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Haemochromatosis
Classification and external resources
ICD-10 E83.1
ICD-9 275.0
OMIM 235200 602390 606464 604720 604653
DiseasesDB 5490
eMedicine med/975  derm/878
MeSH D006432

Haemochromatosis (American spelling hemochromatosis), is a hereditary disease characterized by excessive absorption of dietary iron resulting in a pathologic increase in total body iron stores. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Humans, like virtually all animals, have no means to excrete excess iron. [1] Excess iron accumulates in tissues and organs disrupting their normal function. The most susceptible organs include the liver, adrenal glands, the heart and the pancreas; patients can present with cirrhosis, adrenal insufficiency, heart failure or diabetes. The liver is a vital organ in the human body and is present in Vertebrates and some other animals In Mammals the adrenal glands (also known as suprarenal glands) are the triangle-shaped Endocrine glands that sit on top of the Kidneys their The heart is a muscular organ in all Vertebrates responsible for pumping Blood through the Blood vessels by repeated rhythmic The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc [2] The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of British descent. [3]

"Haemochromatosis" less often refers to the condition of iron overload as a consequence of multiple transfusions. A more preferred term in the United States for transfusional iron overload is hemosiderosis. Those with hereditary anemias such as beta-thalassaemia major, sickle cell anemia and Diamond-Blackfan anemia who require regular transfusions of red blood cells are all at risk for developing life-threatening iron overload. Older patients with various forms of bone marrow failure such as with myelodysplastic syndrome who become transfusion-dependent are also at risk for iron overload.

Contents

History

The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin. Armand Trousseau ( October 14, 1801 — June 27, 1867) was a notable French Internist. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc [4] Trousseau did not associate diabetes with iron accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Friedrich Daniel von Recklinghausen (ˈʁɛklɪŋhaʊzən December 2, 1833 &ndash August 26, 1910) was a German Pathologist [5][6] In 1978 the Iron Overload Diseases Association (IOD) was formed to act as a support group and information center for people affected by hemochromatosis.

Signs and symptoms

Haemochromatosis is protean in its manifestations, i. e. , often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon and for most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity. [7] The more common clinical manifestations include:[8][9][10]

Less common findings including:

Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation (which ceases in menopause). Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle Diabetes mellitus type 2 or Type 2 Diabetes (formerly called non - Insulin -dependent Diabetes mellitus (NIDDM or adult-onset diabetes is a metabolic The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Hypogonadism is a medical term for a defect of the Reproductive system that results in lack of function of the Gonads ( ovaries or testes) Libido in its common usage means Sexual desire however more technical definitions such as those found in the work of Carl Jung, are more general referring to libido Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply Dysrhythmia redirects here For the American band see Dysrhythmia (band. Pericarditis is an Inflammation ( -itis) of the Pericardium (the fibrous sac surrounding the heart Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body In Human anatomy, the wrist is the flexible and narrower connection between the Forearm and the palm. The knee is the lower extremity Joint connecting the Femur, Patella, and the Tibia. The glenohumeral joint, commonly known as the Shoulder joint, is a synovial Ball and socket joint and involves articulation between the A joint is the location at which two or more Bones make contact In Mammals the adrenal glands (also known as suprarenal glands) are the triangle-shaped Endocrine glands that sit on top of the Kidneys their Adrenal insufficiency is a condition in which the Adrenal glands located above the Kidneys do not produce adequate amounts of steroid hormones (chemicals produced by the Dyskinesia refers to involuntary movements similar to a Tic or Chorea. Parkinsonism (also known as Parkinson's syndrome, atypical Parkinson's, or secondary Parkinson's) is a neurological Syndrome characterized Endocrinology (from Greek grc ἔνδον endon, "within" grc κρῑνω krīnō, "to separate" and grc -λογία The parathyroid glands are small endocrine Glands in the neck usually located behind the Thyroid gland, which produce Parathyroid hormone. In Medicine, hypocalcaemia is the presence of low serum Calcium levels in the Blood, usually taken as less than 2 The pituitary gland, or hypophysis, is an Endocrine gland about the size of a Pea. For the drug referred to as "pigment" see Black tar heroin. Armand Trousseau ( October 14, 1801 — June 27, 1867) was a notable French Internist. Year 1865 ( MDCCCLXV) was a Common year starting on Sunday (link will display the full calendar of the Gregorian calendar (or a Common year An infectious disease is a clinically evident Disease resulting from the presence of Pathogenic microbial agents including Pathogenic viruses Pathogenic Vibrio vulnificus is a species of Gram-negative, motile curved rod-shaped bacteria in the genus Vibrio. Seafood is any Sea Animal or Seaweed that is served as Food, or is suitable for eating particularly saltwater animals such Listeria monocytogenes is a Gram-positive Bacterium, in the division Firmicutes, named for Joseph Lister. Yersinia enterocolitica is a species of Gram-negative coccobacillus-shaped Bacterium, belonging to the family Enterobacteriaceae. Salmonella enterica is a rod shaped Flagellated Gram-negative Bacterium, and a member of the Genus Salmonella Klebsiella pneumoniae is a Gram-negative, non- Motile, Encapsulated, Lactose fermenting, Facultative anaerobic Rhizopus arrhizus is fungus of the family Mucoraceae, characterized by Sporangiophores that arise from nodes at the point where the Rhizoids are formed See also "Mensuration" a term sometimes used to describe Measurement, particularly in the context of Forestry. Menopause is the permanent shutting down of the female Reproductive system, a considerable length of time before the end of the lifespan The severity of clinical disease in the hereditary form varies considerably. There is evidence suggesting that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Diagnosis

