Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder most often associated with HFE gene mutations. Patients have increased iron intestinal absorption and iron deposition in several organs, such as the liver, heart, skin, and pancreas. The clinical presentation includes the triad of cirrhosis, diabetes, and skin bronzing. Other findings depend on the organ(s) involved. Diagnosis consists of iron studies, showing transferrin (Tf) and ferritin elevation. Genetic screening is recommended among family members. Imaging and invasive studies are performed depending on the associated complications. Management requires phlebotomy (or iron chelation therapy in some cases) to prevent disease progression. The prognosis is good for patients who are early in the disease and undergoing treatment. The presence of hepatic fibrosis is a poor prognostic factor.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp



Hereditary hemochromatosis (HH) is:

  • The most common autosomal recessive disorder in Caucasians
  • The most frequent cause of severe iron overload
  • Caused by different gene mutations that ultimately lead to low production of hepcidin, resulting in increased iron absorption


  • HFE gene: 
    • Specific for HH
    • Within the human leukocyte antigen (HLA) region on chromosome 6
    • Common missense mutations in the HFE gene: 
      • C282Y (cysteine-to-tyrosine substitution at amino acid position 282)
      • H63D (histidine-to-aspartic acid substitution at amino acid position 63)
    • Common HH genotypes:
      • Homozygosity for C282Y (C282Y/C282Y)
      • Compound heterozygosity (C282Y/H63D) 
  • Non-HFE gene:
    • Mutations in other genes involved in iron metabolism
    • Rare 
    • Found in juvenile hemochromatosis
  • Effects of gene mutations:
    • ↑ Iron absorption in the intestine: up to 2–4 mg of dietary iron/day (normal: 1–2 mg/day)
    • ↑ Iron deposition in different organs (e.g., liver)

Iron overload

It is important to note that causes of iron overload may overlap or occur at the same time.

Secondary iron overload disorders (acquired):

  • Common causes:
    • Increased iron intake (transfusions) 
    • Ineffective erythropoiesis (thalassemia)
    • Loss of hepatocyte mass resulting in reduced hepcidin (chronic liver disease) 
  • Iron deposits affecting different organs exhibit similar clinical and pathologic features as HH.


  • 1 in 200–500 people
  • Highest in people of Celtic or Nordic origin
  • C282Y variant: 
    • Most common finding in patients with HH
    • 85% of patients with HH are homozygous for the C282Y mutation.
  • Less common in people of African descent
  • Men affected 2–3 times more than women
  • Age of onset:
    • Men: after 40 years
    • Women: after 50 years
    • Juvenile hemochromatosis: onset at age 10–30 years
  • Mortality: 1.7 cases per 10,000 deaths


Iron homeostasis

  1. Dietary iron undergoes intestinal uptake in the duodenum.
  2. Iron moves from the duodenum via the iron exporter, ferroportin (Fpn), and enters the circulation via transferrin (Tf).
  3. Transferrin supplies iron to the bone marrow for hemoglobin synthesis.
  4. As the red blood cells (RBCs) age, they are phagocytosed by macrophages (in the spleen), releasing iron again into the circulation through Fpn. 
  5. Iron that is not used for biochemical processes is stored in ferritin.

Iron regulation via hepcidin

Certain conditions require a decrease or increase in iron absorption and circulating iron, a pathway regulated by hepcidin:

  • Liver-derived peptide regulating the plasma iron concentration
  • Actions (through binding Fpn):
    • Inhibits intestinal iron uptake
    • Inhibits the release of iron from macrophages with old RBCs
  • Iron sensing is mediated by different proteins: 
    • HFE
    • Transferrin (Tf) receptor 2 (Tfr2)
    • Hemojuvelin
  • Affected by:
    • ↑ Iron: ↑ hepcidin to reduce iron
    • ↑ Inflammation: ↑ hepcidin to limit iron availability to microorganisms
    • ↑ Erythropoietin: ↓ hepcidin to increase iron for hematopoiesis

Mutations in the hepcidin pathway

  • HH:
    • Gene mutations involving the HFE protein and non-HFE proteins (Tfr2, hemojuvelin, Fpn, and hepcidin) → decreased hepcidin release and increased iron absorption
    • Increased iron absorption → saturation of Tf and progressive increase of ferritin → iron overload → iron deposition
  • ↑ iron results in excess oxidative stress → inflammation and cell injury → organ damage

