Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of

hereditary hemochromatosis Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, h ...

, 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 Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...

, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates. It is a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

that can be caused by mutations in either the HJV (also called HFE2) or HAMP genes, and is inherited in an autosomal recessive 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 Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...

Lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...

Hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

(darkening of the skin) *

Arthropathy An arthropathy is a disease of a joint. Types Arthritis is a form of arthropathy that involves inflammation of one or more joints, while the term arthropathy may be used regardless of whether there is inflammation or not. Joint diseases can be ...

(joint disease) *

Diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

* Heart disease (

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...

). Complications of heart disease are the main cause of death in those with untreated hemochromatosis. *

Hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...

(reduced activity of the genitals), which may result in decreased libido and infertility *

Amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

in females * Erectile dysfunction in males * Loss of appetite * Increased risk of

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

by certain bacteria including '' V. vulnificus''. Other common complications include: * Congenital hepatic fibrosis Less common symptoms and complications include: * Osteoporosis *

Hepatomegaly Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdo ...

(liver enlargement) * Liver

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...

* Cardiac arrhythmias * Hypothyroidism *

Adrenocortical insufficiency The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...

Genetics

Juvenile hemochromatosis can be caused by inheriting two mutated copies (

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

s), one from each parent, of the genes for the proteins

hemojuvelin Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosi ...

(HFE2/HJV) or

hepcidin Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals. During conditions in which the hepcidin level is abnormally high, such as inflammation, se ...

(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

s, one from each parent, for the HJV (aka HFE2) gene, which encodes the protein

. 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 is responsible for regulating absorption of iron from the small intestine to the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

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

Atransferrinemia Atransferrinemia is an autosomal recessive metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood. Atransferrinemia is characterized by anemia and hemosiderosis in the heart and ...

Aceruloplasminemia Aceruloplasminemia is a rare autosomal recessive disorder in which the liver can not synthesize the protein ceruloplasmin properly, which is needed to transport copper around the blood. Copper deficiency in the brain results in neurological proble ...

African iron overload African iron overload, also known as Bantu siderosis or dietary iron overload, is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. Dietary iron overload is the consumption of large amo ...

* Neonatal hemochromatosis * Transfusional iron overload and other forms of secondary hemochromatosis *

Porphyria cutanea tarda Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fift ...

Blood Testing

The presence of hemochromatosis may be discovered incidentally on blood testing, or a diagnosis suspected based on symptoms may be supported or ruled out by blood testing. Elevated serum ferritin, an indicator of blood iron levels, and

transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value ...

, 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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

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 Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment. Medica ...

, 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 Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...

and

, 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 Phlebotomy is the process of making a puncture in a vein, usually in the arm, with a cannula for the purpose of drawing blood. The procedure itself is known as a venipuncture, which is also used for intravenous therapy. A person who performs a p ...

, 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, 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 Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...

and

deferasirox Deferasirox, sold under the brand name Exjade & Asunra (in injectable form) & Oleptiss (Tablet formulation) both by Novartis among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving l ...

Dietary Modification

It is recommended that those with juvenile hemochromatosis refrain from eating

iron supplement Iron supplements, also known as iron salts and iron pills, are a number of iron formulations used to treat and prevent iron deficiency including iron deficiency anemia. For prevention they are only recommended in those with poor absorption, h ...

vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

supplements, and uncooked/undercooked seafood and shellfish, and reduce or eliminate consumption of

alcoholic beverages An alcoholic beverage (also called an alcoholic drink, adult beverage, or a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The cons ...

and

red meat In gastronomy, red meat is commonly red when raw and a dark color after it is cooked, in contrast to white meat, which is pale in color before and after cooking. In culinary terms, only flesh from mammals or fowl (not fish) is classified as ...

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 as indicated. * Heart failure may require followup with cardiology specialist, as well as medical treatment with certain medications including ACE inhibitors and

diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

. * Hypogonadism may require treatment with

hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

, which has also been shown to reduce the likelihood of developing osteoporosis later on. * Liver cirrhosis may require

beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...

s, 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 tha ...

medication. * Joint pain, called arthralgias, can be treated with NSAIDs, a type of pain medication available

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...

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