The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or excessive iron binding saturation of transferrin exceeding the normal value of 50%. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint. The evaluation of abnormal transferrin saturation commonly involves determining the level of ferritin, a protein found in serum made by liver that binds iron. Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis. [14]

Imaging features

Clinically the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity at MR imaging. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Computed tomography (CT is a Medical imaging method employing Tomography. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. An arthropathy is a Disease of a Joint. Although the terms "arthropathy" and Arthritis have very similar meanings the former is traditionally Osteoarthritis ( OA, also known as degenerative Arthritis, degenerative joint disease) is a clinical syndrome in which low-grade inflammation Calcium pyrophosphate deposition disease ( CPPD) is a rheumatologic disorder with varied clinical manifestations due to precipitation of Calcium pyrophosphate The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand. An arthropathy is a Disease of a Joint. Although the terms "arthropathy" and Arthritis have very similar meanings the former is traditionally The arthropathy can therefore be an early clue as to the diagnosis of haemochromatosis. An arthropathy is a Disease of a Joint. Although the terms "arthropathy" and Arthritis have very similar meanings the former is traditionally MRI algorithms are available at research institutions to quantify the amount of iron present in the liver, therefore reducing the necessity of a liver biopsy (see below) to measure the liver iron content. The liver is a vital organ in the human body and is present in Vertebrates and some other animals A biopsy (in Greek: βίος life and όψη look/appearance is a Medical test involving the removal of cells or tissues The liver is a vital organ in the human body and is present in Vertebrates and some other animals Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 As of May, 2007, this technology was only available at a few sites in the USA, but documented reports of radiographic measurements of liver iron content were becoming more common. For medical radiography see Radiology Radiography is the use of X-rays to view unseen or hard-to-image objects The liver is a vital organ in the human body and is present in Vertebrates and some other animals [15]

Chemistry

Serum transferrin and transferrin saturation Transferrin binds iron and is responsible for iron transport in the blood. Transferrin is a Blood plasma Protein for Iron Ion delivery Transferrin is a Glycoprotein, which binds iron very tightly but reversibly [16] Measuring transferrin provides a crude measure of iron stores in the body. Saturation values in excess of 62% are recognized as a threshold for further evaluation of haemochrmoatosis. [17]

Serum Ferritin- Ferritin, a protein synthesized by the liver is the primary form of iron storage within cells and tissues. Ferritin is a Globular protein complex consisting of 24 protein subunits and is the main intracellular iron storage protein in both Prokaryotes Measuring ferritin provides another crude estimate of whole body iron stores though many conditions notably inflammation can elevate serum ferritin. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for female, 12-150 ng/ml. [18][19] Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)). A complete blood count ( CBC) also known as full blood count ( FBC) or full blood exam ( FBE) or blood panel, is Renal function, in Nephrology, is an indication of the state of the Kidney and its role in Renal physiology. Liver function tests (LFTs or LFs which include liver enzymes, are groups of Clinical biochemistry laboratory blood assays designed to give information about the An electrolyte is any substance containing free Ions that behaves as an electrically conductive medium Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. A glucose tolerance test in medical practice is the administration of Glucose to determine how quickly it is cleared from the blood

