From the Guidelines
Hereditary hemochromatosis (HH) is primarily classified into four main types: Type 1, caused by mutations in the HFE gene (particularly C282Y and H63D mutations); Type 2, also known as juvenile hemochromatosis, resulting from mutations in either the HJV gene (Type 2A) or HAMP gene (Type 2B); Type 3, caused by mutations in the TFR2 gene; and Type 4, also called ferroportin disease, resulting from mutations in the SLC40A1 gene 1.
Types of Hereditary Hemochromatosis
- Type 1: This is the most common form, typically caused by mutations in the HFE gene, with the C282Y mutation being the most prevalent, found in almost 90% of those affected 1.
- Type 2 (Juvenile Hemochromatosis): This is a rare, early-onset form that can be caused by mutations in either the HJV gene (Type 2A) or the HAMP gene (Type 2B).
- Type 3: This results from mutations in the TFR2 gene.
- Type 4 (Ferroportin Disease): Caused by mutations in the SLC40A1 gene.
Diagnosis and Management
Diagnosis of hereditary hemochromatosis is usually based on a combination of genetic or phenotypic criteria, including direct DNA testing for the HFE gene mutations and assessment of transferrin saturation and serum ferritin levels 1. Management typically involves regular phlebotomy to reduce iron levels, with the frequency determined by the severity of iron overload.
Importance of Early Diagnosis
Early diagnosis of hereditary hemochromatosis is crucial because it can lead to organ damage, such as cirrhosis and hepatocellular cancer, if left untreated 1. However, the variability in case definition and diagnostic standards makes early diagnosis challenging. Future developments in technology and genetic screening are expected to improve the diagnosis and management of hereditary hemochromatosis.
From the Research
Types of Hereditary Hemochromatosis (HH)
- Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent 2
- Non-HFE associated HH is caused by mutations in other recently identified genes involved in iron metabolism 2
- Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body 3
- The disease can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations 3
Characteristics of Hereditary Hemochromatosis
- Hereditary hemochromatosis is an autosomal recessive disorder that disrupts iron homeostasis, resulting in systemic iron overload 4
- The deposition of excess iron into parenchymal cells leads to cellular dysfunction and the clinical manifestations of the disease 4
- The liver, pancreas, joints, heart, skin, and pituitary gland are the most commonly involved organs 4
- Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages, and defective hepcidin gene expression or function may underlie most forms of HH 2
Diagnosis and Treatment
- Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition 4
- Phlebotomy is the mainstay of treatment and can help improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications 4
- Iron chelation therapy can be used in patients where venesection is contraindicated, and selected protocols using deferoxamine, deferiprone, and their combination could be designed for optimizing chelation therapy in HH patients 5