Hemochromatosis: Symptoms, Types, Causes and Treatment

Hemochromatosis is an often underrecognized disorder in which the body absorbs and stores excessive amounts of iron. Over time, this iron overload can damage vital organs, especially the liver, heart, and pancreas. While it is one of the most common genetic diseases among people of Northern European descent, its symptoms are often subtle or mistaken for other conditions, leading to delays in diagnosis and treatment. Understanding the symptoms, types, causes, and treatments of hemochromatosis is essential for early detection, intervention, and improving patient outcomes.

Symptoms of Hemochromatosis

Symptoms of hemochromatosis can be elusive, nonspecific, and often develop gradually over years. Many people are asymptomatic in the early stages, with clinical features only manifesting as iron accumulates and causes damage to various organs. Recognizing these symptoms early is crucial to prevent irreversible complications.

Symptom	Description	Frequency/Notes	Source(s)
Fatigue	Persistent tiredness	Most common presenting symptom	1 2 3 4 5
Joint pain	Arthralgia/arthritis	Affects hands, knees; may mimic arthritis	1 3 4 5 8
Liver disease	Hepatomegaly, cirrhosis	52% had liver involvement at diagnosis	1 2 3 4 5
Loss of libido	Impotence, amenorrhea	26% reported loss of libido	1 3 4
Skin pigmentation	Hyperpigmentation/bronzing	Classic but less common in early diagnosis	2 3 4 8
Diabetes	Hyperglycemia	Late complication, classic triad component	2 3 4 8
Cardiac symptoms	Arrhythmia, heart failure	May present as palpitations, edema, dyspnea	2 4 5 8
Abdominal pain	Discomfort, fullness	Affects up to 16% at presentation	3
Asymptomatic	No clinical symptoms	Up to 46% in family screening	2 3 5

Table 1: Key Symptoms of Hemochromatosis

Early and Nonspecific Symptoms

The majority of individuals with hemochromatosis initially report vague symptoms such as extreme fatigue and joint pain. Fatigue is the most frequent complaint, affecting nearly half of symptomatic patients, while joint pain (arthralgia), particularly in the hands and knees, is also very common. Many patients experience these symptoms for years—sometimes over a decade—before a correct diagnosis is made 1 2 3 4 5.

Organ-Specific Manifestations

As iron continues to build up, it deposits in the liver, pancreas, heart, joints, and endocrine organs, leading to:

• Liver disease: Manifestations include hepatomegaly, elevated liver enzymes, fibrosis, cirrhosis, and in severe cases, liver cancer 1 2 3 4 5.
• Endocrine and sexual dysfunction: Loss of libido, impotence in men, and amenorrhea in women arise due to pituitary and gonadal iron deposition 1 3 4.
• Diabetes mellitus: Iron toxicity damages pancreatic beta cells, leading to “bronze diabetes,” part of the classic triad 2 3 4 8.
• Cardiac symptoms: These include arrhythmias, cardiomyopathy, heart failure, and palpitations 2 4 5 8.

Classic but Less Frequent Features

The classic triad—cirrhosis, diabetes, and skin hyperpigmentation (bronze skin)—is now rare due to earlier detection. Hyperpigmentation or “bronzing” occurs as iron is deposited in the skin, but is seen less frequently with modern screening 3 4 8.

Asymptomatic Presentation

With the rise of family and population screening, many individuals are diagnosed before symptoms appear. Up to 46% of family-screened homozygotes have no symptoms at diagnosis, highlighting the importance of proactive screening in those with a family history 2 3 5.

Types of Hemochromatosis

Hemochromatosis is not a single disease but encompasses several genetic and acquired forms, each with its own genetic basis, age of onset, and clinical implications. Understanding the types helps in diagnosis and management.

