Chapter 428 - Hemochromatosis Flashcards
Hemochromatosis and hemosiderosis are synonyms.
True or False?
False.
“Hemochromatosis is a common inheridted disorder of iron metabolism in which dysregulation of intestinal iron absorption results in deposition of excessive amounts of iron in parenchymal cells with eventual tissue damage and impaired function in a wide range of organs.”
“The term hemosiderosis is used to descbribe the presence of stainable iron in tissues, but tissure iron must be quantified to assess body-iron status accurately.”
Name the major tissues that might be affected due to hemochromatosis.
Liver, pancreas, heart, articulations and endocrine glands, aswell as the skin. Thus, “Cirrhosis of the liver, diabetes mellitus, arthritis, cardiomyopathy, and hypogonadotropic hypogonadism are the major clinical manifestations.”
Hemochromatosis is only recognizable when there is significant organ damage.
True or False?
False.
“The disease can be recognized during its early stages when iron overload and organ damage are minimal. At this stage, the disease is best referred to as early hemochromatosis or precirrhotic hemochromatosis.”
What is the most frequent gene mutation associated with hemochromatosis? How frequent is it?
HFE gene, tightly linked to the HLA-A locus on chromosome 6p. It occurs in 0,3-0,5% as homozygoty and 1:10 as heterozygoty in persons of northern European descent. In this group of patients, 80-90% of clinical hereditary hemochromatosis is due to homozygous HFE mutation gene (85-90% due to C282Y HFE mutation).
Which group of diseases might lead to secundary (acquired) hemochromatosis?
Anemia (e.g., thalassemia or sideroblastic anemia).
Are there any factors that might explain different expressions of hemochromatosis in the presence of hereditary hemochromatosis?
Yes, “especially alcohol consumption and dietary iron intake, blood loss, associated with menstruation and pregnancy, and blood donation.
Menstruating young women with a family history of heredtiary hemochromatosis should not be screened periodically for iron overload.
True or False?
False.
When is it that symptoms develop due to iron-overload? do you expect them to occur in every patient with hereditary hemochromatosis?
“Nearly 70% of untreated patients develop the first symptoms between ages 40 and 60. The disease is rarely evident before age 20”
“Recent population studies indicate that approximately 30% of homozygous men develop iron overload-related disease and about 6% develop hepatic cirrhosis; for women, the figure is closer to 1%.”
Non-HFE hemochromatosis affects all races and young people (juvenile hemochromatosis).
True or False?
True.
What type of mutations might occur in HFE gene?
C282Y (G to A; cysteine to tyrosine)
H63D (histidine to acid aspartic)
A single mutation in HFE gene is associated with hereditary hemochromatosis?
True or False?
False.
Hemochromatosis is an autosomic recessive disease which might occur in patients with homozygous C282Y or compound heterozygous H63D (+C282Y, for example).
Heterozygous HFE gene is not associated with any clinical findings.
True or False?
True and False.
True: “heterozygos have no, or minimal, increase in iron stores.”
False: “However, this slight increase in hepatic iron can act as a cofactor that may modify the expression of other diseases such as porphyria cutanea tarda (PCT) or nonalcoholic steatohepatitis.”
Name the non-HFE gene mutation. Which of those might have an involvement of the reticuloendothelial cells and macrophages? How is it so?
Hepcidin, transferrin receptor 2 (TrF2), hemojuvelin and ferroportin. The latter is responsible for the efflux of iron from enterocytes and most other cell types, reason why it might affect the reticuloendothelial cells as well as the macrophages and parenchymal cells.
How do you explain the mollecular mecanisms (namelly hepcidin) that lead to the iron-overload in hemochromatosis?
“Normally, the body-iron content of 3-4g is maintained such that intestinal mucosal absorption of iron is equal to iron loss. This amount is approximately 1mg/d in men and 1,5mg/d in menstruating women. In hemochromatosis, mucosal absorption is greater than body requirements and amounts to 4mg/d or more. The progressive accumulation of iron increases plasma iron and saturation of transferrin and results in a progressive increase of plasma ferritin. A liver-derived peptide, hepcidin, represses basolateral iron transport in the intestine and iron release from macrophages and other cells by binding to ferroportin. Hepcidin, in turn, responds to signals in the liver mediated by HFE, TrF2, and hemojuvelin. Thus, hepcidin is a crucial molecule in iron metabolism, linking body stores with intestinal iron absorption?”
Since C282Y HFE mutation traps the 343-aminoacid intracellulary, one would expect that iron absorption would be decreased. Therefore, which mechanism leads to increased iron absorption?
“This impaired TrF1-mediated iron uptake leads to upregulation of the divalent metal transporteer (DMT1) on the brush border of the villus cells, causing inappropriatelly increased intestinal iron absorption.”
