Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in
British English
British English (BrE, en-GB, or BE) is, according to Lexico, Oxford Dictionaries, "English language, English as used in Great Britain, as distinct from that used elsewhere". More narrowly, it can refer specifically to the English language in ...
) indicates increased total accumulation of
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
in the body from any cause and resulting organ damage.
The most important causes are
hereditary haemochromatosis
Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, h ...
(HH or HHC), a genetic disorder, and
transfusional iron overload, which can result from repeated
blood transfusions
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
.
Signs and symptoms
Organs most commonly affected by hemochromatosis include the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
,
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
, and
endocrine gland
Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid ...
s.
Hemochromatosis may present with the following clinical syndromes:
* liver:
chronic liver disease
Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease ...
and
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
of the liver.
* heart:
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
,
cardiac arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
.
* hormones: diabetes (see below) and
hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
(insufficiency of the sex hormone producing glands) which leads to low sex drive and/or loss of fertility in men and loss of menstrual cycle in women.
* metabolism:
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
in people with iron overload occurs as a result of selective iron deposition in islet
beta cells
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
in the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
leading to functional failure and cell death.
* skeletal:
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, from
calcium pyrophosphate
Calcium pyrophosphate (Ca2P2O7) is a chemical compound, an insoluble calcium salt containing the pyrophosphate anion. There are a number of forms reported: an anhydrous form, a dihydrate, Ca2P2O7·2H2O and a tetrahydrate, Ca2P2O7·4H2O. Deposition ...
deposition in joints leading to joint pains. The most commonly affected joints are those of the hands, particularly the
knuckle
The knuckles are the joints of the fingers. The word is cognate to similar words in other Germanic languages, such as the Dutch "knokkel" (knuckle) or German "Knöchel" (ankle), i.e., ''Knöchlein'', the diminutive of the German word for bone (' ...
s of the second and third fingers.
[ Literature review current through: Jun 2016. , This topic last updated: Apr 14, 2015.]
* skin: melanoderma (darkening or 'bronzing' of the skin).
The skin's deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: "bronze diabetes" (for more information, see
the history of hemochromatosis).
Causes
The term ''hemochromatosis'' was initially used to refer to what is now more specifically called
hemochromatosis type 1 (or
HFE-related hereditary hemochromatosis). Currently, hemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause, or originating from a metabolic disorder. However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, ''hereditary hemochromatosis''. Hereditary hemochromatosis is an autosomal recessive disorder with estimated prevalence in the population of 1 in 200 among patients with European ancestry, with lower incidence in other ethnic groups. The gene responsible for hereditary hemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary hemochromatosis patients have mutations in this HFE gene.
Hereditary hemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
in combination with
hypopituitarism
Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...
,
cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
,
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, or
hyperpigmentation
Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.
Causes
Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...
. Because of the severe
sequelae
A sequela (, ; usually used in the plural, sequelae ) is a pathological condition resulting from a disease, injury, therapy, or other trauma. Derived from the Latin word, meaning “sequel”, it is used in the medical field to mean a complication ...
of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.
In general, the term ''
hemosiderosis
Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.
Types include:
* Transfusion hemosiderosis
* Idiopathic pulmonary hemosiderosis
* Transfusional diabetes
Organs affected:
* Hemosiderin depositi ...
'' is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex
hemosiderin
Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin
Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives rise ...
. Sometimes, the simpler term
siderosis
Siderosis is the deposition of excess iron in body tissue. When used without qualification, it usually refers to an environmental disease of the lung, also known more specifically as pulmonary siderosis or Welder's disease, which is a form of pneu ...
is used instead.
Other definitions distinguishing hemochromatosis or hemosiderosis that are occasionally used include:
* Hemosiderosis is hemochromatosis caused by excessive blood transfusions, that is, hemosiderosis is a form of secondary hemochromatosis.
* Hemosiderosis is hemosiderin deposition within cells, while hemochromatosis is hemosiderin within cells and interstitium.