Types of HH

  • Type 1 (HFE related): classic form of HH 
  • Type 2: juvenile hemochromatosis:
    • Type 2a: mutations of the hemojuvelin gene 
    • Type 2b: mutations of the hepcidin gene 
  • Type 3: mutations of the Tf receptor-2 gene  
  • Type 4: mutations of the Fpn gene

Clinical Presentation

General findings

  • Manifestations depend on the degree of iron accumulation.
  • Often asymptomatic; diagnosed incidentally on blood tests or on family screening
  • Liver: 1st organ to be affected
  • Classic triad (found late in the disease):
    1. Cirrhosis
    2. Diabetes (“bronze diabetes” due to the associated discoloration)
    3. Skin bronzing/increased pigmentation

Specific findings and complications

  • Liver:
    • Abnormal liver function tests
    • Hepatomegaly (in 95% of patients), abdominal pain
    • Chronic liver disease/cirrhosis: palmar erythema, spider angiomas, splenomegaly
    • Hepatic failure: encephalopathy, jaundice, ascites
    • Hepatocellular carcinoma
  • Pancreas: 
    • Diabetes: elevated glucose
    • Fatigue, polyuria, polydipsia, weight loss, recurrent infections
  • Skin:
    • Bronze/slate-grey skin coloration (melanoderma)
    • Prominent on face, neck, forearms, and genital regions
    • Koilonychia (spoon-shaped nails)
  • Heart:
    • Dilated cardiomyopathy, congestive heart failure
    • Arrhythmias
  • Joints:
    • Arthralgia: small joints of the hands, especially the 1st, 2nd, and 3rd metacarpophalangeal joints
    • Others: knees, wrists
    • No joint warmth, redness, or deformity
    • Osteoporosis
  • Pituitary gland:
    • Hypogonadism (most common pituitary dysfunction): infertility, loss of libido, amenorrhea
    • Adrenal insufficiency
    • Hypothyroidism
    • Hypoparathyroidism
  • Decreased host defenses: 
    • Impaired phagocytosis and reduced lymphocyte proliferation, with readily available iron to microorganisms
    • ↑ Risk of infection from Listeria monocytogenes, Yersinia enterocolitica, and Vibrio vulnificus
Clinical features of hemochromatosis

Clinical features of hemochromatosis

Image by Lecturio.


Laboratory tests

  • Tf saturation (TSAT): ratio of serum iron to total iron-binding capacity (TIBC): 
    • If > 45% → screen for hemochromatosis
    • If > 60% (men) and > 50% (women) → highly specific for diagnosis
  • Serum iron: > 150 mcg/dL
  • TIBC: 200–300 mcg/dL
  • Serum ferritin: 
    • An acute phase reactant
    • Less sensitive, because serum ferritin can be ↑ in other liver and inflammatory diseases
    • Indicative of disease when: 
      • > 200 mcg/L in premenopausal women
      • > 300 mcg/L in men and in postmenopausal women
      • If > 1,000 mcg/L → increased risk of organ damage
  • Abnormal liver function tests: ↑ alanine transaminase (ALT), ↑ aspartate transaminase (AST)
  • Additional tests: 
    • Hormone tests in cases consistent with pituitary disorders
    • Hemoglobin A1c and metabolic panel in those with diabetes

Genetic testing

  • C282Y and H63D mutations in the HFE gene
  • Homozygous for C282Y or heterozygous for C282Y/H63D: indicative of HH
  • Screen all 1st-degree relatives.


  • Radiographs: may see cardiomegaly and pulmonary vascularity
  • Magnetic resonance imaging (MRI) of the liver: 
    • Evaluates liver damage or tumor development
    • Noninvasive way to estimate iron stores
  • Cardiac MRI: performed for those with cardiac failure
  • Echocardiogram: shows dilated cardiomyopathy, diastolic dysfunction


  • Skin: can sample any site except for legs (may be non-specific due to stasis)
  • Liver biopsy: 
    • Performed when initial approach yields uncertain results
    • Indications:
      • Abnormal liver function tests
      • Ferritin > 1,000 mcg/L
      • Other liver disease is suspected.
    • Helps determine the extent of liver damage and iron concentration
    • Hepatic fibrosis: most important prognostic factor
Liver biopsy for iron hemochromatosis

Hepatocyte iron accumulation in a patient with hemochromatosis (stained with Perls Prussian blue)

Image: “Grade 3 hepatocyte iron accumulation” by Mathew, J. et al. License: CC BY 3.0.

