Haemochromatosis

Haemochromatosis

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Haemochromatosis type 1 (also HFE hereditary haemochromatosis or HFE-related hereditary haemochromatosis) is a hereditary disease characterized by excessive intestinal absorption of dietary iron
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...

 resulting in a pathological increase in total body iron stores. Human
Human
Humans are the only living species in the Homo genus...

s, like most animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...

s, have no means to excrete excess iron. Excess iron accumulates in tissues and organs disrupting their normal function. The most susceptible organs include 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...

, adrenal glands, 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...

, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

, gonads, joints, and the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

; patients can present with 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...

, polyarthropathy, adrenal insufficiency, heart failure or diabetes. The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of Celtic descent.

Pathophysiology


Since the regulation 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...

 metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene
HFE gene
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.The HFE gene is located on short arm of chromosome 6 at location...

, where a mutation puts the intestinal absorption of iron into overdrive. Normally, HFE facilitates the binding of 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...

, which is iron's carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

 stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, 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
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...

 in the liver, a function that is impaired in HFE mutations.

People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus the iron stores of the body increase. As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

, probably at least partially by inducing oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

. Iron is a pro-oxidant
Pro-oxidant
Pro-oxidants are chemicals that induce oxidative stress, through either creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues...

. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease
Wilson's disease
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease...

, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".

Terminology


The term "haemochromatosis" is used by many different sources in many different ways.

It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, it is now known that there are many different genetic associations with this condition. The older the text, or the more general the audience, the more likely that HFE is implied.

The term "haemochromatosis" has also been in contexts where there had not been a known genetic association for the iron accumulation. However, it should be noted that in some cases, the understanding of a condition that was considered due to behaviour can be refined to accommodate new known genetic associations, as in 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:...

.

History


The disease was first described in 1865 by Armand Trousseau
Armand Trousseau
Armand Trousseau was a French internist. His contributions to medicine include Trousseau sign of malignancy, Trousseau sign of latent tetany, Trousseau-Lallemand bodies , and the truism, "use new drugs quickly, while they still work."-Biography:A native of Tours, Indre-et-Loire, Armand Trousseau...

 in a report on diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

 in patients presenting with a bronze pigmentation of their skin. Trousseau did not associate diabetes with 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...

 accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen was a German pathologist who practiced medicine in Würzburg and Strassburg . Born in Gütersloh, Westphalia, he was the father of physiologist Heinrich von Recklinghausen ....

 in 1890.

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 most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity.

The classic triad of cirrhosis, bronze skin and diabetes is not as common anymore because of earlier diagnosis.

The more common clinical manifestations include:
  • Fatigue
  • Malaise
    Malaise
    Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...

  • Joint and bone pain
    Pain
    Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

  • Liver cirrhosis (with an increased risk of hepatocellular carcinoma
    Hepatocellular carcinoma
    Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...

    ) Liver disease is always preceded by evidence of liver dysfunction including elevated serum enzymes specific to the liver. Presence of Cirrhosis can also be discovered by the victim suffering from jaundice
    Jaundice
    Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

     (yellowing of the skin).
  • Insulin resistance
    Insulin resistance
    Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

     (often patients have already been diagnosed with diabetes mellitus type 2
    Diabetes mellitus type 2
    Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

    ) due to pancreatic damage from 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...

     deposition
  • Erectile dysfunction
    Erectile dysfunction
    Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

     and hypogonadism
    Hypogonadism
    Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...

    , resulting in decreased libido
    Libido
    Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...

  • Congestive heart failure, arrhythmias or pericarditis
    Pericarditis
    Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

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

     of the hands (especially the second and third MCP joint
    Metacarpophalangeal joint
    The metacarpophalangeal joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cavities on the proximal ends of the first phalanges, with the exception of that of the thumb, which presents more of the characters of a ginglymoid joint...

    s), but also the knee and shoulder joint
    Joint
    A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...

    s
  • Damage to the adrenal gland
    Adrenal gland
    In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...

    , leading to adrenal insufficiency
    Adrenal insufficiency
    Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...



Less common findings including:
  • Deafness
  • Dyskinesia
    Dyskinesia
    Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

    s, including Parkinsonian symptoms
  • Dysfunction of certain endocrine organs:
    • Parathyroid gland
      Parathyroid gland
      The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...

       (leading to hypocalcaemia
      Hypocalcaemia
      In medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...

      )
    • Pituitary gland
      Pituitary gland
      In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

  • More commonly a slate-grey or less commonly darkish colour to the skin (see pigmentation, hence its name Diabetes bronze when it was first described by Armand Trousseau in 1865)
  • An increased susceptibility to certain infectious disease
    Infectious disease
    Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

    s caused by siderophilic microorganisms
    Siderophilic bacteria
    Siderophilic bacteria are bacteria that require or are facilitated by free iron. They may include Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolica, Salmonella enterica , Klebsiella pneumoniae and Escherichia coli...