Type	Genetic Cause/Mutation	Typical Onset	Source(s)
Classic (Type 1, HFE)	HFE gene (C282Y, H63D)	Adulthood (30–50 years)	4 7 8 9 11 12 13 17
Juvenile (Type 2)	HJV (hemojuvelin), HAMP (hepcidin)	Teens–Young adulthood	7 10 11 12 13
Transferrin Receptor 2 (3)	TFR2 gene	Early–mid adulthood	7 11 12 13
Ferroportin Disease (Type 4)	SLC40A1 (ferroportin)	Variable	6 7 11 12 13
Secondary Hemochromatosis	Chronic transfusions/other causes	Variable	8 11

Table 2: Major Types of Hemochromatosis

Classic (Type 1) HFE Hemochromatosis

The most common form, especially among people of Northern European descent, is caused by mutations in the HFE gene, primarily C282Y and to a lesser extent H63D 4 7 8 9 11 12 13 17. This type typically manifests in adulthood, with men presenting earlier than women due to the protective effect of menstruation and pregnancy delaying iron accumulation.

Juvenile Hemochromatosis (Type 2)

This rare, severe form appears in adolescence or early adulthood and is associated with mutations in the hemojuvelin (HJV) or hepcidin (HAMP) genes 7 10 11 12 13. It is characterized by rapid iron accumulation, leading to early-onset heart disease and endocrine failure (notably hypogonadism).

Transferrin Receptor 2-Related (Type 3)

Mutations in the TFR2 gene cause another rare, autosomal recessive form, which can resemble classic HFE hemochromatosis in presentation and age of onset 7 11 12 13.

Ferroportin Disease (Type 4)

Also known as autosomal dominant hemochromatosis, this form is caused by mutations in the SLC40A1 gene encoding ferroportin 6 7 11 12 13. It can present at any age and often shows a unique pattern of iron overload, with iron accumulating in macrophages as well as in parenchymal cells.

Secondary Hemochromatosis

Unlike the hereditary forms, secondary hemochromatosis is acquired due to chronic transfusions (e.g., in thalassemia), excessive dietary iron, or other conditions that disrupt normal iron regulation 8 11. It is important to distinguish this from primary forms for appropriate management.

Causes of Hemochromatosis

The underlying cause of hemochromatosis is a failure of the body’s normal iron-regulating mechanisms. Most cases are genetic, but environmental and secondary causes also play a role.

Cause	Mechanism/Pathway	Notes	Source(s)
HFE gene mutations	Reduced hepcidin, increased absorption	Most common, especially C282Y	4 7 8 9 11 12 13 17
Hepcidin deficiency	Disrupted iron hormone regulation	Central to all hereditary types	7 11 12 13
Non-HFE gene defects	Mutations in HJV, HAMP, TFR2, SLC40A1	Less common, often more severe	6 7 10 11 12 13
Environmental factors	Alcohol, vitamin C, iron supplements	Can worsen or trigger symptoms	1 8 13
Secondary causes	Chronic transfusions, liver disease	Not genetic; acquired iron overload	8 11

Table 3: Key Causes of Hemochromatosis

Genetic Mutations and Iron Regulation

The vast majority of hemochromatosis cases are caused by inherited mutations that disrupt the regulation of hepcidin, the hormone responsible for controlling iron absorption and distribution 7 11 12 13.

HFE Gene Mutations

• The C282Y mutation in the HFE gene is by far the most frequent cause, especially in Caucasians 4 7 8 9 11 12 13 17.
• H63D is a less common variant, and compound heterozygosity (one C282Y, one H63D) can also lead to disease, though usually less severe 8 9 17.

Non-HFE Genetic Defects

• Mutations in the genes coding for hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2), and ferroportin (SLC40A1) each disrupt the hepcidin–ferroportin axis in unique ways, leading to various forms of hereditary hemochromatosis 6 7 10 11 12 13.

