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Hereditary type- characterized by progressive abnormal deposition of iron in the liver, heart, pancreas, anterior pituitary and other vital organs.
Hemochromatosis, a syndrome of systemic iron overload, may be caused by hereditary hemochromatosis, transfusional iron overload, chronic hemolysis, or excess dietary iron.
Hereditary hemochromatosis (HH) of which there are five subtypes, is the most common genetic disease among individuals of northern European descent.
Hereditary hemachromatosis is a group of disorders characterized by abnormal iron homeostasis leading to iron overload.
Of these five subtypes, hemochromatosis type 1 is the most common, with population studies in the United States indicating a frequency of homozygosity at about 0.3%.
HH is caused by variants in at least five genes that reduce production of hepcidin, or less commonly, cause ferroportin resistance to hepcidin.
The cause of 95% of cases of hemachromatosis is a homozygous mutation in HFE (hemostatic iron regulator) on chromosome, 6P which results in a pC28Y substitution and is termed HFE hemachromatosis.
Simple heterozygosity for pC282Y affecys 1 in seven persons and minor p.H6 3D variant in HFE affects one in three persons of northern European descent.
The disease results from a failure in the regulation of the key liver derived iron regulatory hormone hepcidin to respond to increasing iron stores.
Liver fibrosis occurs in about 8% of women and 25% of men with hemachromatosis.
Risk factors for liver fibrosis include excessive alcohol consumption, diabetes, arthritis, serum ferritin levels exceeding 1000 µg per liter, platelet levels less than 200,000×10 to the 9th per liter, elevated AST levels, liver ion concentration greater than 200 micro moleeer gram, and total mobilizable ion stores on therapeutic phlebotomy of more than 9.6 g.
Men with homozygous C282Y have a lifetime risk of primary liver cancer that is 12 times greater than the risk in men who do not have HFE variants (7.2% vs 0.6%).
Patients with advanced liver, fibrosis, are at greatest risk of primary liver cancer.
Regression of advanced liver fibrosis is associated with a significant reduction in the long-term risk of hepatocellular carcinoma, although the majority of cases of cirrhosis persist after treatment.
Hereditary type-most common genetic disease among persons of northern European descent: prevalence is one case per 300 people.
Mutations in the HFE gene (an upstream activator of hepcidin expression) is associated with low levels of circulating hepcidin and with the unregulated expression activity of ferroportin which results in increased absorption of dietary iron.
Men, but not women who are hormones homozygous for p.C282Y have a significantly increased mean risk of death by the age of 75 compared with those who do not have HFE variants.
Men and women homozygous for p.C282Y have an increased risk of sarcopenia. frailty, and chronic pain after age 60 compared with persons who are not homozygotes for p.C282Y mutation.
This mutation causes low serum hepcidin levels and provides the connection between the genetic mutations and the pathogenesis of iron overload.
The earliest laboratory manifestations of hemachromatosis are elevations in serum transferrin saturation, mean red cell hemoglobin level, and red cell volume.
An elevation of the mean red cell volume above 94 fl can identify 34% of all men and 62% of all women with hemachromatosis, an increase by a factor of more than 30 as compared with the general population screening.
These changes precede an elevation in the serum ferritin level.
A serum ferritin level above 300 µg per liter in men has a sensitivity of 88%, and an elevation above 200 µg per liter in women has a sensitivity of 57% for diagnosis.
A transferin saturation of less than 45% combined with the serum ferritin level within the reference range has an overall negative predictive value of 97%.
Approximately 8% of patients with homozygous PC282Y disease have a ferritin level above 1000 µg per liter.
Dietary iron is absorbed in the duodenum.
Ferroportin, a transport proteins on duodenal epithelial cells, hepatocytes, and macrophages, transfers iron from the duodenum and proximal jejunum into the circulation.
Iron circulates bound to transferrin and is deposited as ferritin in tissues.
Hepcidin, a protein produced by hepatocytes in response to circulating iron, binds to ferroportin leading to its degradation, which reduces iron release from enterocytes to the circulation.
Molecular defects that causes hepcidin deficiency, such as those in the HFE gene (homeostatic iron regulator gene), result in uncontrolled iron absorption and iron accumulation in tissues.