    :
    • Vibrio vulnificus
      Vibrio vulnificus
      Vibrio vulnificus is a species of Gram-negative, motile, curved, rod-shaped bacteria of the Vibrio Genus. It was first reported by Hollis et al. in 1976. It was subsequently given the name Beneckea vulnifica by Reichelt et al. in 1976 , and finally Vibrio vulnificus by Farmer in 1979...

      infections from eating seafood
      Seafood
      Seafood is any form of marine life regarded as food by humans. Seafoods include fish, molluscs , crustaceans , echinoderms . Edible sea plants, such as some seaweeds and microalgae, are also seafood, and are widely eaten around the world, especially in Asia...

       or wound infection
    • Listeria monocytogenes
    • Yersinia enterocolica
    • Salmonella enterica
      Salmonella enterica
      Salmonella enterica is a rod-shaped flagellated, facultative anaerobic, Gram-negative bacterium, and a member of the genus Salmonella.- Epidemiology :...

      (serotype Typhymurium)
    • Klebsiella pneumoniae
      Klebsiella pneumoniae
      Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose fermenting, facultative anaerobic, rod shaped bacterium found in the normal flora of the mouth, skin, and intestines....

    • Escherichia coli
    • Rhizopus arrhizus
      Rhizopus arrhizus
      Rhizopus arrhizus is a fungus of the family Mucoraceae, characterized by sporangiophores that arise from nodes at the point where the rhizoids are formed and by a hemispherical columella...

    • Mucor species


Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...

 (which ceases in menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...

). 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 elevation of the transferrin saturation. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.

Blood tests


Serum transferrin and transferrin saturation
Transferrin saturation
Transferrin saturation, abbreviated as TSAT and measured as a percentage, is a medical laboratory value. It is the ratio of serum iron and total iron-binding capacity, multiplied by 100. Of the transferrin that is available to bind iron, this value tells a clinician how much serum iron is actually...

 are commonly used as screening for haemochromatosis. 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...

 binds iron and is responsible for iron transport in the blood. Measuring transferrin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45% (or 35% in premenopausal women) are recognized as a threshold for further evaluation of haemochromatosis. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene
HFE gene
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.The HFE gene is located on short arm of chromosome 6 at location...

.

Serum Ferritin: Ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

, a protein synthesized by the liver is the primary form of iron storage within cells and tissues. Measuring ferritin provides another crude estimate of whole body iron stores though many conditions, particularly inflammation (but also chronic alcohol consumption, non-alcoholic fatty liver disease and others), can elevate serum ferritin - which can account for up to 90% of cases where elevated levels are observed. Normal values for males are 12–300 ng/ml (nanograms per millilitre) and for female, 12–150 ng/ml. Serum ferritin in excess of 1000 nanograms per millilitre of blood is almost always attributable to haemochromatosis.

Other blood tests routinely performed: blood count
Blood Count
"Blood Count" is a 1967 jazz composition by Billy Strayhorn. It was originally meant for a three-piece work Strayhorn was writing for Duke Ellington and initially titled "Blue Cloud". However, Strayhorn was hospitalized in 1967 due to cancer and finished the composition while in the hospital. He...

, renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...

, liver enzymes, electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....

s, glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 (and/or an oral glucose tolerance test (OGTT)).

Liver biopsy



Liver biopsies
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:...

 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
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...

, measured microscopically. 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.

MRI


FerriScan http://www.ferriscan.com/ is a MRI-based test to non-invasively and accurately measure liver iron concentrations. It is safer and generally cheaper to perform than liver biopsy; does not suffer from problems with sampling variability; and can be used more frequently than performing liver biopsies. FerriScan has regulatory approval in the USA, Canada, Europe and Australasia. A FerriScan takes about 10 minutes to perform and doesn't require any contrast agents. It can be quickly and easily established on most 1.5 T MRI scanners.

Other Imaging


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 in MRI scans
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

. Haemochromatosis arthropathy
Arthropathy
-Scope: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.Spondylarthropathy is any form of arthropathy of the vertebral column....

 includes degenerative osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

 and chondrocalcinosis. The distribution of the arthropathy
Arthropathy
-Scope: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.Spondylarthropathy is any form of arthropathy of the vertebral column....

 is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand. The arthropathy
Arthropathy
-Scope: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.Spondylarthropathy is any form of arthropathy of the vertebral column....

 can therefore be an early clue as to the diagnosis of haemochromatosis.