* Hemosiderosis is iron overload that does not cause tissue damage, while hemochromatosis does.
* Hemosiderosis is arbitrarily differentiated from hemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.
The causes of hemochromatosis broken down into two subcategories: ''primary cases'' (hereditary or genetically determined) and less frequent ''secondary cases'' (acquired during life).
People of
Celtic
Celtic, Celtics or Keltic may refer to:
Language and ethnicity
*pertaining to Celts, a collection of Indo-European peoples in Europe and Anatolia
**Celts (modern)
*Celtic languages
**Proto-Celtic language
* Celtic music
*Celtic nations
Sports Fo ...
(Irish, Scottish, Welsh, Cornish, Breton etc.),
English
English usually refers to:
* English language
* English people
English may also refer to:
Peoples, culture, and language
* ''English'', an adjective for something of, from, or related to England
** English national ide ...
, and
Scandinavia
Scandinavia; Sámi languages: /. ( ) is a subregion#Europe, subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, ...
n origin have a particularly high incidence, with about 10% being carriers of the principal genetic variant, the C282Y mutation on the
HFE gene, and 1% having the condition. This has been recognized in several layman's alternative names such as ''Celtic curse'', ''Irish illness'', ''British gene'', and ''Scottish sickness''.
The overwhelming majority depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary hemochromatosis",
"non-HFE related hereditary hemochromatosis",
or "non-HFE hemochromatosis".
Most types of hereditary hemochromatosis have
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance, while type 4 has
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance.
Secondary hemochromatosis
* Severe chronic
hemolysis
Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
of any cause, including intravascular hemolysis and
ineffective erythropoiesis Ineffective erythropoiesis is active erythropoiesis with premature death of red blood cells, a decreased output of red blood cells, RBCs from the bone marrow, and, consequently, anemia.
It is a condition characterised by the presence or abundance of ...
(hemolysis within the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
)
* Multiple frequent
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s (either whole blood or just
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s), which are usually needed either by individuals with hereditary
anaemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
s (such as
beta-thalassaemia major,
sickle cell anaemia
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
, and
Diamond–Blackfan anaemia) or by older patients with severe acquired anaemias such as in
myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
s.
* Excess parenteral (non-ingested) iron supplements, such as what can acutely happen in
iron poisoning
Iron poisoning typically occurs from ingestion of excess iron that results in acute toxicity. Mild symptoms which occur within hours include vomiting, diarrhea, abdominal pain, and drowsiness. In more severe cases, symptoms can include tachypnea, l ...
* Excess dietary iron
* Some disorders do not normally cause hemochromatosis on their own, but may do so in the presence of other predisposing factors. These include
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
(especially related to
alcohol use disorder
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomin ...
),
steatohepatitis
Steatohepatitis is a type of fatty liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver. Mere deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes.
...
of any cause,
porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fift ...
, prolonged
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
, and post-
portacaval shunt A portacaval shunt (or portal caval shunt) is a treatment for portal hypertension. A connection is made between the portal vein, which supplies 75% of the liver's blood, and the inferior vena cava, the vein that drains blood from the lower two-thi ...
ing
Diagnosis
There are several methods available for diagnosing and monitoring iron loading.
Blood test
Blood tests are usually the first test if there is a clinical suspicion of iron overload. Serum ferritin testing is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a variety of other medical conditions including infection, inflammation, fever, liver disease, kidney disease, and cancer. Also,
total iron binding capacity
Total iron-binding capacity (TIBC) or sometimes transferrin iron-binding capacity is a medical laboratory test that measures the blood's capacity to bind iron with transferrin. Transferrin can bind two atoms of ferric iron (Fe3+) with high affinity ...
may be low, but can also be normal. In males and
postmenopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
females, normal range of
serum ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
is between 12 and 300 ng/mL (670 pmol/L) .
