to multiple organ dysfunction, the differential diagnosis is broad. Some of these differential diagnoses are as follows:1

  • Nonalcoholic fatty liver disease (NAFLD)
  • Alcoholic liver disease
  • Hereditary aceruloplasminemia
  • Iron overload from chronic transfusion
  • Excessive iron supplementation
  • Hepatitis B or C
  • Hemolytic anemia
  • Dysmetabolic hyperferritinemia
  • Marrow hyperplasia
  • Porphyria cutanea tarda
  • Biliary cirrhosis

Hemochromatosis Management

Phlebotomy

Phlebotomy is the conventional therapy for primary hemochromatosis, as iron toxicity can be minimized by drawing red blood cells out of the body.1 Blood draws are usually performed once or twice a week at first, drawing around 500 mL per visit.6 Patients may need between 50 and 100 phlebotomies before their iron levels return to normal.1

Once blood iron levels normalize, the frequency of blood removal is reduced based on the patient’s individual needs — typically once every two to three months.6 The goal is to reach a serum ferritin level of less than 50 mcg/L.1 It should be noted that preexisting end-organ damage is rarely reversed with phlebotomy, and issues such as cirrhosis, hypogonadism, and arthropathy will remain unchanged.1

For patients contraindicated for phlebotomy, chelation therapy is a secondary option.6 When it comes to mobilizing and excreting iron, deferoxamine — an intravenous agent — and deferiprone and deferasirox — oral agents — are all equally efficient iron chelators.1

Lifestyle and Dietary Changes

Known to some as the hemochromatosis diet, the goal is to decrease dietary intake of iron to help keep serum levels in a normal range. Alcohol should be strictly prohibited for patients with primary hemochromatosis as it accelerates pancreatic and liver toxicity.1 Supplements and multivitamins that contain iron should be avoided. Similarly, patients should not take any supplement containing vitamin C, as this vitamin increases iron absorption.6 Beyond this, no special dietary interventions are required.1 

Individuals with hemochromatosis are at risk for infections due to siderophilic organisms, however; they should avoid consumption of undercooked seafood until their iron overload has been treated. A diet that minimizes red meats and iron enriched foods, contains ample amounts of fruits, vegetables, and whole grains, and is based mostly on whole foods or minimally processed foods with little or no added sugar may help reduce dietary iron absorption.7

Hemochromatosis Monitoring

On-going phlebotomy visits will be required for most patients, although the frequency will reduce with time. Iron levels should be tested on a regular basis to determine frequency of treatment. Hepatocellular carcinoma accounts for roughly 30% of mortality in hemochromatosis, so all patients should undergo surveillance with biannual checks of alpha-fetoprotein levels and ultrasound.

Other potential complications that need to be monitored include:1

  • Diabetes mellitus
  • Cirrhosis
  • Hypogonadism
  • Congestive heart failure
  • Osteoporosis
  • Infection from Yersinia enterocolitica, Listeria monocytogenes, and Vibrio vulnificus

An interprofessional effort is needed to help monitor and manage complications. Depending on the patient, this could include gastroenterologists, hepatologists, cardiologists, orthopedists, and endocrinologists.1

References

  1. Porter JL, Prashanth Rawla. Hemochromatosis. In: StatPearls. NCBI Bookshelf version. Published May 4, 2019. Accessed July 23, 2022.
  1. Bacon BR. Hemochromatosis: discovery of the HFE geneMissouri medicine. 2012;109(2):133-136.
  2. Hemochromatosis (Iron Overload): Causes, Symptoms, Treatment, Diet & More. Cleveland Clinic. Published January 1, 2021. Accessed July 23, 2022.
  3. Hereditary hemochromatosis: MedlinePlus Genetics. MedlinePlus. Accessed July 23, 2022.
  4. Hereditary Hemochromatosis. Centers for Disease Control and Prevention. Published July 20, 2020. Accessed July 23, 2022.
  5. Hemochromatosis – Diagnosis and treatment. Mayo Clinic. Published 2018. Accessed July 23, 2022.
  6. Milman NT. Managing Genetic Hemochromatosis: An Overview of Dietary Measures, Which May Reduce Intestinal Iron Absorption in Persons With Iron Overload. Gastroenterology Research. 2021;14(2):66-80. doi:10.14740/gr1366

Author Bio

Jonathan Poole is a freelance writer and copy-editor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: https://www.unstoppableathletes.com