What is Hereditary Hemochromatosis (HH)?

From the Guidelines

Hemochromatosis is a genetic disorder characterized by elevated transferrin saturation and progressive iron loading, mainly affecting the liver, and can be diagnosed and treated effectively with phlebotomy to prevent complications such as cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and other conditions. This condition occurs when the body cannot properly regulate iron absorption, resulting in iron accumulation in organs like the liver, heart, and pancreas. The most common form is hereditary hemochromatosis, typically caused by mutations in the HFE gene, particularly the p.Cys282Tyr variant, as noted in the EASL clinical practice guidelines on haemochromatosis 1. Symptoms often don't appear until middle age and may include fatigue, joint pain, abdominal pain, decreased sex drive, and skin darkening. If left untreated, hemochromatosis can lead to serious complications.

Key Points

• Hemochromatosis is characterized by increased transferrin saturation and liver iron overload, in the absence of anemia and/or reticulocytosis, as defined in the EASL guidelines 1.
• The condition is caused by a deficiency or impairment in hepcidin synthesis or function due to pathogenic variants in genes regulating hepcidin production or function, leading to increased intestinal iron absorption and iron release from macrophages 1.
• Diagnosis can be based on genetic testing for HFE gene mutations, particularly the p.Cys282Tyr variant, and phenotypic markers such as transferrin saturation and serum ferritin levels 1.
• Treatment primarily involves regular phlebotomy sessions to reduce iron stores, with targets of ferritin <50 µg/L during the induction phase and <100 µg/L during the maintenance phase, as recommended by the EASL guidelines 1.
• Early diagnosis and treatment are crucial to prevent organ damage and allow patients to have a normal lifespan, with dietary modifications complementing medical treatment but not replacing phlebotomy 1.

Management and Treatment

The management of hemochromatosis involves the removal of excess iron through phlebotomy, which is the primary treatment for reducing iron overload and preventing complications. The frequency and volume of phlebotomy are determined based on the severity of iron overload and the patient's response to treatment. As outlined in the treatment guidelines for iron overload 1, one phlebotomy (removal of 500 mL of blood) is typically performed weekly or biweekly, with monitoring of hematocrit and serum ferritin levels to adjust the treatment schedule as needed.

Conclusion is not allowed, so the answer just ends here.

From the Research

Definition and Overview of Hemochromatosis

• Hemochromatosis is a genetic disorder characterized by excessive absorption and accumulation of iron in the body 2, 3.
• It is one of the most common inherited disorders, particularly in individuals of European descent 2, 4.
• The disorder leads to toxic effects due to the lack of an effective excretory mechanism for excess iron, causing damage to various organs such as the liver, heart, pancreas, and joints 2, 3.

Causes and Genetics

• Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, often associated with genetic polymorphisms of the HFE gene 2.
• The HFE gene mutations, such as rs1800562, rs1799945, and rs1800730, affect the normal activity of hepcidin, a negative regulator of iron homeostasis 2.
• Other genes, including transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin, can also contribute to hereditary hemochromatosis when defective 5.

Clinical Features and Diagnosis

• Symptoms of hemochromatosis develop after marked accumulation of iron stores, causing functional insufficiency of organs such as the liver, heart, and pancreas 6.
• Clinical onset of symptoms occurs more frequently in adult men than women, as menstruation slows down iron accumulation in women 2.
• Diagnosis is typically made through genetic testing, liver biopsy, or elevated ferritin and serum transferrin saturation levels, often accompanied by asymptomatic hepatomegaly 2, 4.

Treatment and Management

• Therapeutic phlebotomy is the primary form of treatment for hemochromatosis, combined with the use of chelating agents 2.
• Early detection and treatment can prevent manifestations of the disease, and in some cases, reverse skin pigmentation and cardiac damage 4.
• Orthotopic liver transplantation (OTL) may be performed in patients with advanced cirrhosis 2.