Functional testing

Based on the history, the doctor might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes. A physician, medical practitioner or medical doctor who practices Medicine, and is concerned with maintaining or restoring human Health An echocardiogram is a Sonography of the Heart. Also known as a cardiac ultrasound it uses standard ultrasound techniques to image two-dimensional slices of Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc

Histopathology

Liver biopsy - Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, measured microscopically. Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative Formerly, this was the only way to confirm a diagnosis of haemochromatosis but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, it is debatable whether a liver biopsy is still necessary to quantify the amount of accumulated iron. A biopsy (in Greek: βίος life and όψη look/appearance is a Medical test involving the removal of cells or tissues [20]

Screening

Screening specifically means looking for a disease in people who have no symptoms. A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly A symptom' (from Greek σύμπτωμα, "accident misfortune that which befalls" from συμπίπτω, "I befall" from Diagnosis, on the other hand refers to testing people who have symptoms of a disease. Diagnosis is the identification by Process of elimination, of the nature of anything A symptom' (from Greek σύμπτωμα, "accident misfortune that which befalls" from συμπίπτω, "I befall" from A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly Standard diagnostic measures for haemochromatosis, serum transferrin saturation and serum ferritin tests, are not a part of routine medical testing. Transferrin saturation, measured as a percentage is a Medical laboratory value Ferritin is a Globular protein complex consisting of 24 protein subunits and is the main intracellular iron storage protein in both Prokaryotes Screening for haemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms:[21][22]

Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. The USPSTF recommended against genetic screening of the general population for hereditary hemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than 1 in 1000. Although there is strong evidence that treatment of iron overload can saves lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit. [23] [24] Recently, it has been suggested that patients be screened for iron overload using serum ferritin as a marker -- if serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.

Differential diagnosis

There exist other causes of excess iron accumulation, which have to be considered before Haemochromatosis is diagnosed.

Epidemiology

Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 150. Thus, about 1 in 12 people of this demographic carry a mutation in one of the genes regulating iron metabolism, the most common allele being the C282Y allele in the HFE gene. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. The prevalence of mutations in iron metabolism genes varies in different populations. In Epidemiology, the prevalence of a Disease in a Statistical population is defined as the total number of cases of the disease in the population at a given History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous 5% were homozygous for an HFE mutation, and only 0. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous 25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations will not manifest clinically relevant haemochromatosis (see genetics below). Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism [26] Other populations have a lower prevalence of both the genetic mutation and the clinical disease. Genetic studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60-70 generations ago. Genetics (from Ancient Greek grc-Latn genetikos, “genitive” and that from grc-Latn genesis, “origin” a discipline of Biology, is In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism Celts (ˈkɛlts or /ˈsɛlts/, see Names of the Celts At that time when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided a natural selection reproductive advantage by maintaining higher iron levels in the blood. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism Natural selection is the process by which favorable Heritable traits become more common in successive Generations of a Population of Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26

Genetics

Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion.
Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion.
Haemochromatosis type 4 is inherited in an autosomal dominant fashion.
Haemochromatosis type 4 is inherited in an autosomal dominant fashion.

The regulation of dietary iron absorption is complex and our understanding is incomplete. One of the better characterized genes responsible for hereditary haemochromatosis is HFE which codes for a protein that participates in the regulation of iron absorption. HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 The HFE gene has two common alleles, C282Y and H63D. HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 [27] Heterozygotes for either allele do not manifest clinical iron accumulation. Mutations of the HFE gene account for 90% of the cases of non-transfusional iron overload. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance This gene is closely linked to the HLA-A3 locus. Genetic linkage occurs when particular genetic loci or Alleles for genes are inherited jointly The human leukocyte antigen system ( HLA) is the name of the Major histocompatibility complex (MHC in humans In the fields of Genetics and Evolutionary computation, a locus (plural loci) is a fixed position on a Chromosome such as the position of a Homozygosity for the C282Y mutation is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, results in clinically evident iron overload. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous There is considerable debate regarding the penetrance -- the probability of clinical expression of the trait given the genotype -- is for clinical disease in HHC homozygotes. Penetrance is a term used in Genetics describing the proportion of individuals carrying a particular variation of a Gene (an Allele or genotype that also Most, if not all, males homozygous for HFE C282Y will show manifestations of liver dysfunction such as elevated liver-specific enzymes such as serum gamma glutamyltransferase (GGT) by late middle age. Homozygous females are delay the onset of iron accummulation because of iron loss through menstruation. Each patient with the susceptible genotype accummulates iron at different rates depending on iron intake, the exact nature of the mutation and the presence of other insults to the liver such as alcohol and viral disease. As such the degree to which the liver and other organs is affected, expressivity, is highly variable and is dependent on such these other factors and co-morbidities as well as age at which they are studied for manifestations of disease. [26] Penetrance differs between different populations.