[Ferritin](_blank)
by: Mark Levin, MD, Hematologist and Oncologist, Newark, NJ. Review provided by VeriMed Healthcare Network[ Updated: Jan 02, 2016]Molar concentration
Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solut ...
is derived from mass value using molar mass of 450,000 g•mol−1 for ferritin In premenopausal females, normal range of serum ferritin is between 12 and 150
or 200
ng/mL (330 or 440 pmol/L).
If the person is showing the symptoms, they may need to be tested more than once throughout their lives as a precaution, most commonly in women after menopause. Transferrin saturation is a more specific test.
Genetics
DNA/screening: the current standard of practice in diagnosis of hemochromatosis, places emphasis on genetic testing.
Positive HFE analysis confirms the clinical diagnosis of hemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of hemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with hemochromatosis; a negative report for HFE gene does not rule out hemochromatosis.
First degree relatives of those with primary hemochromatosis should be screened to determine if they are a carrier or if they could develop the disease. This can allow preventive measures to be taken. Screening the general population is not recommended.
Biopsy
Liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.
Medica ...
is the removal of small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of hemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of hemochromatosis.
Magnetic resonance imaging (MRI) is used as a noninvasive way to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland.
Treatment
Phlebotomy
Phlebotomy
Phlebotomy is the process of making a puncture in a vein, usually in the arm, with a cannula for the purpose of drawing blood. The procedure itself is known as a venipuncture, which is also used for intravenous therapy. A person who performs a p ...
/
venesection
In medicine, venipuncture or venepuncture is the process of obtaining intravenous access for the purpose of venous blood sampling (also called ''phlebotomy'') or intravenous therapy. In healthcare, this procedure is performed by medical labor ...
: routine treatment consists of regularly scheduled phlebotomies (
bloodletting
Bloodletting (or blood-letting) is the withdrawal of blood from a patient to prevent or cure illness and disease. Bloodletting, whether by a physician or by leeches, was based on an ancient system of medicine in which blood and other bodily flu ...
or
erythrocytapheresis
Erythrocytapheresis is an apheresis procedure by which erythrocytes (red blood cells) are separated from whole blood. It is an extracorporeal blood separation method whereby whole blood is extracted from a donor or patient, the red blood cells are ...
). When first diagnosed, the phlebotomies may be performed every week or fortnight, until iron levels can be brought to within normal range. Once the serum ferritin and transferrin saturation are within the normal range, treatments may be scheduled every two to three months depending upon the rate of reabsorption of iron. A phlebotomy session typically draws between 450 and 500 mL of blood. The blood drawn is sometimes
donated
A donation is a gift for charity, humanitarian aid, or to benefit a cause. A donation may take various forms, including money, alms, services, or goods such as clothing, toys, food, or vehicles. A donation may satisfy medical needs such as blo ...
.
Diet
A diet low in iron is generally recommended, but has little effect compared to venesection. The human diet contains iron in two forms:
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
iron and non-heme iron. Heme iron is the most easily absorbed form of iron. People with iron overload may be advised to avoid food that are high in heme iron. Highest in heme iron is red meat such as beef,
venison
Venison originally meant the meat of a game animal but now refers primarily to the meat of antlered ungulates such as elk or deer (or antelope in South Africa). Venison can be used to refer to any part of the animal, so long as it is edible, in ...
, lamb, buffalo, and fish such as
bluefin tuna Bluefin tuna is a common name used to refer to several species of tuna of the genus ''Thunnus
''Thunnus'' is a genus of ocean-dwelling, ray-finned bony fish from the mackerel family, Scombridae. More specifically, ''Thunnus'' is one of five ...
. A strict low-iron diet is usually not necessary. Non-heme iron is not as easily absorbed in the human system and is found in plant-based foods such as grains, beans, vegetables, fruits, nuts, and seeds.
