Iron Overload Flashcards
Used to designate an increase of tissue iron resulting in a disease state
Iron storage disease and hemochromatosis
The hemoglobin concentration in the blood may be halfway back to normal after 4–5 weeks of therapy.
Denotes an increase of tissue iron stores with or without tissue damage
Hemosiderosis
Occurs in patients who receive multiple blood transfusions, particularly when they have ineffective erythropoiesis and hence hyperabsorb dietary iron
Secondary hemochromatosis
Characterized by increased quantities of brain iron
Found in Alzheimer disease, parkinsonism, Friedreich ataxia, Hallervorden-Spatz disease, and multiple-system atrophy.
Aceruloplasminemia
Characterized by hepatic and extrahepatic iron deposition and fulminant hepatitis caused by the maternal immune response to fetal antigens.
Neonatal hemochromatosis
Types of Hereditary Hemochromatosis
- Classical hemochromatosis (HFE hemochromatosis) (type 1)- most common
-
Juvenile hemochromatosis (type 2)
Abnormality in hemojuvelin (HFE2, HJV)
Abnormality of hepcidin (Hamp) - Transferrin receptor-2 deficiency (type 3)
-
Ferroportin abnormalities (type 4)- (SLC40A1)
Gain of function (systemic iron overload)
Loss of function (macrophage iron overload) - Ferritin H-chain iron-responsive element mutation
- African iron overload
Classic Young TransFeree
Hereditary hemochromatosis usually is applied to the common genetic form of the disorder, found principally in those of northern European ancestry, and as a result of mutation of this gene
HFE gene
The patient’s gender is clearly a modifying factor, with more severe manifestations observed in males, because pregnancy and menstrual iron losses tend to ameliorate the disease in women.
The most important HFE gene mutation
c.845 A→G (C282Y) mutation
Gene frequency of approximately 0.07 in the northern European population, approximately 5 in 1000 northern Europeans are homozygous for the mutation.
Haber-Weiss reaction
Fe++ + H2O2 → Fe+++ + OH– + HO∙
O2− + Fe+++ → O2 + Fe++
Fenton reaction:
O2− + H2O2 → O2 + OH− + HO∙
Subunit of ferritin that exerts most of its ferroxidase activity in the cytosol
H-ferritin (heavy)
The common pathway that causes hyperabsorption of iron is
Deficiency of hepcidin
The erythroid suppressors of hepcidin
GDF-15 and erythroferrone
In the liver of patients with classical hemochromatosis, TfR2 mutations and in juvenile hemochromatosis, hemosiderin is found primarily in____________. Kupffer cells are relatively spared.
Hepatocytes
In the case of patients with ferroportin mutations that prevent transport of iron, storage of iron takes place mostly in the _________ and fibrosis seems to be absent
Kupffer cells
Ferroportin mutations that prevent interaction with hepcidin, on the other hand, are associated with hepatocyte iron overload, as is seen in classical hemochromatosis.
An iron concentration of more than________ μmol/g dry weight (or about _______μmol/g wet weight) is considered strong evidence for hemochromatosis when factors such as transfusions are eliminated as the cause.
300 μmol/g dry weight (or about 50 μmol/g wet weight)
TRUE OR FALSE
Iron accumulates more slowly in the myocardium than in the liver but the heart is less sensitive to its toxic effects.
FALSE
Iron accumulates more slowly in the myocardium than in the liver but the heart is more sensitive to its toxic effects.
The leading cause of death in transfused patients with β-thalassemia major.
Accumulation of cardiac iron
Direct cardiac iron measurement using _______________ predicts cardiac complications and can stratify the risk of subsequent cardiac dysfunction.
Magnetic resonance imaging
Measures the half-life, T2*, of cardiac muscle darkening (with respect to echo time) produced by magnetically active stored cardiac iron
Iron overload in the marrow is characteristically distributed into small, equal-size granules located in ___________ rather than in macrophages.
The quantity of iron in the marrow of patients with classical hereditary hemochromatosis is only modestly increased, if at all.
Endothelial lining cells
The most common cause of hereditary hemochromatosis
Mutation of the HFE gene
The HFE gene, an HLA-like gene, resides on chromosome ______.
