Iron Overload

Question 1

Used to designate an increase of tissue iron resulting in a disease state

Answer 1

Iron storage disease and hemochromatosis

The hemoglobin concentration in the blood may be halfway back to normal after 4–5 weeks of therapy.

Question 2

Denotes an increase of tissue iron stores with or without tissue damage

Answer 2

Hemosiderosis

Question 3

Occurs in patients who receive multiple blood transfusions, particularly when they have ineffective erythropoiesis and hence hyperabsorb dietary iron

Answer 3

Secondary hemochromatosis

Question 4

Characterized by increased quantities of brain iron

Found in Alzheimer disease, parkinsonism, Friedreich ataxia, Hallervorden-Spatz disease, and multiple-system atrophy.

Answer 4

Aceruloplasminemia

Question 5

Characterized by hepatic and extrahepatic iron deposition and fulminant hepatitis caused by the maternal immune response to fetal antigens.

Answer 5

Neonatal hemochromatosis

Question 6

Types of Hereditary Hemochromatosis

Answer 6

• 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

Question 7

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

Answer 7

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.

Question 8

The most important HFE gene mutation

Answer 8

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.

Question 9

Haber-Weiss reaction

Answer 9

Fe++ + H2O2 → Fe+++ + OH– + HO∙
O2− + Fe+++ → O2 + Fe++

Question 10

Fenton reaction:

Answer 10

O2− + H2O2 → O2 + OH− + HO∙

Question 11

Subunit of ferritin that exerts most of its ferroxidase activity in the cytosol

Answer 11

H-ferritin (heavy)

Question 12

The common pathway that causes hyperabsorption of iron is

Answer 12

Deficiency of hepcidin

Question 13

The erythroid suppressors of hepcidin

Answer 13

GDF-15 and erythroferrone

Question 14

In the liver of patients with classical hemochromatosis, TfR2 mutations and in juvenile hemochromatosis, hemosiderin is found primarily in____________. Kupffer cells are relatively spared.

Answer 14

Hepatocytes

Question 15

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

Answer 15

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.

Question 16

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.

Answer 16

300 μmol/g dry weight (or about 50 μmol/g wet weight)

Question 17

TRUE OR FALSE

Iron accumulates more slowly in the myocardium than in the liver but the heart is less sensitive to its toxic effects.

Answer 17

FALSE

Iron accumulates more slowly in the myocardium than in the liver but the heart is more sensitive to its toxic effects.

Question 18

The leading cause of death in transfused patients with β-thalassemia major.

Answer 18

Accumulation of cardiac iron

Question 19

Direct cardiac iron measurement using _______________ predicts cardiac complications and can stratify the risk of subsequent cardiac dysfunction.

Answer 19

Magnetic resonance imaging

Measures the half-life, T2*, of cardiac muscle darkening (with respect to echo time) produced by magnetically active stored cardiac iron

Question 20

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.

Answer 20

Endothelial lining cells

Question 21

The most common cause of hereditary hemochromatosis

Answer 21

Mutation of the HFE gene

Question 22

The HFE gene, an HLA-like gene, resides on chromosome ______.

Answer 22

Chromosome 6

Question 23

Three polymorphic HFE mutations have been identified

Answer 23

• 187- H63D
• 193 - S65C
• 845- C282Y

Question 24

The phenotypic severity of HFE mutations on iron homeostasis is manifested in the following order:

Answer 24

C282Y > H63D > S65C

Question 25

Mode of inheritance of Hereditary hemochromatosis

Answer 25

Autosomal recessive

Question 26

Rare mutation of hepcidin associated with severe juvenile hemochromatosis

Answer 26

Hamp (Hepcidin)

Question 27

Mode of inheritance of SLC40A1 (Ferroportin) Mutations

Answer 27

Autosomal dominant

Question 28

Two types of SLC40A1 (Ferroportin) Mutations

Answer 28

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

Question 29

Mode of inheritance of TfR2 Mutations

Answer 29

Autosomal recessive

Question 30

Known to be a key regulator of hepcidin transcription

Answer 30

Bone morphogenetic protein receptor

BMP

Question 31

Mutation associated with hepatic hemosiderosis and most with abnormal liver function tests in addition to microcytic hypochromic anemia