Other genes whose mutations have been associated with iron overload include the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). These mutations, and the iron overload they cause, are much rarer than HFE-haemochromatosis.

Recently, a classification has been developed (with chromosome locations):

Description OMIM Mutation Locus
Haemochromatosis type 1: "classical"-haemochromatosis 235200 HFE 6p21. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them In the fields of Genetics and Evolutionary computation, a locus (plural loci) is a fixed position on a Chromosome such as the position of a HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 3
Haemochromatosis type 2A: juvenile haemochromatosis 602390 hemojuvelin ("HJV", also known as HFE2) 1q21
Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B 19q13
Haemochromatosis type 3 604720 transferrin receptor-2 (TFR2 or HFE3) 7q22
Haemochromatosis type 4 autosomal dominant haemochromatosis (all others are recessive), gene mutation 604653 ferroportin (SLC11A3) 2q32

Pathophysiology

The normal distribution of body iron stores
The normal distribution of body iron stores

Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available as of May, 2007. Hemojuvelin (HJV/HFE2/RGMc is a membrane-bound and soluble protein that is responsible for the iron overload condition known as Juvenile hemochromatosis, a severe form of Transferrin receptor (TfR is a Carrier protein for Transferrin. Ferroportin is a Transmembrane protein that transports Iron from the inside of a cell to the outside of it Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 For example, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 The genotype is the genetic constitution of a cell an organism or an individual (i A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations. Hepcidin is a recently discovered Peptide hormone produced by the Liver, that appears to be the master regulator of iron homeostasis in humans and [28]

People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Thus the iron stores of the body increase. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 As they increase the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress. Ferritin is a Globular protein complex consisting of 24 protein subunits and is the main intracellular iron storage protein in both Prokaryotes Hemosiderin or haemosiderin is an abnormal Microscopic Pigment found in the Human body Toxicity is the degree to which a substance is able to damage an exposed organism Tissue is a cellular organizational level intermediate between cells and a complete organism Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily [29]. Iron is a pro-oxidant. Pro-oxidants are chemicals that induce Oxidative stress, either through creating Reactive oxygen species or inhibiting Antioxidant systems Thus, haemochromatosis shares common symptomology (e. g. , cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. Wilson's disease or hepatolenticular degeneration is an Autosomal recessive Genetic disorder in which Copper accumulates in tissues Manganism or manganese Poisoning is a Toxic condition resulting from chronic exposure to Manganese and first identified in 1837 by James The latter also experience "bronzing".

Intestinal crypt enterocytes and iron overload

The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus. In Biology the small Intestine is the part of the Gastrointestinal tract (gut between the Stomach and the Large intestine, and comprises Enterocytes, or intestinal absorptive cells, are Simple columnar Epithelial cells found in the Small intestines and Colon. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron. Enterocytes, or intestinal absorptive cells, are Simple columnar Epithelial cells found in the Small intestines and Colon. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 Depending on this information, the enterocyte cell can regulate the quantity of iron receptors and channel proteins. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling If there is little iron, the enterocyte cell will express many of these proteins. Iron (ˈаɪɚn is a Chemical element with the symbol Fe (ferrum and Atomic number 26 If there is a lot, the cell will turn off the expression of iron transporters. In haemochromatosis, a mutation in the HFE gene leads to a lack of the basolateral transporter that endocytoses iron from the plasma into the epithelial cell. As a consequence of being unable to detect serum iron concentrations, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption. These iron transport proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, the only known cellular iron exporter, for the basal side of the cell. DMT1 ("divalent metal transporter 1" is a transporter involved in Human iron metabolism. Ferroportin is a Transmembrane protein that transports Iron from the inside of a cell to the outside of it

