Chemical pathology VII - Iron Metabolism

Question 1

3 stages of iron deficiency

Answer 1

Stage I - Depletion of iron stores

Stage II - Functional Iron deficiency

Stage III - Iron deficiency anemia

Question 2

Low serum Ferritin 
Normal Plasma Iron 
Normal TIBC 
Normal Transferrin saturation
Normal plasma soluble transferrin receptor 

Interpret iron profile

Answer 2

Stage I depletion of iron store

Question 3

Low plasma iron 
High TIBC 
Low Transferrin Saturation % 
Low Ferritin 
High plasma soluble transferrin receptor 
Normocytic, Normal Hb 

Interpret iron profile

Answer 3

Stage II Functional iron deficiency

Question 4

Low plasma iron 
High TIBC 
Low Transferrin Saturation % 
Low Ferritin 
High plasma soluble transferrin receptor 
Microcytic, Anemic/ Low Hb 

Interpret Iron profile

Answer 4

Stage III Iron deficiency anemia

* Microcytic, Low Hb is the differential from stage II*

Question 5

How to delineate stage II functional iron deficiency with Stage III iron deficiency anemia?

Answer 5

* Stage 3 Microcytic, Low Hb is the differential from stage II*

Question 6

Rate of Hb response to iron supplements?

Answer 6

Increase >1g/ dL Hb after 1 months of Iron therapy

Question 7

List 4 blood biochemical tests for iron deficiency assessment

Answer 7

1. Serum ferritin concentration
2. Serum iron concentration
3. Total iron binding capacity (approx. transferrin)
4. Transferrin saturation (Serum iron: TIBC)

Question 8

Serum Iron alone is a good indicator of iron deficiency. True or False? Explain.

Answer 8

False

Range of serum iron = 4 fold from minimum
Large range affected by different physiological reactions

Must use TIBC, Ferritin, Transferrin saturations too

Question 9

List 4 causes of low serum iron concentration

Answer 9

• Iron deficiency
• During inflammation or malignancy
• Low during acute phase reaction/ negative APR
• Evening: 50% lower than daytime

Question 10

Transferrin function?

Normal functional load?

Regulation?

Answer 10

Carrier protein for iron

1/3 loaded with iron
Saturation at 20-50%

Transferrin production increases with Low serum iron (liver expressed, try to release transferrin to carry as much Fe in blood as possible)

Question 11

How to calculate Transferrin saturation?

Explain the change in saturation with low serum iron?

Answer 11

Saturation (%) = serum iron/ TIBC

Low serum iron causes high expression of Transferrin/ High TIBC

Question 12

3 scenarios that can cause low transferrin saturation?

Answer 12

Low serum iron/ High TIBC = Decreased saturation
Low serum iron/ normal TIBC = Decreased saturation
Normal serum iron/ High TIBC = decreased saturation

Question 13

What can cause high TIBC/ high transferrin production even when serum iron is normal? (4)

Answer 13

Transferrin goes up due to physiological or pathological cause, sometimes even without serum iron depletion:

• Pregnancy (from 2nd trimester to 6 weeks postpartum)
• OC pills/ estrogen therapy
• Acute hepatitis
• Exercise (10% increase immediately after)

Question 14

Female taking oral contraceptive pills.

Expected iron profile?

Answer 14

OC pills induce Transferrin production&raquo_space; High TIBC

High TIBC
Low Transferrin saturation

Question 15

What is the most sensitive and specific marker for iron deficiency? Why?

Answer 15

Serum ferritin

No diurnal variation
Not effected by pregnancy or estrogen effects
Can detect early iron deficiency before other markers respond - Stage I depletion of iron stores

Question 16

Which marker alone can Dx iron deficiency?

Answer 16

Serum ferritin

Low serum ferritin = Stage I - Depletion of iron stores

Question 17

Why is the ferritin reference range so large?

Implications on reading ferritin levels?

Answer 17

Not tailored to specific patient groups e.g. pediatric, pregnant, geriatric…etc

Must apply age specific cut-offs for ferritin instead of reading reference range!

Question 18

Outline the Adult, Elderly (hospitalized or community-based) serum ferritin cut-offs for Dx of low ferritin level.

Answer 18

Adult = <34 pmol/L

Elderly

• Hospitalized <100pmol/L
• Community <49pmol/L

Question 19

Patient:
86/F, Lives in hospital

Serum iron low
TIBC high
Transferrin saturation: low
Ferritin at 37 (reference 24-675)

Interpret

Answer 19

Never use refernece interval for ferritin, always refer to age and setting

Old age + hospitalization:
Serum ferritin <100pmol/L

> > > > > Ferritin is actually low, indicate Stage II or Stage III iron deficiency with other profiles

Question 20

Patient:
82/F, Hospitalized

Serum iron Low 
TIBC Low*
Transferrin saturation Low 
Ferritin very high 
High ESR and CRP 

Interpret?

Answer 20

TIBC not increased with low serum iron + High ferritin

Ferritin is a positive acute phase reactant
Serum iron and transferrin are negative acute phase reactants
Iron stores are retained in reticuloendothelial system, not available for RBC

> > Anemia of chronic disease (ACD)

Question 21

Anemia of chronic disease (ACD) without iron deficiency

Causes?
Mechanism?
Expected iron profile?

Answer 21

Cause:
Chronic infective, inflammatory, neoplastic disease

Adequate iron stores retained in the reticuloendothelial system, not available for erythropoiesis

Low serum iron, transferrin sat, TIBC (NEGATIVE acute phase reactants)
High Ferritin, CRP, ESR (POSITIVE acute phase reactants)

Question 22

Patient:

High serum iron
Normal - Low TIBC
High transferrin Saturation
Extremely high ferritin

Interpret?

Answer 22

High serum iron with high transferrin saturation + suppression of TIBC/ transferrin

Common possibilities:

• massive transfusion
• iron overload by iron supplements
• Deranged liver function, cannot make transferrin

Question 23

3 common possibilities of high serum iron with normal or low transferrin?

Answer 23

• massive transfusion
• iron overload by iron supplements
• Deranged liver function, cannot make transferrin

Question 24

High serum iron is found/ Haemochromatosis.

Outline the next steps in differentiating the underlying genetic causes?

Answer 24

Look at serum transferrin saturation and ferritin level:

a) TS <45% + normal ferritin = normal
b) TS >45% and/or high ferritin = Check HFE genotype

HFE genotypes:
i) Compound heterozygote C282Y/H63D or non-C282Y heterozygote&raquo_space; exclude other liver or blood diseases&raquo_space; optional phlebotomy

ii) Homozygous C282Y/C282Y&raquo_space; Ferritin >1000 or high liver enzyme&raquo_space; liver biopsy for histopathology&raquo_space; Therapeutic phlebotomy
iii) Homozygous C282Y/C282Y&raquo_space; Ferritin <1000 and normal liver enzyme&raquo_space; Therapeutic phlebotomy

Question 25

1 Major hereditary cause of iron overload?

Answer 25

HFE-related: C282Y homozygous, C282Y/H63D heterozygous, other non-C282Y heterozygous

Question 26

3 causes of secondary iron overload?

Answer 26

1) Iron loading anemias: Thalassemia major, aplastic anemia, Chronic hemolytic anemia…etc
2) Parental iron overload: Hemodialysis, Transfusion, iron supplements…
3) Chronic liver disease: HepB, HepC, Alcoholic liver disease, NASH…

Question 27

Which infections are related to secondary iron overload?

Answer 27

Hep B

Hep C