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Iron overload disorder

Iron overload disorder

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In medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....

, iron overload indicates accumulation of iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...

 in the body from any cause. The most important causes are hereditary hemochromatosis (HHC), a genetic disease, and transfusional iron overload
Transfusion hemosiderosis
Transfusional hemosiderosis is the accumulation of iron in the liver and/or heart but also endocrine organs, in patients who receive frequent blood transfusions ....

, which can result from repeated blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...

.

Haemochromatosis or haemosiderosis


Historically, the term haemochromatosis (spelled hemochromatosis in American English
American English
American English is a set of dialects of the English language used mostly in the United States. Approximately two-thirds of the world's native speakers of English live in the United States....

) was initially used to refer to what is now more specifically called haemochromatosis type 1 (or HFE-related hereditary haemochromatosis). Currently, haemochromatosis (without further specification) is mostly defined as iron overload with a hereditary/primary cause, or originating from a metabolic disorder. However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, hereditary haemochromatosis. Hereditary haemochromatosis is an autosomal recessive disease with estimated prevalence in the population of 2 in 1,000 among patients with European ancestry, with lower incidence in other ethnic groups. The gene responsible for hereditary haemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary haemochromatosis patients have mutations in this HFE gene. Hereditary haemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues that typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

 in combination with hypopituitarism
Hypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...

, cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...

, diabetes, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, or hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...

. Because of the severe sequelae of this disease if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.

In general, the term haemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of haemosiderin. Sometimes, the simpler term siderosis
Siderosis
Siderosis is the deposition of iron in tissue.When used without qualification, it usually refers to an environmental disease of the lung.Also Siderosis Bulbi, deposition of iron into the eye causing injury as the material chemically reacts with tissues and cells.-Causative agent:Iron oxide present...

is used instead.

Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include:
  • Haemosiderosis is haemochromatosis caused by excessive blood transfusions, that is, haemosiderosis is a form of secondary haemochromatosis.
  • Haemosiderosis is hemosiderin deposition within cells, while haemochromatosis is hemosiderin within cells and interstitium.
  • Haemosiderosis is iron overload that does not cause tissue damage, while haemochromatosis does.
  • Haemosiderosis is arbitrarily differentiated from haemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.

Clinical presentation


Organs commonly affected by haemochromatosis are the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, and endocrine glands.

Haemochromatosis may present with the following clinical syndromes:
  • Cirrhosis
    Cirrhosis
    Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

     of the liver
  • Diabetes due to pancreatic islet cell failure
  • Cardiomyopathy
    Cardiomyopathy
    Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...

  • Arthritis
    Arthritis
    Arthritis is a form of joint disorder that involves inflammation of one or more joints....

     (iron deposition in joints)
  • Testicular failure
  • Tanning of the skin
  • Joint pain and bone pain http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=symptoms

Causes


The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life). People of Celtic (Irish, Scottish, Welsh) origin have a particularly high incidence of whom about 10% are carriers of the gene and 1% sufferers from the condition.

Primary haemochromatosis


The fact that most cases of haemochromatosis were inherited was well known for most of the 20th century, though they were incorrectly assumed to depend on a single gene. The overwhelming majority actually depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis", "non-HFE related hereditary haemochromatosis", or "non-HFE haemochromatosis".
Description OMIM Mutation
>-
| haemochromatosis type 1: "classical" haemochromatosis
>-
| Haemochromatosis type 2A: juvenile haemochromatosis
Haemojuvelin
Hemojuvelin
Hemojuvelin is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene...

 ("HJV", also known as RGMc and HFE2)
>-
| Haemochromatosis type 2B: juvenile haemochromatosis
HAMP
HAMP
Hepcidin is a protein that in humans is encoded by the HAMP gene.The product encoded by this gene is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption...

) or HFE2B
>-
| Haemochromatosis type 3
Haemochromatosis type 3
Haemochromatosis type 3 is a type of Iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern....

 
>-
| Haemochromatosis type 4/
African iron overload
African iron overload
African iron overload, formerly known as "Bantu siderosis", is an iron overload disorder first observed among people of African descent in Southern Africa.-Causes:...

 
ferroportin
Ferroportin
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:*Enterocytes in the duodenum*Hepatocytes...

 (SLC11A3/SLC40A1)
>-
| Neonatal haemochromatosis 
>-
| Acaeruloplasminemia (very rare)
>-
| Congenital atransferrinaemia (very rare)
transferrin
Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...


>-
| GRACILE syndrome
GRACILE syndrome
GRACILE syndrome is an autosomal recessive genetic disorder, one of the Finnish heritage diseases. It is caused by mutation in BCS1L gene.GRACILE is an acronym for growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death...

 (very rare)
BCS1L
BCS1L
-Further reading:...



Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance.