Transferin binding sites in plasma become saturated, and leading to the appearance of redox-active non-transferrin bound iron, which is rapidly cleared by the liver and other organs such as the pancreas, heart, and pituitary, where it causes oxidant mediated tissue damage.
Autosomal recessive with a prevalence of 1:1200 to 1:250 for homozygosity and a carrier rate of 1:8 to 1:12.
Hereditary hemachromatosis is prevalent with more than 6% of the white population having one variant allele.
It has low penetrance, so only 20% of homozygous men and 1.4% of homozygous women have clinical symptoms.
Localization of the gene to the short arm of chromosome 6 (6p).
Process results from inadequate production of the iron regulatory hormone hepcidin.
Hemochromotosis results from mutations that normally induce hepcidin, and its severity is inversely correlated with hepcidin levels.
Approximately 95% of cases involve HFE and the C282Y variant.
This disorder affects approximately one in every 150 to 220 persons of northern European descent.
Homozygous C282Y accounts 90% of HH cases with 5% attributed to 282Y/H63D heterozygotes.
Hereditary type-screening for HFE gene for the C282y mutation in families with hereditary hemochromatosis is recommended.
Women with C282Y-C 282 genotype often present with symptoms later in life than men with the same mutation because of the blood loss from menstruation.
C282Y is the most common genetic abnormality in patients with hereditary hemachromatosis, but it is not the only one.
Oxidative stress related tissue injury is responsible for the pathogenesis of the disease.
Among men, but not women, the risk of liver disease is significantly increased by a factor of 4.3, for pC282Y homozygotes, as compared with men who do not have HFE variants: The risks of arthritis and colorectal cancer are double, and the risks of pneumonia, and diabetes mellitus are increased by a factor of 1.5.
Among women, who are homozygous for p.C282Y, the risks of colorectal cancer and breast are doubled, and the risk of arthritis is increased by a factor of 1.3 as compared with women who do not have HFE variants.
Hemachromatosis related to arthritis affects at least 24% of patients. It is a major cause of disability and reduced quality of life.
Hemachromatosis affects the metacarpalphalangeal joints, followed by the hip, ankle, radiocarpal, elbow, shoulder, and knee joints, as well as the lumbar spine.
Arthritis may occur at any point during the natural history of hemachromatosis and risk factors include increased age, increased liver, fibrosis, seum ferritin levels exceeding 1000 µg per liter, and serum transferrin saturation above 50% for at least six years.
Liver disease and arthritis tend to occur concurrently.
Men untreated for HH have approximately a 9% lifetime risk of developing cirrhosis, with an increased risk of hepatocellular carcinoma.
Approximately 15% of patients with HH have cardiac involvement, but only 0.9 to 3% of patients with HH develop cardiomyopathy.
Arthralgias are common with early disease, and usually involve the second and third metacarpophalangeal joints.
Endocrine manifestations include diabetes or hypogonado tropic hypogonadism due to iron deposition in the pancreas and pituitary gland, respectively.
Approximately 70% of patients with advanced HH develop skin hyperpigmentation.
Therapeutic phlebotomy normalizes total body iron stores, promotes iron use through hematopoiesis, and decrease iron mediated free radical damage.
Phlebotomy is indicated when TSAT level is greater than 45% combined with ferritin level greater than 300 ng/mL in men or greater than 200 ng/mL in women.
Initial treatment involves removal of 500 mL of blood every 1 to 2 weeks until the ferritin level decreases to 50 to 100 ng/ml, at which time maintenance phlebotomy is performed four to six times per year.
Both hepatic fibrosis and cardiac dysfunction can improve with therapeutic phlebotomy in patiempnts withhereditary hemochromatosis.
Patients with cirrhosis up to 45% of deaths are attributed to have hepatocellular carcinoma.
Therapy with deferasirox, an oral iron chelator, may be considered in patients who are intolerant or who do not respond to phlebotomy or has potential for harm.
Patients should avoid iron and vitamin C supplementation and limit alcohol intake.
Phlebotomy reduces the risk for cirrhosis, fibrosis, hepatoma, improves liver function, heart dysfunction, and fatigue.
Phlebotomy does not improve diabetes, hypogonadism or arthralgias.
General population screening for hemachromatosis is not recommended because the variable and incomplete penetrance and lack of any proof of resulting survival advantage.
