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Last updated: 8/24/2023
Years published: 2010, 2013, 2016, 2019, 2023
NORD gratefully acknowledges William JH Griffiths, MB BChir, FRCP, PhD, Consultant Hepatologist, Addenbrookeโs Hospital, Cambridge, UK, for assistance in the preparation of this report.
Ferroportin disease, also known as hemochromatosis type 4, is a rare genetic disorder characterized by the abnormal accumulation of iron in the body. Ferroportin disease is caused by changes (variants or mutations) of the SLC40A1 gene. The specific symptoms associated with ferroportin disease can vary greatly from one person to another. Some individuals may only have elevated levels of ferritin, a protein that binds to iron and is used as an indicator of the bodyโs iron stores in the blood plasma. Other individuals may develop symptoms similar to classic HFE-related hemochromatosis.
Ferroportin disease is classified as an iron overload disorder, a group of disorders characterized by the abnormal accumulation of iron in the body. It is a separate, distinct disorder from classic hereditary hemochromatosis. Ferroportin disease is caused by variants in a different gene and is inherited in a different manner from other forms of hemochromatosis.
The symptoms of ferroportin disease vary greatly from one person to another. Researchers believe that different variants in the SLC40A1 gene are associated with different symptoms. Generally, ferroportin disease is separated into two main forms.
Most individuals with ferroportin disease develop a mild form of the disorder. These individuals have elevated levels of ferritin in the blood plasma (hyperferritinemia) and low levels of saturated transferrin (the protein that carries iron in the blood). As affected individuals age, mild liver damage (hepatic fibrosis) and joint symptoms may occur.
Other individuals develop a rarer form of ferroportin disease that resembles the more common classic form of hemochromatosis (hemochromatosis type 1 or HFE-related). The transferrin saturation is significantly elevated in this form. Symptoms associated with this form include joint pain, abnormalities in the heartโs rhythm or heartbeat pattern (arrhythmias) and diabetes. Liver damage is more prevalent in this form of ferroportin disease and can progress to cause advanced scarring (cirrhosis) of the liver.
Ferroportin disease is caused by variants in the SLC40A1 gene. The SLC40A1 gene contains instructions for creating ferroportin, a specialized protein that is crucial to the proper export of iron from cells. Ferroportin also plays a role in the proper breakdown (metabolism) of iron. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).
Variants in the SLC40A1 gene result in low levels of functional ferroportin. The lack of functional ferroportin ultimately results in the abnormal accumulation of iron in the cells and tissues of the body. Different variants of the SLC40A1 gene affect the ferroportin protein in different ways, altering the export and metabolism of iron accordingly. Researchers believe that the different ways in which SLC40A1 variants affect ferroportin account for the two different forms of the disorder.
Ferroportin disease is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
Ferroportin disease affects males and females in equal numbers. The exact incidence of ferroportin disease is unknown. Researchers believe that the disorder occurs more frequently than has been reported in the medical literature. Ferroportin affects individuals of all races and ethnicities. Some researchers believe that ferroportin disease is the most common form of hereditary iron overload after classic (type 1 or HFE-related) hemochromatosis.
A diagnosis of ferroportin disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A family history with affected individuals in successive generations is highly suggestive (autosomal dominant inheritance). Blood tests can reveal certain findings associated with ferroportin disease including high levels of ferritin in the blood and, in the milder form of the disease, low or normal saturation of transferrin, another protein that plays a role in the proper transport of iron within the body. Molecular genetic testing for variants in the SLC40A1 gene is available and necessary to confirm the diagnosis.
Treatment
The treatment of ferroportin disease is directed toward the specific symptoms that are apparent in each individual. Specific treatment may depend on the severity and form of ferroportin disease.
Individuals with the form of ferroportin disease that resembles classic hemochromatosis may be treated with regular phlebotomy, a procedure in which blood is removed via a vein. Individuals with the mild form of ferroportin disease may not necessarily require treatment and phlebotomy in these individuals is often complicated by anemia.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Additional therapies have been used to treat individuals with disorders of iron overload. Such therapies include iron chelators and antioxidants. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Antioxidants such as vitamin E are substances that are believed to protect cells from damage from unstable molecules called free radicals.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Wallace DF, Subramaniam VN. Non-HFE hemochromatosis. World J Gastroenterol. 2007;13:4690-4698.
Griffiths WJ. Review article: the genetic basis of hemochromatosis. Aliment Pharmacol Ther. 2007;26:331-342.
Cremonesi L, Forni GL, Soriani N, et al. Genetic and clinical heterogeneity of ferroportin disease. Br J Haematol. 2005;131:663-670.
Nemeth E. Ferroportin mutations: a tale of two phenotypes. Blood. 2005;105:3763-3764.
Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis. 2004;32:131-138.
Cazzola M. Genetic disorders of iron overload and the novel โferroportin diseaseโ. Haematologica. 2003;88:721-724.
Ponka P. Rare cases of hereditary iron overload. Semin Hematol. 2002;39:249-262.
Girelli Dm, Busti F, Brissot P, et al. Hemochromatosis classification: update and recommendations by the BIOIRON society. Blood 2022;139:3018-3029.
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:606069; Last Update: 03/11/2020. Available at: https://omim.org/entry/606069 Accessed Aug 24, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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