iron overload iron overload iron overload or haemochromatosis (also spelled hemochromatosis in american english) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. the most important causes are hereditary haemochromatosis (hh or hhc), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions. iron overloadother nameshaemochromatosis or hemochromatosismicrograph of liver biopsy showing iron deposits due to haemosiderosis. iron stain.specialtyhematology signs and symptoms organs most commonly affected by hemochromatosis include the liver, heart, and endocrine glands. hemochromatosis may present with the following clinical syndromes: liver: chronic liver disease and cirrhosis of the liver. heart: heart failure, cardiac arrhythmia. hormones: diabetes (see below) and hypogonadism (insufficiency of the sex hormone producing glands) which leads to low sex drive and/or loss of fertility in men and loss of fertility and menstrual cycle in women. metabolism: diabetes in people with iron overload occurs as a result of selective iron deposition in islet beta cells in the pancreas leading to functional failure and cell death. skeletal: arthritis, from iron deposition in joints leading to joint pains. the most commonly affected joints are those of the hands, particularly the knuckles or metacarpophalangeal joints, wrists or radiocarpal joints, elbow, hip, knee and ankle joints. risk factors for the development of arthritis in those with hemochromatosis include elevated iron levels (ferritin greater than 1000 or transferrin saturation greater than 50%) for an extended period of time, increasing age and concurrent advanced liver fibrosis. skin: melanoderma (darkening or 'bronzing' of the skin). hemochromatosis leading to secondary diabetes (through iron deposition in the insulin secreting beta cells of the pancreas), when combined with a bronzing or darkening of the skin, is sometimes known as "bronze diabetes". 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. mutations of the hfe gene (hemostatic iron regulator) located on chromosome 6 (responsible for iron regulatory protein hepcidin production) are responsible for most cases of hereditary hemochromatosis; 95% of cases of hereditary hemochromatosis involve a mutation of this hfe gene. non-hfe hereditary hemochromatosis involves mutations in genes coding for the iron regulatory proteins hemojuvelin, transferrin receptor-2 and ferroportin. 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 in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation. because of the severe sequelae 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 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. sometimes, the simpler term siderosis 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 northern european descent, including celtic (irish, scottish, welsh, cornish, breton etc.), english, and scandinavian 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. 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". descriptionomimmutation hemochromatosis type 1: "classical" hemochromatosis 235200hfe hemochromatosis type 2a: juvenile hemochromatosis 602390haemojuvelin (hjv, also known as rgmc and hfe2) hemochromatosis type 2b: juvenile hemochromatosis 606464hepcidin antimicrobial peptide (hamp) or hfe2b hemochromatosis type 3 604250transferrin receptor-2 (tfr2 or hfe3) hemochromatosis type 4 / african iron overload 604653ferroportin (slc11a3/slc40a1) neonatal hemochromatosis 231100(unknown) acaeruloplasminaemia (very rare) 604290caeruloplasmin congenital atransferrinaemia (very rare) 209300transferrin gracile syndrome (very rare) 603358bcs1l most types of hereditary hemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance. secondary hemochromatosis severe chronic hemolysis of any cause, including intravascular hemolysis and ineffective erythropoiesis (hemolysis within the bone marrow) multiple frequent blood transfusions (either whole blood or just red blood cells), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major, sickle cell anaemia, and diamond–blackfan anaemia) or by older patients with severe acquired anaemias such as in myelodysplastic syndromes. excess parenteral (non-ingested) iron supplements, such as what can acutely happen in iron poisoning 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 (especially related to alcohol use disorder), steatohepatitis of any cause, porphyria cutanea tarda, prolonged hemodialysis, and post-portacaval shunting pathophysiology defects in iron metabolism, specifically involving the iron regulatory protein hepcidin are thought to play an integral role in the pathogenesis of hereditary hemochromatosis. normally, hepcidin acts to reduce iron levels in the body by inhibiting intestinal iron absorption and inhibiting iron mobilization from stores in the bone marrow and liver. iron is absorbed from the intestines (mostly in the duodenum) and transported across intestinal enterocytes or mobilized out of storage in liver hepatocytes or from macrophages in the bone marrow by the transmembrane ferroportin transporter. in response to elevated plasma iron levels, hepcidin inhibits the ferroportin transporter leading to decreased iron mobilization from stores and decreased intestinal iron absorption, thus functioning as a negative iron regulatory protein. in hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including