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Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of hereditary hemochromatosis, which emerges in young individuals, typically between 15 and 30 years of age, but occasionally later. It is characterized by an inability to control how much iron is absorbed by the body, in turn leading to iron overload, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates. It is a genetic disorder that can be caused by
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in either the HJV (also called HFE2) or HAMP genes, and is inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
fashion. Depending on which of these genes is affected, the disease can be further subdivided into types 2A and 2B.


Signs and Symptoms

The most common symptoms of juvenile hemochromatosis are as follows: * Weakness * Lethargy * Hyperpigmentation (darkening of the skin) * Arthropathy (joint disease) * Diabetes * Heart disease ( dilated cardiomyopathy). Complications of heart disease are the main cause of death in those with untreated hemochromatosis. * Hypogonadism (reduced activity of the genitals), which may result in decreased libido and
infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
* Amenorrhea in females *
Erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
in males * Loss of appetite * Increased risk of infection by certain bacteria including '' V. vulnificus''. Other common complications include: *
Congenital hepatic fibrosis Congenital hepatic fibrosis is an inherited fibrocystic liver disease associated with proliferation of interlobular bile ducts within the portal areas and fibrosis that do not alter hepatic lobular architecture. The fibrosis would affect resist ...
Less common symptoms and complications include: *
Osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
* Hepatomegaly (liver enlargement) * Liver cirrhosis * Cardiac
arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
s *
Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
* Adrenocortical insufficiency


Genetics

Juvenile hemochromatosis can be caused by inheriting two mutated copies ( alleles), one from each parent, of the genes for the proteins hemojuvelin (HFE2/HJV) or hepcidin (HAMP), and the disease can be subdivided into hemochromatosis types 2A and 2B according to which gene/protein is affected. * Type 2A is caused by inheriting two mutated alleles, one from each parent, for the HJV (aka HFE2) gene, which encodes the protein hemojuvelin. Hemojuvelin is responsible for the maintaining correct levels of the protein hepcidin, which regulates iron absorption in the blood. Without functional hemojuvelin, hepcidin levels are reduced, and the amount of iron absorbed into the blood during digestion is unable to be halted. * Type 2B is caused by inheriting two mutated alleles, one from each parent, for the HAMP gene, which encodes the protein hepcidin. Hepcidin is responsible for regulating absorption of iron from the
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
to the blood during the digestion of food, such to prevent blood iron levels from becoming too high. A lack of functional hepcidin prevents the body from stopping iron absorption when it has already reached adequate levels. Type 2A is the most common form, accounting for roughly 9 out of every 10 cases of the disease.


Diagnosis

An individual may be suspected to have this condition based on their medical history, physical exam findings, and blood tests, and confirmation of the diagnosis can be made with further testing, often with use of gene panels.


Differential Diagnosis

Juvenile hemochromatosis shares signs and symptoms with many other conditions including: * Other types of hereditary hemochromatosis * Atransferrinemia * Aceruloplasminemia * African iron overload *
Neonatal hemochromatosis Neonatal Hemochromatosis is a rare and severe liver disease of unknown origin, though research suggests that it may be alloimmune condition. Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the ...
* Transfusional iron overload and other forms of secondary hemochromatosis * Porphyria cutanea tarda


Blood Testing

The presence of hemochromatosis may be discovered incidentally on
blood testing A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose test or a cholester ...
, or a diagnosis suspected based on symptoms may be supported or ruled out by blood testing. Elevated
serum ferritin Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
, an indicator of blood iron levels, and transferrin saturation, which is involved with absorption of iron from the gut, are very common. * Transferrin saturation may approach or reach 100%, where a normal value would lie between 16% and 45%. If transferrin saturation is normal, juvenile hemochromatosis can be ruled out. * Serum ferritin may only be slightly elevated as the disease progresses, however may quickly reach in excess of 1000ng/mL.


Genetic Testing

In patients suspected to have juvenile hemochromatosis, the diagnosis can be confirmed through genetic testing for specific genes: * A single gene study may be considered in those that demonstrate iron overload at a very young age, and specifically looks for mutations in either the HJV (HFE2) or HAMP genes. As HJV is more commonly associated with the disease, this may be checked first, and if no alterations are found, HAMP may be tested next. * A multi-gene study may be considered to more effectively search for genetic causes of the patient's symptoms, and can include HJV, HAMP, and other genes associated with similar conditions like HFE.


Imaging

MRI may be utilized in order to assess the extent to which iron has been deposited in certain tissues and organs, however does not have significant weight in the diagnosis of the condition.


Biopsy

Liver biopsy, or removal of a small piece of liver tissue for analysis, can be done to assess the extent of iron overload in the liver, however is considered not to have a significant weight in the diagnosis of the condition.


Treatment

Treatment for juvenile hemochromatosis is similar to that for other forms of hemochromatosis and iron overload, and focuses on reducing the amount of iron in the body in order to prevent complications of iron overload. However, if the disease is not discovered early enough, or if progress is not well controlled, further treatments may be aimed at the symptoms of organ damage which may develop.


Phlebotomy

Phlebotomy, the removal of blood from the body, is the main treatment for juvenile hemochromatosis. One unit of blood, the amount typically given during
blood donation A blood donation occurs when a person voluntarily has blood drawn and used for blood transfusion, transfusions and/or made into biopharmaceutical medications by a process called Blood fractionation, fractionation (separation of whole blood com ...
, is typically removed per session, and it is generally recommended that this be done once weekly until acceptable levels of iron are in the blood, which may take years. After these levels are reached, phlebotomy will be continued, but less often than once weekly, perhaps every few months.


Chelation Therapy

In the event that phlebotomy is not an appropriate option or is not enough on its own to reduce iron levels, chelation medications, those that bind and remove certain metals from the blood, may be utilized. Examples of chelators specifically for iron include deferoxamine and deferasirox.


Dietary Modification

It is recommended that those with juvenile hemochromatosis refrain from eating iron supplements, vitamin C supplements, and uncooked/undercooked seafood and shellfish, and reduce or eliminate consumption of alcoholic beverages and red meat.


Additional Treatments

If the disease is advanced enough, further treatments can be aimed at the complications of the disease, depending on which are present: * Diabetes may be treated with oral medications and/or
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
as indicated. * Heart failure may require followup with cardiology specialist, as well as medical treatment with certain medications including
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
s and diuretics. * Hypogonadism may require treatment with hormone replacement therapy, which has also been shown to reduce the likelihood of developing
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
later on. * Liver cirrhosis may require beta blockers, a kind of
antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that ...
medication. * Joint pain, called arthralgias, can be treated with NSAIDs, a type of pain medication available over-the-counter.


Epidemiology

The incidence of juvenile hemochromatosis in the general population remains unknown at this time, however it is very rare. It more commonly occurs in those of European descent, becoming apparent during the first to third decades of life, and affects males and females at similar rates.


References


External links


GeneReview/NIH/UW entry on Juvenile Hereditary Hemochromatosis
Iron metabolism Rare diseases {{blood-disease-stub