Secondary haemochromatosis

  • Severe chronic haemolysis of any cause, including intravascular haemolysis and ineffective erythropoiesis
    Ineffective erythropoiesis
    Ineffective erythropoiesis a kinetic term that describes active erythropoiesis with premature death of red blood cells, a decreased output of RBCs from the bone marrow, and, consequently, anemia....

     (haemolysis within the bone marrow
    Bone marrow
    Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

    ).
  • Multiple frequent blood transfusion
    Blood transfusion
    Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...

    s (either whole blood or just red blood cell
    Red blood cell
    Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

    s), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major, sickle cell anaemia, and Diamond–Blackfan anaemia) or by older patients with severe acquired anaemias such as in myelodysplastic syndrome
    Myelodysplastic syndrome
    The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....

    s.
  • Excess parenteral iron supplements, such as can acutely happen in iron poisoning
    Iron poisoning
    Iron poisoning is an iron overload caused by a large excess of iron intake and usually refers to an acute overload rather than a gradual one. The terms has been primarily associated with young children who consumed large quantities of iron supplement pills, which resemble sweets and are widely...

  • Excess dietary iron
  • Some disorders do not normally cause haemochromatosis on their own, but may do so in the presence of other predisposing factors. These include cirrhosis
    Cirrhosis
    Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

     (especially related to alcohol abuse
    Alcohol abuse
    Alcohol abuse, as described in the DSM-IV, is a psychiatric diagnosis describing the recurring use of alcoholic beverages despite negative consequences. Alcohol abuse eventually progresses to alcoholism, a condition in which an individual becomes dependent on alcoholic beverages in order to avoid...

    ), steatohepatitis
    Steatohepatitis
    Steatohepatitis is a type of liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver...

     of any cause, porphyria cutanea tarda
    Porphyria cutanea tarda
    Porphyria cutanea tarda is the most common subtype of porphyria. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs...

    , prolonged haemodialysis, post-portacaval shunt
    Portacaval shunt
    A portacaval shunt is a treatment for high blood pressure in the liver. A connection is made between the portal vein, which supplies 75% of the liver's blood, and the inferior vena cava, the vein that drains blood from the lower two-thirds of the body...

    ing.

Diagnosis


There are several methods available for diagnosing and monitoring iron loading including:
  • Serum ferritin
  • Liver biopsy
    Liver biopsy
    Liver biopsy is the biopsy 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.-History:...

  • HFE
  • MRI


Serum ferritin is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a range of other medical conditions unrelated to iron levels including infection, inflammation, fever, liver disease, renal disease, and cancer. Also, total iron binding capacity may be low, but can also be normal.

The standard of practice in diagnosis of hemochromatosis was recently reviewed by Pietrangelo. Positive HFE analysis confirms the clinical diagnosis of hemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of hemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with hemochromatosis; a negative report for HFE gene does not rule out hemochromatosis. In a patient with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of hemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of hemochromatosis.

MRI is emerging as an alternative to liver biopsy for measuring liver iron loading. For measuring liver iron concentrations, R2-MRI (also known as FerriScan) http://www.ferriscan.com/ has been extensively validated. More than 11,000 FerriScans have now been conducted in over 120 medical centres across 25 countries. FerriScan is now specifically recommended as a method to measure liver iron concentrations in clinical practice guidelines for thalassemias, sickle cell disease myelodysplastic syndrome (MDS) and hereditary hemochromatosis.

Family members of those diagnosed with primary hemochromatosis may be advised to be screened genetically to determine if they are a carrier or if they could develop the disease. This can allow preventative measures to be taken.

Treatment


Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting
Bloodletting
Bloodletting is the withdrawal of often little quantities of blood from a patient to cure or prevent illness and disease. Bloodletting was based on an ancient system of medicine in which blood and other bodily fluid were considered to be "humors" the proper balance of which maintained health...

). When first diagnosed, the phlebotomies may be fairly frequent, perhaps as often as once a week, until iron levels can be brought to within normal range. Once iron and other markers are within the normal range, phlebotomies may be scheduled every other month or every three months depending upon the patient's rate of iron loading.

For those unable to tolerate routine blood draws, there is a chelating agent available for use. The drug Deferoxamine
Deferoxamine
Deferoxamine is a bacterial siderophore produced by the actinobacteria Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body...

 binds with iron in the bloodstream and enhances its elimination via urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily. Two newer iron chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassemia (and, thus, who develop iron overload as a result) are deferasirox
Deferasirox
Deferasirox is a rationally-designed oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias...

 and deferiprone
Deferiprone
Deferiprone is an oral drug that chelates iron and is used to treat thalassaemia major.It has been licensed for use in Europe and Asia for many years while awaiting approval in Canada and the United States. On October 14, 2011, however, "the U.S...

.

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