Management and Prognosis


  • Objectives:
    • Remove excess iron from the body.
    • Reduce progression of disease and complications, including risk for HCC.
  • Phlebotomy:
    • Treatment of choice
    • Performed weekly or twice weekly, removing 500 mL, and continued until the serum ferritin level is approximately 50–100 mcg/L
    • After ferritin drops to the goal level, it is maintained with phlebotomy (the frequency depends on serum iron studies and blood count). 
    • Can improve or slow the natural disease progression
  • Iron chelating agents:
    • Treatment options for patients who have heart disease, anemia, or difficult intravenous access
    • Options:
      • Deferoxamine: intravenous/intramuscular/subcutaneous
      • Deferiprone: oral chelator (↓ cardiac iron overload)
      • Deferasirox: oral iron chelator
  • Dietary restrictions:
    • No iron supplements
    • Limit vitamin C supplements (↑ iron absorption).
    • No alcohol to limit liver injury
    • No raw seafood (Vibrio vulnificus contamination → sepsis) 
  • Complication-specific treatments:
    • Conventional therapy for diabetes, cirrhosis, and cardiac failure/arrhythmia 
    • Hormone replacement or gonadotropin therapy for pituitary effects
    • HCC screening for those at high risk
  • Surgical management for advanced complications:
    • Liver transplantation: for liver failure
    • Arthroplasty: for severe joint infiltration


  • With treatment:
    • 5-year survival rate: 89%
    • Patients without hepatic fibrosis: expected to have a normal life expectancy
  • Effects of treatment/phlebotomy on complications:
    • Cardiac failure may be reversed.
    • Liver function and skin pigmentation improve.
    • 40% of patients with diabetes reach better glucose control.
    • Minimal effect on arthropathy and hypogonadism
  • Once liver cirrhosis sets in, it is irreversible; HCC is a late sequela.
  • Main causes of death:
    • Cardiac failure
    • Hepatic failure
    • Hepatocellular carcinoma

Differential Diagnosis

  • Alcoholic liver disease: Patients with a history of chronic alcoholism and who have developed chronic liver disease and cirrhosis may manifest with increased iron levels. Treatment is alcohol cessation.
  • Multiple transfusions: In patients who require a lot of blood transfusions (patients with thalassemia, myelodysplastic syndrome), there may be an increased iron level, comparable to patients with hemochromatosis. Levels return to normal after transfusions are stopped. 
  • Chronic anemia: a condition of chronically low RBC counts. Due to the body adjusting to chronic anemia, there is increased efficient erythropoiesis and iron absorption. Treatment is iron replacement in addition to treating the underlying cause.


  1. Bacon, B. (2019). Clinical manifestations and diagnosis of hereditary hemochromatosis. In Mentzer, W., Lindor, K., Tirnauer, J., & Kunins, L. (Eds). UpToDate. Retrieved 21 Nov 2020 from UpToDate – Clinical manifestations and diagnosis of hereditary hemochromatosis
  2. Duchini, A., Sfier, H., & Klachko, D. (2017). Hemochromatosis. In Roy, P. Medscape. Retrieved 21 Nov 2020 from
  3. Friedman, L.S. (2021). Hemochromatosis. In Papadakis M.A., & McPhee S.J., & Rabow M.W. (Eds.),  Current Medical Diagnosis & Treatment 2021. McGraw-Hill.
  4. Kelley, M., Joshi, N., Xie, Y., & Borgaonkar, M. (2014) Iron overload is rare in patients homozygous for the H63D mutation. Can J Gastroenterol Hepatol. 28(4): 198–202. doi: 10.1155/2014/468521
  5. Nemeth, E., & Ganz, T. (2009). The role of hepcidin in iron metabolism. Acta Haematol. 122(2–3): 78–86. doi: 10.1159/000243791
  6. Porter, J., & Rawla, P. (2020). Hemochromatosis.
  7. Powell, L.W. (2018). Hemochromatosis. In Jameson J., Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., & Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.