Hepcidin-ferroportin axis and iron overload

Recently, a new unifying theory for the pathogenesis of hereditary haemochromatosis has been proposed that focuses on the hepcidin-ferroportin regulatory axis. Hepcidin is a recently discovered Peptide hormone produced by the Liver, that appears to be the master regulator of iron homeostasis in humans and Inappropriately low levels of hepcidin, the iron regulatory hormone, can account for the clinical phenotype of iron overload. Hepcidin is a recently discovered Peptide hormone produced by the Liver, that appears to be the master regulator of iron homeostasis in humans and A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties In this theory, low levels of circulating hepcidin result in higher levels of ferroportin expression in intestinal enterocytes and reticuloendothelial macrophages. Hepcidin is a recently discovered Peptide hormone produced by the Liver, that appears to be the master regulator of iron homeostasis in humans and Ferroportin is a Transmembrane protein that transports Iron from the inside of a cell to the outside of it In Anatomy, the intestine is the segment of the alimentary canal extending from the Stomach to the Anus and in humans and other mammals consists Enterocytes, or intestinal absorptive cells, are Simple columnar Epithelial cells found in the Small intestines and Colon. As a result, this causes iron accumulation. HFE, hemojuvelin, BMP's and TFR2 are implicated in regulating hepcidin expression. HFE gene ( Hemochromatosis) is a Gene located on short arm of Chromosome 6 at location 6p21 Hemojuvelin (HJV/HFE2/RGMc is a membrane-bound and soluble protein that is responsible for the iron overload condition known as Juvenile hemochromatosis, a severe form of Hepcidin is a recently discovered Peptide hormone produced by the Liver, that appears to be the master regulator of iron homeostasis in humans and In particular, mutations in hemojuvelin (HJV), also called RGMc (Repulsive Guidance Molecule c), result in a severe form of iron overload that has a juvenile onset (by the second decade of life) called juvenile hemochromatosis (JH).

End-organ damage

Iron is stored in the liver, the pancreas and the heart. Long term effects of haemochromatosis on these organs can be very serious, even fatal when untreated. [30] For example, similar to alcoholism, haemochromatosis can cause cirrhosis of the liver. Alcoholism is a term with multiple and sometimes conflicting definitions Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative The liver is a vital organ in the human body and is present in Vertebrates and some other animals The liver is a primary storage area for iron and will naturally accumulate excess iron. Over time the liver is likely to be damaged by iron overload. Cirrhosis itself may lead to additional and more serious complications, including bleeding from dilated veins in the esophagus and stomach (varices) and severe fluid retention in the abdomen (ascites). The esophagus or oesophagus (see American and British English spelling differences) sometimes known as the gullet, is an organ in In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following In Vertebrates such as Mammals the abdomen (belly constitutes the part of the body between the Thorax (chest and Pelvis. In Medicine ( Gastroenterology) ascites (also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy). In Medicine, a coma (from the Greek koma, meaning deep sleep is a profound state of Unconsciousness. Encephalopathy /ɛnˌsɛfəˈlɒpəθi/ literally means Disease of the Brain.

Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. The liver is a vital organ in the human body and is present in Vertebrates and some other animals Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer. )

Diabetes: The pancreas which also stores iron is very important in the body’s mechanisms for sugar metabolism. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Diabetes affects the way the body uses blood sugar (glucose). Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease. Renal failure or kidney Cardiovascular disease or cardiovascular diseases refers to the class of diseases that involve the Heart or Blood vessels ( arteries and

Congestive heart failure: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur including death. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.

Heart arrhythmias: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life threatening. The heart is a muscular organ in all Vertebrates responsible for pumping Blood through the Blood vessels by repeated rhythmic Dysrhythmia redirects here For the American band see Dysrhythmia (band. This condition can often be reversed with treatment for haemochromatosis.

Pigment changes: Deposits of iron in skin cells can turn skin a bronze or gray color. For the drug referred to as "pigment" see Black tar heroin.