Functional testing


Based on the history, the doctor
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...

 might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.

Differential diagnosis


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

    , formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa
    Southern Africa
    Southern Africa is the southernmost region of the African continent, variably defined by geography or geopolitics. Within the region are numerous territories, including the Republic of South Africa ; nowadays, the simpler term South Africa is generally reserved for the country in English.-UN...

    . Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer
    Beer
    Beer is the world's most widely consumed andprobably oldest alcoholic beverage; it is the third most popular drink overall, after water and tea. It is produced by the brewing and fermentation of sugars, mainly derived from malted cereal grains, most commonly malted barley and malted wheat...

    . Further investigation has shown that only some people drinking this sort of beer get an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer
    Beer
    Beer is the world's most widely consumed andprobably oldest alcoholic beverage; it is the third most popular drink overall, after water and tea. It is produced by the brewing and fermentation of sugars, mainly derived from malted cereal grains, most commonly malted barley and malted wheat...

     (e.g., African Americans). This led investigators to the discovery of a gene polymorphism
    Polymorphism (biology)
    Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...

     in the gene for 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...

     which predisposes some people of African descent to iron overload.
  • Transfusion haemosiderosis
    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 ....

    is the accumulation of iron, mainly in 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...

    , in patients who receive 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 (such as those with thalassaemia
    Thalassemia
    Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...

    ).
  • Dyserythropoeisis, also known as 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....

    , is a disorder in the production of red blood cells. This leads to increased iron recycling from 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...

     and accumulation in the liver.

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. For example, similar to alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...

, haemochromatosis can cause 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
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...

. 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
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...

 (esophageal varices
Esophageal varices
In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...

) and stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 (gastric varices
Gastric varices
Gastric varices are dilated submucosal veins in the stomach, which can be a life-threatening cause of upper gastrointestinal hemorrhage. They are most commonly found in patients with portal hypertension, or elevated pressure in the portal vein system, which may be a complication of cirrhosis...

) and severe fluid retention in the abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...

 (ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...

). Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

 (hepatic encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

).

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...

 cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)

Diabetes: The pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

 which also stores iron is very important in the body’s mechanisms for sugar metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

. Diabetes affects the way the body uses blood sugar (glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

). Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

.

Congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur including death. The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.

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...

 arrhythmias
: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life threatening. This condition can often be reversed with treatment for haemochromatosis.

Pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...

 changes
: Bronze or grey coloration of the skin is caused primarily by increased melanin deposition, with iron deposition playing a lesser role.

Phlebotomy


Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies
Venipuncture
In medicine, venepuncture, venopuncture or venipuncture is the process of obtaining intravenous access for the purpose of intravenous therapy or for blood sampling of venous blood. This procedure is performed by medical laboratory scientists, medical practitioners, some EMTs, paramedics,...

 (by venesection) comparable in volume to blood donation
Blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....

s. Treatment is initiated when ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

 levels reach 300 milligrams per litre (or 200 in nonpregnant premenopausal women).

Every bag of blood (450–500 ml) contains 200–250 milligrams of iron. Phlebotomy (or 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...

) is usually done at a weekly interval until ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

 levels are less than 20 milligrams per litre. After that, 1–6 donations per year are usually needed to maintain iron balance.

Desferrioxamine mesilate


Where venesection is not possible, long-term administration of desferrioxamine mesilate is useful. Desferrioxamine is an iron-chelating compound, and excretion induced by desferrioxamine is enhanced by administration of Vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.

Treatment of organ damage

  • Treatment of organ damage (heart failure with diuretic
    Diuretic
    A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...

    s and ACE inhibitor
    ACE inhibitor
    ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...

     therapy).

Diet

  • Limiting intake of alcoholic beverage
    Alcoholic beverage
    An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...

    s, vitamin C
    Vitamin C
    Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

     (increases iron absorption in the gut), red meat
    Meat
    Meat is animal flesh that is used as food. Most often, this means the skeletal muscle and associated fat and other tissues, but it may also describe other edible tissues such as organs and offal...

     (high in 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...

    ) and potential causes of food poisoning (shellfish
    Shellfish
    Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...

    , seafood
    Seafood
    Seafood is any form of marine life regarded as food by humans. Seafoods include fish, molluscs , crustaceans , echinoderms . Edible sea plants, such as some seaweeds and microalgae, are also seafood, and are widely eaten around the world, especially in Asia...

    ).
  • Increasing intake of substances that inhibit iron absorption, such as high-tannin
    Tannin
    A tannin is an astringent, bitter plant polyphenolic compound that binds to and precipitates proteins and various other organic compounds including amino acids and alkaloids.The term tannin refers to the use of...

     tea
    Tea
    Tea is an aromatic beverage prepared by adding cured leaves of the Camellia sinensis plant to hot water. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world...

