Iron overload

We established in the Labs section that the patient’s iron indices are consistent with iron overload:

There are many reasons for an elevated ferritin. To test your memory from a previous question, what parameter(s) in this iron panel points to iron overload as a cause?

a
The ferritin is >2000
b
The serum iron is high
c
The total iron binding capacity (TIBC) is low
d
The transferrin saturation (TSAT) is elevated
20%-50% is considered normal; > 50% indicates possible iron overload.

This patient had received many transfusions since he was a child. How much iron does each unit of red cells contain?

a
50 mg
b
250 mg
0.47 mg iron/mL of whole donor blood or 1.08 mg iron/mL of pure red blood cells.
c
500 mg
d
1000 mg

What is a normal total body iron store?

a
1000 mg
b
3500 mg
40 to 50 mg/kg of iron.
c
5000 mg

Ineffective erythropoiesis

  • Defined as the inability to produce adequate number of red blood cells in the presence of increased immature erythroid precursors.
  • Leads to decreased production of hepcidin by the liver that:
    • Occurs via an erythroid signal/erythropoietic factor that overrides negative feedback signals from replete iron stores causing and perpetuating iron overload.
    • Results in activation of the cellular iron exporter ferroportin leading to increased iron flow into the plasma.

What organs are primarily affected in transfusional iron overload?

a
Brain
b
Liver
c
Lungs
d
Heart
e
Endocrine glands

In our patient, which questions are relevant to a history of iron overload:

a
Do you have erectile dysfunction?
b
Have you been diagnosed with diabetes?
c
Do you have orthopnea?
d
Are you having trouble swallowing?
e
Have you noted discoloration of your flinger tips in cold weather?

Let’s consider a more complete list of potential symptoms and signs in states of iron overload:

Target organSymptomsSigns
LiverSymptoms associated with cirrhosisHepatomegaly
HeartIncreased shortness of breath, failure to tolerate standard transfusionRight heart failure: neck vein distension,
hepatomegaly, peripheral edema; Left heart failure: exertional dyspnea, orthopnea; Conduction changes: dizziness, presyncope or palpitations
EndocrineHypogandism: secondary amenorrhea
delayed puberty, decreased libido,
erectile dysfunction, worsened sense of well-being; Symptoms associated with hypothyroidism
Hypogonadism: diminished facial and body hair, decreased muscle mass, appearance of fine facial wrinkles, gynecomastia, small testes; Physical findings associated with hypothyroidism
SkinHyperpigmentationHyperpigmentation

Which of the following statements is/are correct:

a
In otherwise healthy patients, serum ferritin correlates with total body iron
b
Ferritin is limited as a biomarker because it may be elevated in the absence of iron overload
c
Liver iron concentration (LIC) serves as estimate of total body iron stores
d
Magnetic resonance imaging (MRI) is a viable, noninvasive procedure for estimation of LIC

The following study demonstrated a correlation between serum ferritin and liver iron concentration in patients with pyruvate kinase deficiency.

Forty-five patients had paired ferritin and LIC measurements available. Using a ferritin cut off of 1000 ng/mL, the sensitivity to predict LIC >3 mg/g DW was 53% and the specificity was 100%. At a ferritin cut off of 500 ng/mL, the sensitivity for LIC >3 mg/g DW was 90% and the specificity was 67%.

Our patient (red circle) had a ferritin of about 2250 ng/ml, which would predict for an LIC of about 8 mg/g DW.

Forty-five patients had paired ferritin and LIC measurements available (Figure 1). Using a ferritin cut off of 1000 ng/mL, the sensitivity to predict LIC >3 mg/g DW was 53% and the specificity was 100%. At a ferritin cut off of 500 ng/mL, the sensitivity for LIC >3 mg/g DW was 90% and the specificity was 67%.

The patient had an MRI of the liver, which showed:

Liver iron concentration (LIC):

  • Normal LIC ranges from 0.17-1.8 mg iron/g dry weight.
  • < 7 mg iron/g dry weight may not be associated with adverse effects.
  • > 15 mg iron/g dry weight associated with:
    • Expansion of the chelatable iron pool and labile plasma iron levels.
    • Liver fibrosis, liver dysfunction, endocrinopathies, cardiac iron accumulation, and mortality (in patients with thalassemia major).

149 micromoles per gram = 8.3 mg per gram – very close to what was predicted on the last slide.

Our patient has severe iron overload. Should he receive chelation therapy?

a
Yes
b
No

The approach to chelation in PKD is similar to other red cell and iron loading disorders.

  • Three types of treatment:
    • Prevention therapy – chelation therapy to prevent iron accumulation; for example initiate DFO if ≥ 1 of the following:
      • ≥ 10-20 transfusions
      • serum ferritin > 1,000 ng/mL
    • Rescue therapy
      • Removal of iron that has already accumulated as a result of blood transfusion.
      • Increase frequency, duration and dose to achieve negative iron balance, depending on the transfusion rate.
      • Increase frequency, duration and dose to achieve negative iron balance, depending on the transfusion rate.
    • Emergency therapy – intensification of therapy in cases of cardiac iron accumulation and heart failure.
  • Therapy may include one or more chelators.

Iron chelators include:

  • Deferoxamine (DFO)
    • First available chelating agent.
    • Poorly absorbed after oral administration, thus necessitating subcutaneous or IV administration.
    • Very short half-life necessitates administration as a continuous infusion over ≥ 8 hours.
    • Typical dose 25-40 mg/kg/day (up to 60 mg/kg/day) for 5-7 days/week for 8-12 hours/day.
    • Adverse effects include:
      • Local infusion site reactions
      • Ophthalmologic abnormalities 
      • Audiologic abnormalities 
      • Hypersensitivity reactions
      • Increased risk of infection (Yersinia and Klebsiella)
  • Deferasirox (DFX) (Jadenu)
    • Well-absorbed from the gastrointestinal tract.
    • Available as an oral suspension, film-coated tablet, or granule form.
    • Cleared from the circulation slowly (longest half-life of the 3 chelators).
    • Typical dose for transfusion-dependent patients for dispersible tablet is 20-40 mg/kg by mouth once daily and 14-28 mg/kg once daily for film coated tablet or granule forms.
    • Adverse effects include:
      • Gastrointestinal (GI) effects
      • Skin rash 
      • Renal impairment
  • Deferiprone (DFP)
    • Rapidly absorbed with a peak blood level about 45 minutes after ingestion.
    • Best used for management of cardiac iron overload.
    • Typical dose 25 mg/kg three times daily (up to 99 mg/kg/day) by mouth.
    • Available as oral tablet or solution.
    • Adverse effects include:
      • Gastrointestinal effects
      • Agranulocytosis
      • Neutropenia 
      • Arthropathy
      • Hepatic toxicity
      • Neurologic abnormalities

In this case, the patient had been started on iron chelation (Jadenu) in his teenage years but developed auditory symptoms and discontinued the medication. At this time, he is unwilling to try another iron chelator despite evidence of progressive iron overload.

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