Treatment

Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations. In medicine venipuncture or venepuncture (also known as phlebotomy, venesection, blood draw, drawing blood or taking blood [31] Treatment is initiated when ferritin levels reach 300 milligrams per litre (or 200 in nonpregnant premenopausal women). Ferritin is a Globular protein complex consisting of 24 protein subunits and is the main intracellular iron storage protein in both Prokaryotes Menopause is the permanent shutting down of the female Reproductive system, a considerable length of time before the end of the lifespan

Every bag of blood (450-500 ml) contains 200-250 milligrams of iron. The litre or liter (see spelling differences) is a unit of Volume. For other uses of the words gram or gramme see Gram (disambiguation. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 20 milligrams per litre. Bloodletting (or blood-letting, in modern medicine referred to as phlebotomy) was a tremendously popular medical practice from antiquity up to the late Ferritin is a Globular protein complex consisting of 24 protein subunits and is the main intracellular iron storage protein in both Prokaryotes After that, 1-4 donations per year are usually needed to maintain iron balance.

Other parts of the treatment include:

References

  1. ^ The interaction of iron and erythropoietin.
  2. ^ Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
  3. ^ Celtic Curse.
  4. ^ Trousseau A (1865). "Glycosurie, diabète sucré". Clinique médicale de l'Hôtel-Dieu de Paris 2: 663–98.  
  5. ^ von Recklinghausen FD (1890). "Hämochromatose". Tageblatt der Naturforschenden Versammlung 1889: 324.  
  6. ^ Biography of Daniel von Recklinghausen
  7. ^ Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U. S. Department of Health and Human Services
  8. ^ Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
  9. ^ Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U. S. Department of Health and Human Services
  10. ^ Hemochromatosis-Signs and Symptoms Mayo Foundation for Medical Education and Research (MFMER)
  11. ^ a b Jones H, Hedley-Whyte E (1983). "Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs". Neurology 33 (11): 1479-83. PMID 6685241.  
  12. ^ Costello D, Walsh S, Harrington H, Walsh C (2004). "Concurrent hereditary haemochromatosis and idiopathic Parkinson's disease: a case report series". J Neurol Neurosurg Psychiatry 75 (4): 631-3. PMID 15026513.  
  13. ^ Nielsen J, Jensen L, Krabbe K (1995). "Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome". J Neurol Neurosurg Psychiatry 59 (3): 318-21. PMID 7673967.  
  14. ^ Screening and Diagnosis
  15. ^ Tanner MA, He T, Westwood MA, Firmin DN, Pennell DJ (2006). "Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron". Haematologica 91 (10): 1388-91. PMID 17018390.  
  16. ^ Transferrin and Iron Transport Physiology
  17. ^ Screening and Diagnosis
  18. ^ Screening and Diagnosis
  19. ^ Ferritin Test Measuring iron in the body
  20. ^ Screening and diagnosis Mayo Foundation for Medical Education and Research (MFMER) Retrieved 18 March, 2007
  21. ^ Screening and Diagnosis Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007
  22. ^ [http://www.annals.org/cgi/content/full/143/7/I-46 Screening for Hereditary Hemochromatosis: Recommendations from the American College of Physicians Annals of Internal Medicine (2005) 4 October, Volume 143 Issue 7. (Page I-46). American College of Physicians. Retrieved 18 March, 2007
  23. ^ "Screening for haemochromatosis: recommendation statement" (2006). Ann. Intern. Med. 145 (3): 204-8. PMID 16880462.  
  24. ^ Screening for Hemochromatosis U. S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007
  25. ^ Gordeuk V, Caleffi A, Corradini E, Ferrara F, Jones R, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo I, Gomo Z, Moyo V, Rouault T, MacPhail P, Pietrangelo A (2003). "Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene". Blood Cells Mol Dis 31 (3): 299-304. PMID 14636642.  
  26. ^ a b Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L (1999). "A population-based study of the clinical expression of the hemochromatosis gene". N Engl J Med 341 (10): 718-24. PMID 10471457.  
  27. ^ Hemochromatosis-Causes Mayo Foundation for Medical Education and Research (MFMER) Retrieved March 12, 2007
  28. ^ Vujić Spasić M, Kiss J, Herrmann T, et al (2008). "Hfe acts in hepatocytes to prevent hemochromatosis". Cell Metab. 7 (2): 173–8. doi:10.1016/j.cmet.2007.11.014. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 18249176.  
  29. ^ Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D (2007). "Oxidative stress in asymptomatic subjects with hereditary hemochromatosis". Am J Hematol 82 (3): 249-50. PMID 16955456.  
  30. ^ Haemochromatosis Complications
  31. ^ Hemochromatosis - Treatment

See also

External links

Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative
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