    , calcium
    Calcium
    Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

    , and foods containing oxalic
    Oxalic acid
    Oxalic acid is an organic compound with the formula H2C2O4. This colourless solid is a dicarboxylic acid. In terms of acid strength, it is about 3,000 times stronger than acetic acid. Oxalic acid is a reducing agent and its conjugate base, known as oxalate , is a chelating agent for metal cations...

     and phytic acid
    Phytic acid
    Phytic acid is the principal storage form of phosphorus in many plant tissues, especially bran and seeds. Phytate is not digestible to humans or nonruminant animals, however, so it is not a source of either inositol or phosphate if eaten directly...

    s (such as collard greens
    Collard greens
    Collard greens are various loose-leafed cultivars of Brassica oleracea , the same species as cabbage and broccoli. The plant is grown for its large, dark-colored, edible leaves and as a garden ornamental, mainly in Brazil, Portugal, the southern United States, many parts of Africa, Montenegro,...

    , which must be consumed at the same time as the iron-containing foods in order to be effective).

Screening


Standard diagnostic measures for haemochromatosis, transferrin saturation
Transferrin saturation
Transferrin saturation, abbreviated as TSAT and measured as a percentage, is a medical laboratory value. It is the ratio of serum iron and total iron-binding capacity, multiplied by 100. Of the transferrin that is available to bind iron, this value tells a clinician how much serum iron is actually...

 and ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

 tests, are not a part of routine medical testing. Screening
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....

 for haemochromatosis is recommended if the patient has a parent, child or sibling with the disease.

Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force
U.S. Preventive Services Task Force
The U.S. Preventive Services Task Force is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services." The task force, a panel of primary care physicians and...

 (USPSTF), among other groups. The USPSTF recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than 1 in 1,000. Although there is strong evidence that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy
Phlebotomy
Phlebotomy is the process of making an incision in a vein.It is associated with the following concepts:* Venipuncture, the practice of collecting venous blood samples* The main practice of a phlebotomist, an individual trained to draw blood...

) provides any clinical benefit. 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.

Epidemiology


Haemochromatosis is one of the most common heritable genetic conditions in people of northern European extraction with a prevalence of 1 in 200. The disease has a variable penetration and about 1 in 10 people of this demographic carry a mutation in one of the genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

 regulating 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...

 metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

, the most common allele being the C282Y allele in the HFE gene. The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 of mutations in iron metabolism genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

 varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% 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). Other populations have a lower prevalence of both the genetic mutation and the clinical disease.

Genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 studies suggest the original haemochromatosis mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

 arose in a single person, possibly of Celt
Celt
The Celts were a diverse group of tribal societies in Iron Age and Roman-era Europe who spoke Celtic languages.The earliest archaeological culture commonly accepted as Celtic, or rather Proto-Celtic, was the central European Hallstatt culture , named for the rich grave finds in Hallstatt, Austria....

ic ethnicity, who lived 60–70 generations ago. At that time when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...

 or natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....

 reproductive advantage by maintaining higher 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...

 levels in the blood.

Genetics


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
HFE gene
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.The HFE gene is located on short arm of chromosome 6 at location...

 on chromosome 6 which codes for a protein that participates in the regulation of iron absorption. The HFE gene
HFE gene
Human hemochromatosis protein also known as the HFE protein is a protein which in humans is encoded by the HFE gene.The HFE gene is located on short arm of chromosome 6 at location...

 has two common alleles, C282Y and H63D. The C282Y allele is a transition
Transition (genetics)
In genetics, a transition is a point mutation that changes a purine nucleotide to another purine or a pyrimidine nucleotide to another pyrimidine . Approximately two out of three single nucleotide polymorphisms are transitions....

 point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

 from guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...

 to adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...

 at nucleotide 845 in the HFE gene, resulting in a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...

 that replaces the cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 residue at position 282 with a tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 amino acid. Heterozygotes for either allele do not manifest clinical iron overload but may display an increased iron uptake. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s of the HFE gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 account for 90% of the cases of non-transfusional iron overload. This gene is closely linked
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...

 to the HLA-A3
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...

 locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

. Homozygosity for the C282Y mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

 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. There is considerable debate regarding the penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...

—the probability of clinical expression of the trait given the genotype—is for clinical disease in HHC homozygotes. 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 can delay the onset of iron accumulation because of iron loss through menstruation. Each patient with the susceptible genotype accumulates 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. Penetrance differs between different populations.

External links