Chromosome 6
Three polymorphic HFE mutations have been identified
- 187- H63D
- 193 - S65C
- 845- C282Y
The phenotypic severity of HFE mutations on iron homeostasis is manifested in the following order:
C282Y > H63D > S65C
Mode of inheritance of Hereditary hemochromatosis
Autosomal recessive
Rare mutation of hepcidin associated with severe juvenile hemochromatosis
Hamp (Hepcidin)
Mode of inheritance of SLC40A1 (Ferroportin) Mutations
Autosomal dominant
Two types of SLC40A1 (Ferroportin) Mutations
Gain of function mutations: C326S mutation, interfere with hepcidin binding to ferroportin or with the resulting ferroportin endocytosis
Loss-of-function mutations: (more common); ferroportin mutations that do not localize to the cell surface, or prevent transport of iron
Mode of inheritance of TfR2 Mutations
Autosomal recessive
Known to be a key regulator of hepcidin transcription
Bone morphogenetic protein receptor
BMP
Mutation associated with hepatic hemosiderosis and most with abnormal liver function tests in addition to microcytic hypochromic anemia
DMT-1 Human Mutations
The clinical features of the most common form of hereditary hemochromatosis
Cirrhosis of the liver, darkening of the skin, cardiomyopathies, and diabetes
“Bronze diabetes”
Onset of Juvenile Hemochromatosis
Second or third decade of life
Onset of classical hereditary hemochromatosis
Fifth or sixth decade of life
Characteristic features of the arthropathy of patients with hemochromatosis
Begin at the small joints of the hands, especially the second and third metacarpal joints, and in some cases, episodes of acute synovitis
Features considered distinctive to arthropathy of patients with hemochromatosis
- Joint distribution
- The presence of shape osteophytes emerging from the radial sides of the metacarpal distal epiphysis
- Presence of radiolucent zones in the subchondral area of the femoral head
Arthritis does not respond to phlebotomy therapy
Major clinical features of Juvenile Hemochromatosis
Cardiomyopathies and endocrine deficiencies
The main laboratory features of hereditary hemochromatosis
High transferrin saturation, and increased serum ferritin level
An uncommon autosomal dominant defect in which a mutation in the 5′ iron-responsive element of the ferritin light chain prevents binding of the iron-regulatory proteins, resulting in unrestrained constitutive production of the ferritin chains
Hyperferritinemia-cataract syndrome
“Gold standard” for the diagnosis of iron overload
No longer required for the diagnosis of hemochromatosis
Liver biopsy
Formula for iron index
Dividing the iron content by the patient’s age
*liver biopsy
An iron index of greater than_______ implies the presence of hemochromatosis.
2
Can detect and reliably quantify increased amounts of iron in the liver
Magnetic resonance imaging
Treatment of choice for iron overload in patients who are able to mount an erythropoietin response
Phlebotomy
Treatment for patient that has marked impairment of erythropoiesis, as in thalassemia and dyserythropoietic anemia
Chelating agents
Occasionally serial phlebotomy will stimulate sufficient erythropoiesis to make it a viable therapy
End point of the initial part of the phlebotomy program
Signs of iron deficiency
The frequency of phlebotomies tailored to maintain the serum ferritin level, the best indicator of body stores, below _______ ng/m
100 ng/m
TRUE OR FALSE
The hematocrit or hemoglobin and the MCV of the red cells should be measured before each phlebotomy is undertaken. If there has been a substantial decrease in the hematocrit or hemoglobin, the phlebotomy should be deferred.
TRUE
The hematocrit or hemoglobin and the MCV of the red cells should be measured before each phlebotomy is undertaken. If there has been a substantial decrease in the hematocrit or hemoglobin, the phlebotomy should be deferred.
During phlebotomy, the transferrin saturation and serum ferritin level should be measured every _______months
Two or three months
When the transferrin saturation is less than 10% and the serum ferritin less than 10 ng/mL, phlebotomy should be discontinued and the patient monitored every 3–6 months so that the rate of ferritin rise can be estimated.
When the serum ferritin is in the 50–100 ng/mL range, the maintenance phase should be initiated.
A naturally occurring iron-chelating compound synthesized by the microorganism Streptomyces pilosus, having evolved to enable the microbe to obtain iron from its environment
Desferrioxamine
Rapid IV or intramuscular injection results in relatively little iron mobilization; instead, it is necessary to administer desferrioxamine by
Slow IV or subcutaneous infusion over a period of 8–10 hours
Poorly absorbed from the gastrointestinal tract
Usual recommended dose of desferrioxamine
30–50 mL/kg
Vitamin C (up to 200 mg daily) may be given to enhance iron excretion.
Large doses of desferrioxamine are associated with
Hearing loss, night blindness and other visual abnormalities, growth retardation, and skeletal changes
Usual recommended dose of deferiprone
75 mg/kg per day divided into three doses
Toxic effects of deferiprone
Gastrointestinal disturbances, arthropathy, transient increases in the serum levels of liver enzymes, and zinc deficiency
Oral chelating agent excreted almost entirely in the urine
Deferiprone
Oral chelating agent that has propensity to produce neutropenia and agranulocytosis
Deferiprone
More effective in removing iron from the heart
Deferiprone
More effective with respect to liver iron accumulations
Desferrioxamine
Usual recommended dose of Deferasirox
30 mg/kg per day
Toxic effects of Deferasirox
Renal and hepatic, but it may also cause gastrointestinal hemorrhage