Medication
Medication: For those unable to tolerate routine blood draws, there are
chelating
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...
agents available for use. The drug
deferoxamine
Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...
binds with iron in the bloodstream and enhances its elimination in urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily. Two newer
iron-chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat
thalassaemia
Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
(and, thus, who develop iron overload as a result) are
deferasirox
Deferasirox, sold under the brand name Exjade & Asunra (in injectable form) & Oleptiss (Tablet formulation) both by Novartis among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving l ...
and
deferiprone
Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and h ...
.
Chelating polymers
A minimally invasive approach to
hereditary hemochromatosis
Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, h ...
treatment is the
maintenance therapy with
polymeric chelators.
These polymers or particles have a negligible or null systemic
biological availability and they are designed to form stable complexes with Fe
2+ and Fe
3+ in the
GIT
Git () is a distributed version control system: tracking changes in any set of files, usually used for coordinating work among programmers collaboratively developing source code during software development. Its goals include speed, data in ...
and thus limiting their uptake and long-term accumulation. Although this method has only a limited efficacy, unlike
small-molecular chelators, the approach has virtually no side effects in sub-chronic studies.
Interestingly, the simultaneous chelation of Fe
2+ and Fe
3+ increases the treatment efficacy.
Prognosis
In general, provided there has been no liver damage, patients should expect a normal life expectancy if adequately treated by venesection. If the serum ferritin is greater than 1000 ug/L at diagnosis there is a risk of liver damage and cirrhosis which may eventually shorten their life. The presence of
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
increases the risk of
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
.
Epidemiology
HHC is most common in certain European populations (such as those of Irish or Scandinavian descent) and occurs in 0.6% of some unspecified population.
[ Men have a 24-fold increased rate of iron-overload disease compared with women.][
]
Stone Age
Diet and the environment are thought to have had large influence on the mutation of genes related to iron overload. Starting during the Mesolithic era
The Mesolithic (Greek: μέσος, ''mesos'' 'middle' + λίθος, ''lithos'' 'stone') or Middle Stone Age is the Old World archaeological period between the Upper Paleolithic and the Neolithic. The term Epipaleolithic is often used synonymous ...
, communities of people lived in an environment that was fairly sunny, warm and had the dry climates of the Middle East. Most humans who lived at that time were foragers and their diets consisted largely of game, fish and wild plants. Archaeologists studying dental plaque
Dental plaque is a biofilm of microorganisms (mostly bacteria, but also fungi) that grows on surfaces within the mouth. It is a sticky colorless deposit at first, but when it forms tartar, it is often brown or pale yellow. It is commonly found bet ...
have found evidence of tuber
Tubers are a type of enlarged structure used as storage organs for nutrients in some plants. They are used for the plant's perennation (survival of the winter or dry months), to provide energy and nutrients for regrowth during the next growing ...
s, nuts, plantains
Plantain may refer to:
Plants and fruits
* Cooking banana, banana cultivars in the genus ''Musa'' whose fruits are generally used in cooking
** True plantains, a group of cultivars of the genus ''Musa''
* ''Plantaginaceae'', a family of flowerin ...
, grasses and other foods rich in iron. Over many generations, the human body became well-adapted to a high level of iron content in the diet.
Neolithic
In the Neolithic era
The Neolithic period, or New Stone Age, is an Old World archaeological period and the final division of the Stone Age. It saw the Neolithic Revolution, a wide-ranging set of developments that appear to have arisen independently in several parts ...