hfe (hemostatic iron regulator), hemojuvelin and transferrin receptor 2 lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization, which thus leads to iron overload. in very rare instances, mutations in ferroportin result in ferroportin resistance to hepcidin's negative regulatory effects, and continued intestinal iron absorption and mobilization despite inhibitory signaling from hepcidin. approximately 95% of cases of hereditary hemochromatosis are due to mutations in the hfe gene. the resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which coupled with oxidative stress leads to organ damage or joint damage and the pathological findings seen in hemochromatosis. diagnosis selective iron deposition (blue) in pancreatic islet beta cells (red) there are several methods available for diagnosing and monitoring iron overload. blood test blood tests are usually the initial 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 ferritin levels may be elevated due to a variety of other causes including obesity, infection, inflammation (as an acute phase protein), chronic alcohol intake, liver disease, kidney disease, and cancer. in males and postmenopausal females, normal range of serum ferritin is between 12 and 300 ng/ml (670 pmol/l) . in premenopausal females, normal range of serum ferritin is between 12 and 150 or 200 ng/ml (330 or 440 pmol/l). in those with hemochromatosis, the serum ferritin level correlates with the degree of iron overload. ferritin levels are usually monitored serially in those with hemochromatosis to assess response to treatment. elevations in serum levels of the iron transporter protein transferrin saturation as well as increased red blood cell mean corpuscular volume and mean corpuscular hemoglobin concentration usually precede ferritin elevations in hemochromatosis. transferrin saturation of greater than 45% combined with an elevated ferritin level is highly sensitive in diagnosing hfe hemochromatosis. total iron binding capacity may be low in hemochromatosis, but can also be normal. genetics general screening for hemochromatosis is not recommended, however first-degree relatives of those affected should be screened. once iron overload has been established, hfe gene mutation genetic testing for hereditary causes of iron overload is indicated. the presence of hfe gene mutations in addition to iron overload confirms the clinical diagnosis of hereditary 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. biopsy histopathology of the liver, showing kupffer cells with significant hemosiderin deposition (shown next to a hepatocyte with lipofuscin pigment, which is a common normal finding). h&e stain. prussian blue iron staining, highlighting the hemosiderin pigment as blue. this finding indicates mesenchymal iron overload (within kupffer cells and/or portal macrophages) rather than parenchymal iron overload (within hepatocytes). liver biopsy 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. imaging magnetic resonance imaging (mri) is used as a noninvasive method to estimate iron deposition levels in the liver and heart, which may aid in determining a response to treatment or prognosis. liver elastography has limited utility in detecting liver fibrosis in hemochromatosis. treatment phlebotomy phlebotomy or venesection is the mainstay of treatment in iron overload, consisting of regularly scheduled blood draws to remove red blood cells (and iron) from the body. upon initial diagnosis of iron overload, the phlebotomies may be performed weekly or twice weekly, until iron levels are normalized. once the serum ferritin and transferrin saturation are within the normal range, maintenance phlebotomies may be needed in some (depending upon the rate of reabsorption of iron), scheduled at varying frequencies to keep iron stores within normal range. a phlebotomy session typically draws between 450 and 500 ml of blood. routine phlebotomy may reverse liver fibrosis and alleviate some symptoms of hemochromatosis, but chronic arthritis is usually not responsive to treatment. in those with hemochromatosis; the blood drawn during phlebotomy is safe to be donated. phlebotomy is associated with improved survival if it is initiated before the onset of cirrhosis or diabetes. diet the human diet contains iron in two forms: heme iron and non-heme iron. heme iron is usually found in red meat, whereas non-heme iron is found in plant based sources. heme iron is the most easily absorbed form of iron. in those with hemochromatosis undergoing phlebotomy for treatment; restriction of dietary iron is not required. however, those who do restrict dietary iron usually require less blood needing to be phlebotomized (about 0.5-1.5 liters of blood less per year). vitamin c and iron supplementation should be avoided as vitamin c accelerates intestinal absorption of iron and mobilization of body iron stores. raw seafood should be avoided because of increased risk of infections from iron loving pathogens such as vibrio vulnificus. alcohol consumption should be avoided due to the risk of compounded liver damage with iron overload. medication medication: for those unable to tolerate routine blood draws, there are chelating agents available for use. the drug deferoxamine 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 (and, thus, who develop iron overload as a result)