Answer 31

DMT-1 Human Mutations

Question 32

The clinical features of the most common form of hereditary hemochromatosis

Answer 32

Cirrhosis of the liver, darkening of the skin, cardiomyopathies, and diabetes

“Bronze diabetes”

Question 33

Onset of Juvenile Hemochromatosis

Answer 33

Second or third decade of life

Question 34

Onset of classical hereditary hemochromatosis

Answer 34

Fifth or sixth decade of life

Question 35

Characteristic features of the arthropathy of patients with hemochromatosis

Answer 35

Begin at the small joints of the hands, especially the second and third metacarpal joints, and in some cases, episodes of acute synovitis

Question 36

Features considered distinctive to arthropathy of patients with hemochromatosis

Answer 36

• 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

Question 37

Major clinical features of Juvenile Hemochromatosis

Answer 37

Cardiomyopathies and endocrine deficiencies

Question 38

The main laboratory features of hereditary hemochromatosis

Answer 38

High transferrin saturation, and increased serum ferritin level

Question 39

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

Answer 39

Hyperferritinemia-cataract syndrome

Question 40

“Gold standard” for the diagnosis of iron overload

No longer required for the diagnosis of hemochromatosis

Answer 40

Liver biopsy

Question 41

Formula for iron index

Answer 41

Dividing the iron content by the patient’s age

*liver biopsy

Question 42

An iron index of greater than_______ implies the presence of hemochromatosis.

Answer 42

2

Question 43

Can detect and reliably quantify increased amounts of iron in the liver

Answer 43

Magnetic resonance imaging

Question 44

Treatment of choice for iron overload in patients who are able to mount an erythropoietin response

Answer 44

Phlebotomy

Question 45

Treatment for patient that has marked impairment of erythropoiesis, as in thalassemia and dyserythropoietic anemia

Answer 45

Chelating agents

Occasionally serial phlebotomy will stimulate sufficient erythropoiesis to make it a viable therapy

Question 46

End point of the initial part of the phlebotomy program

Answer 46

Signs of iron deficiency

Question 47

The frequency of phlebotomies tailored to maintain the serum ferritin level, the best indicator of body stores, below _______ ng/m

Answer 47

100 ng/m

Question 48

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.

Answer 48

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.

Question 49

During phlebotomy, the transferrin saturation and serum ferritin level should be measured every _______months

Answer 49

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.

Question 50

A naturally occurring iron-chelating compound synthesized by the microorganism Streptomyces pilosus, having evolved to enable the microbe to obtain iron from its environment

Answer 50

Desferrioxamine

Question 51

Rapid IV or intramuscular injection results in relatively little iron mobilization; instead, it is necessary to administer desferrioxamine by

Answer 51

Slow IV or subcutaneous infusion over a period of 8–10 hours

Poorly absorbed from the gastrointestinal tract

Question 52

Usual recommended dose of desferrioxamine

Answer 52

30–50 mL/kg

Vitamin C (up to 200 mg daily) may be given to enhance iron excretion.

Question 53

Large doses of desferrioxamine are associated with

Answer 53

Hearing loss, night blindness and other visual abnormalities, growth retardation, and skeletal changes

Question 54

Usual recommended dose of deferiprone

Answer 54

75 mg/kg per day divided into three doses

Question 55

Toxic effects of deferiprone

Answer 55

Gastrointestinal disturbances, arthropathy, transient increases in the serum levels of liver enzymes, and zinc deficiency

Question 56

Oral chelating agent excreted almost entirely in the urine

Answer 56

Deferiprone

Question 57

Oral chelating agent that has propensity to produce neutropenia and agranulocytosis

Answer 57

Deferiprone

Question 58

More effective in removing iron from the heart

Answer 58

Deferiprone

Question 59

More effective with respect to liver iron accumulations

Answer 59

Desferrioxamine

Question 60

Usual recommended dose of Deferasirox

Answer 60

30 mg/kg per day

Question 61

Toxic effects of Deferasirox

Answer 61

Renal and hepatic, but it may also cause gastrointestinal hemorrhage