, significant changes are thought to have occurred in both the environment and diet. Some communities of foragers migrated north, leading to changes in lifestyle and environment, with a decrease in temperatures and a change in the landscape which the foragers then needed to adapt to. As people began to develop and advance their tools, they learned new ways of producing food, and farming also slowly developed. These changes would have led to serious stress on the body and a decrease in the consumption of iron-rich foods. This transition is a key factor in the mutation of genes, especially those that regulated dietary iron absorption. Iron, which makes up 70% of red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
composition, is a critical micronutrient
Micronutrients are nutrient, essential dietary elements required by organisms in varying quantities throughout life to orchestrate a range of physiological functions to maintain health. Micronutrient requirements differ between organisms; for exam ...
for effective thermoregulation
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
in the body. Iron deficiency will lead to a drop in the core temperature. In the chilly and damp environments of Northern Europe, supplementary iron from food was necessary to keep temperatures regulated, however, without sufficient iron intake the human body would have started to store iron at higher rates than normal. In theory, the pressures caused by migrating north would have selected for a gene mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
that promoted greater absorption and storage of iron.
Viking hypothesis
Studies and surveys conducted to determine the frequencies of hemochromatosis help explain how the mutation migrated around the globe. In theory, the disease initially evolved from travelers migrating from the north. Surveys show a particular distribution pattern with large clusters and frequencies of gene mutations along the western European coastline. This led the development of the "Viking
Vikings ; non, víkingr is the modern name given to seafaring people originally from Scandinavia (present-day Denmark, Norway and Sweden),
who from the late 8th to the late 11th centuries raided, pirated, traded and se ...
Hypothesis". Cluster locations and mapped patterns of this mutation correlate closely to the locations of Viking settlements in Europe established c.700 AD to c.1100 AD. The Vikings originally came from Norway, Sweden and Denmark. Viking ships
Viking ships were marine vessels of unique structure, used in Scandinavia from the Viking Age throughout the Middle Ages.
The boat-types were quite varied, depending on what the ship was intended for, but they were generally characterized as bein ...
made their way along the coastline of Europe in search of trade, riches, and land. Genetic studies suggest that the extremely high frequency patterns in some European countries are the result of migrations of Vikings and later Normans
The Normans (Norman language, Norman: ''Normaunds''; french: Normands; la, Nortmanni/Normanni) were a population arising in the medieval Duchy of Normandy from the intermingling between Norsemen, Norse Viking settlers and indigenous West Fran ...
, indicating a genetic link between hereditary hemochromatosis and Viking ancestry.
Modern times
In 1865, Armand Trousseau
Armand Trousseau (14 October 1801 – 23 June 1867) was a French internist. His contributions to medicine include Trousseau sign of malignancy, Trousseau sign of latent tetany, Trousseau–Lallemand bodies (an archaic synonym for Bence Jones ...
(a French internist) was one of the first to describe many of the symptoms of a diabetic patient with cirrhosis of the liver and bronzed skin color. The term hemochromatosis was first used by German pathologist Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen (; December 2, 1833 – August 26, 1910) was a German pathologist born in Gütersloh, Westphalia. He was the father of physiologist Heinrich von Recklinghausen (1867–1942).
Early life
Recklinghausen was b ...
in 1889 when he described an accumulation of iron in body tissues.
Identification of genetic factors
Although it was known most of the 20th century that most cases of hemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.
In 1935 J.H. Sheldon, a British physician, described the link to iron metabolism for the first time as well as demonstrating its hereditary nature.
In 1996 Felder and colleagues identified the hemochromatosis gene, HFE gene. Felder found that the HFE gene has two main mutations, C282Y and H63D, which were the main cause of hereditary hemochromatosis. The next year the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the HFE gene, which helped lead to the population screenings and estimates that are still being used today.
See also
* Human iron metabolism
Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically imp ...
* Iron deficiency
Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...
References
External links
*
GeneReview/NCBI/NIH/UW entry on HFE-Associated Hereditary Hemochromatosis
GeneReview/NCBI/NIH/UW entry on TFR2-Related Hereditary Hemochromatosis
GeneReview/NCBI/NIH/UW entry on Juvenile Hereditary Hemochromatosis
GeneReview/NCBI/NIH/UW entry on Aceruloplasminemia
{{DEFAULTSORT:Iron Overload
Overload disorder
Abnormal clinical and laboratory findings for blood
Articles containing video clips
Iron metabolism