Environmental and Modifying Factors

• The clinical expression is highly variable: not all people with genetic mutations develop severe symptoms.
• Factors such as high alcohol intake, hepatitis, high dietary iron or vitamin C (which increases absorption), and other genetic modifiers can accelerate organ damage in susceptible individuals 1 8 13.
• Blood loss (e.g., menstruation, blood donations) can delay onset or reduce severity 8.

Secondary (Acquired) Hemochromatosis

• Not due to inherited defects, but arises from conditions like chronic blood transfusions, excessive dietary iron, or chronic liver diseases that impair iron regulation 8 11.
• Differentiating primary from secondary hemochromatosis is essential for management.

Treatment of Hemochromatosis

Timely treatment of hemochromatosis can prevent organ damage and restore normal life expectancy. The mainstay is regular removal of excess iron, but comprehensive management includes monitoring, dietary advice, and addressing complications.

Treatment	Purpose/Target	Key Points/Effectiveness	Source(s)
Phlebotomy	Remove iron, deplete stores	Weekly removal until ferritin normalizes; maintenance lifelong	1 4 5 11 15 16 17
Iron chelation	Remove iron (if phlebotomy not possible)	Used in rare cases (anemia, poor veins)	11 17
Diet modifications	Reduce iron intake/absorption	Avoid iron/vitamin C supplements, raw seafood	1 16
Monitoring	Prevent iron reaccumulation	Regular ferritin/transferrin saturation checks	16 17
Treat complications	Manage organ-specific damage	Diabetes, liver, heart, and joint care	4 16 17
Family screening	Early detection in relatives	Genetic counseling/testing	1 2 3 4 9 17

Table 4: Treatments for Hemochromatosis

Phlebotomy: The Cornerstone Therapy

Phlebotomy (venesection) is the first-line and most effective treatment. It involves removal of blood (typically one unit weekly) to lower iron stores:

• Induction phase: Weekly phlebotomy until serum ferritin falls to 10–20 μg/L 16.
• Maintenance phase: Periodic phlebotomy (every 2–4 months) to keep ferritin <50 μg/L 15 16 17.
• Early initiation prevents complications such as cirrhosis, heart disease, and diabetes, and can normalize life expectancy if started before irreversible organ damage 5 11 15 16.

Iron Chelation

For patients who cannot undergo phlebotomy (e.g., due to anemia or poor venous access), iron chelating agents may be used, though they are less common and reserved for select cases 11 17.

Dietary and Lifestyle Management

• Avoid iron and vitamin C supplements: Vitamin C increases iron absorption and should be limited 1 16.
• Limit raw seafood: Risk of infection with iron-loving bacteria (e.g., Vibrio) is increased in iron-overloaded patients 16.
• Moderate alcohol intake: Alcohol exacerbates liver damage 1 8 16.

Monitoring and Managing Complications

• Regular monitoring: Ferritin and transferrin saturation should be checked every few months to guide therapy 16 17.
• Addressing complications: Specific treatments may be required for diabetes, liver cirrhosis, cardiac dysfunction, or joint disease 4 16 17.

Family Screening and Genetic Counseling

Given the hereditary nature, family members should be offered genetic testing and iron studies to identify affected individuals before symptoms develop 1 2 3 4 9 17.

Conclusion

Hemochromatosis is a complex yet manageable disorder when detected early. Its variable symptoms often delay diagnosis, but increased awareness, proactive screening, and advances in genetic testing have improved outcomes drastically.

Key points:

• Symptoms are often vague (fatigue, joint pain), but advanced disease can cause liver, heart, pancreatic, and endocrine damage.
• Types include classic HFE-related disease, severe juvenile forms, and rarer genetic variants, as well as secondary (acquired) iron overload.
• Causes are primarily genetic mutations affecting the hepcidin–ferroportin axis, with environmental factors influencing disease expression.
• Treatment centers around regular phlebotomy, supported by dietary advice, monitoring, and management of complications; early intervention prevents most irreversible damage.

Greater physician awareness and family screening remain key to reducing the burden of this silent but treatable disease.