Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary (i.e., hereditary haemochromatosis, aceruloplasminemia) but may also be secondary to other causes (i.e., transfusional iron overload). Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints.
People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.
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. Literature review current through: Jun 2016. | This topic last updated: Apr 14, 2015. 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, 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 (HFE-related hereditary hemochromatosis or classical hereditary hemochromatosis). Currently, hemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause,thefreedictionary.com > hemochromatosis, citing: The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company McGraw-Hill Concise Dictionary of Modern Medicine. 2002Merriam-Webster's Medical Dictionary > hemochromatosis Retrieved on December 11, 2009 or originating from a metabolic disorder.thefreedictionary.com, citing: Dorland's Medical Dictionary for Health Consumers, 2007 Mosby's Medical Dictionary, 8th edition. 2009 Jonas: Mosby's Dictionary of Complementary and Alternative Medicine. 2005.
Primary hemochromatosis and hemosiderosis Hereditary hemochromatosis Hereditary hemochromatoses (HH or HHC) are genetic disorders. Hereditary hemochromatosis type 1 (HH type 1) is caused by mutations of HFE gene, mainly C282Y/C282Y mutation. This mutation is present in 1:200-300 of the Caucasian population in the United States and Northern Europe with lower incidence in other ethnic groups, but only 10-33% (clinical penetrance) of them will develop iron overload. Mutations of the HFE gene (homeostatic iron regulator) located on chromosome 6 (responsible for iron regulatory protein hepcidin regulation) are responsible for most cases of hereditary hemochromatosis; 80-90% of cases of hereditary hemochromatosis involve a mutation of this HFE gene; 90-95% in Northern Europe. Non-HFE hereditary hemochromatosis involves mutations in genes coding for the iron regulatory proteins hemojuvelin, transferrin receptor-2, ferroportin, and HAMP.
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 clinical presentation of hepatic cirrhosis, hypogonadism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation is uncommon in current patients. 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.
Hemosiderosis 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.Merriam-Webster's Medical Dictionary > hemosideroses Retrieved on December 11, 2009thefreedictionary.com > hemosiderosis, citing: The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company Mosby's Medical Dictionary, 8th edition. 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.eMedicine Specialties > Radiology > Gastrointestinal > Hemochromatosis Author: Sandor Joffe, MD. Updated: May 8, 2009thefreedictionary.com > hemosiderosis, citing: Gale Encyclopedia of Medicine. Copyright 2008 Hemosiderosis is hemosiderin deposition within cells, while hemochromatosis is hemosiderin within cells and the interstitium.Notecards on radiology gamuts, diseases, anatomy 2002, Charles E. Kahn, Jr., MD. Medical College of Wisconsin Hemosiderosis is iron overload that does not cause tissue damage,thefreedictionary.com > hemosiderosis, citing: Dorland's Medical Dictionary for Health Consumers, 2007 Mosby's Dental Dictionary, 2nd ed. Saunders Comprehensive Veterinary Dictionary, 3rd ed. 2007 while hemochromatosis does.The HealthScout Network > Health Encyclopedia > Diseases and Conditions > Hemochromatosis Retrieved on December 11, 2009 Hemosiderosis is arbitrarily differentiated from hemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.thefreedictionary.com > hemosiderosis, citing: McGraw-Hill Concise Dictionary of Modern Medicine. 2002 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 originThe Atlantic: "The Iron in Our Blood That Keeps and Kills Us" by Bradley Wertheim January 10, 2013 have a particularly high incidence of hemochromatosis type 1, with about 1:8 people being carriers of the principal genetic variant, the C282Y mutation on the HFE gene, and 0.5% of the population having the condition.
Non-classical hereditary hemochromatosis
The overwhelming majority of hereditary hemochromatoses are caused by 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". They are hemochromatosis type 2 (2A and 2B), type 3, type 4, type 5nih.gov, other genes related (such as BMP6, SUGP2 and DENND3) and digenic.
Other causes of primary iron overload (non-hemochromatosis)
Aceruloplasminemia Congenital Atransferrinemia GRACILE syndrome
Description OMIM Mutation Hemochromatosis type 1: "classical" hemochromatosis HFE Hemochromatosis type 2A: juvenile hemochromatosis Haemojuvelin (HJV, also known as RGMc and HFE2) Hemochromatosis type 2B: juvenile hemochromatosis hepcidin antimicrobial peptide (HAMP) or HFE2B Hemochromatosis type 3 transferrin receptor-2 (TFR2 or HFE3) Hemochromatosis type 4 ferroportin (SLC11A3/SLC40A1) Hemochromatosis type 5 FTH1 BMP6-related hemochromatosis BMP6 Neonatal hemochromatosis (unknown) Acaeruloplasminaemia (very rare) caeruloplasmin Congenital atransferrinaemia (very rare) transferrin GRACILE syndrome (very rare) BCS1L
Most types of hereditary hemochromatosis have autosomal recessive inheritance, while type 4, type 5 and BMP6-related have 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, 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 (i.e. African iron overload) 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), alcoholic steatohepatitis, prolonged hemodialysis, and post-portacaval shunting
Other causes of iron overload
GALD-NH (Gestacional alloimmune liver disease) Dysmetabolic Iron Overload Syndrome (DIOS) It is a condition characterized by a mild to moderate accumulation of iron in the liver associated with metabolic disorders, particularly Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic syndrome. Transferrin saturation is generally 20-45%; if this is above 60%, it is highly unlikely to be due to DIOS. It is not hemochromatosis.
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 (homeostatic 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 and 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.
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