Iron overload

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 but may also be secondary to other causes. 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 and hypogonadism 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 for an extended period, increasing age, and concurrent advanced liver fibrosis.
skin: melanoderma.

Hemochromatosis leading to secondary diabetes, 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. Currently, hemochromatosis is mostly defined as iron overload with a hereditary or primary cause, or originating from a metabolic disorder.

Primary hemochromatosis and hemosiderosis

Hereditary hemochromatosis

Hereditary hemochromatoses are genetic disorders. Hereditary hemochromatosis 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% of them will develop iron overload. Mutations of the HFE gene located on chromosome 6 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. 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 the 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 and less frequent secondary cases.
People of Northern European descent, including Celtic, English, and Scandinavian origin 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, type 3, type 4, type 5

Other causes of primary iron overload (non-hemochromatosis)

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
Multiple frequent blood transfusions, which are usually needed either by individuals with hereditary anaemias, or by older patients with severe acquired anaemias such as in myelodysplastic syndromes.
Excess parenteral 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, alcoholic steatohepatitis, prolonged hemodialysis, and post-portacaval shunting
Other causes of iron overload
GALD-NH
Dysmetabolic Iron Overload Syndrome

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 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 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, 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

There are several methods available for diagnosing and monitoring iron overload. Current guidelines recommend quantitative liver MRI combined with HFE genotyping as a diagnostic approach; liver biopsy and calculation of the hepatic iron index are reserved for equivocal cases or for staging hepatic fibrosis.

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, 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 . In premenopausal females, normal range of serum ferritin is between 12 and 150 or 200 ng/mL. 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. There are cases of iron overload with normal transferrin saturation.