Iron Part 1 Flashcards
1
Q
Which proteins are complexed with irons?
A
- 65% in haemoglobin (Hb)
- 30% ferritin/haemosiderin
- 3.5% myoglobin (Mb)
- 0.5% haem enzymes
- 0.1% transferrin
2
Q
What is the Physiological Iron Requirement?
A
- Turnover 20-30 mg/day
-
Absorption 1-2 mg/day
- 5-10% of 10-15 mg in diet
- 1 mg/day menstruation
- 1-2 mg/day pregnancy
- 0.5 mg/day paediatric
-
Losses 1-2 mg/day
- Intestines, Bile, Skin, Urine
3
Q
What are causes of increased iron absorption?
A
- Iron deficiency (up to 30%)
- Increased erythropoiesis
- Ingestion of acids, e.g. ascorbate (reduces Fe3+ to Fe2+)
- Pregnancy
4
Q
What are causes of decreased iron absorption?
A
- Decreased erythropoiesis
- Ingestion of alkalis
- Ingestion of tea
- Precipitating agents (phytates, phosphates)
- Desferrioxamine
5
Q
What are features of Intracellular Ferritin?
A
-
Intracellular storage of bioavailable iron
- Hollow spherical particle found in Hepatocytes, macrophages
- Solid-state core of up to 4000 Fe3+ ions
-
450 kDa, 24 subunits
- 21 kDa ‘H’ chains, predominate in heart/kidney isoforms
- 19 kDa ‘L’ chains, predominate in liver/spleen isoforms
- Ferroxidase activity
-
Denatures to hemosiderin
- Heterogenous aggregate of iron, lysosomal components and other products of intracellular digestion
6
Q
What are features of plasma ferritin?
A
- Small amount of ferritin is secreted into plasma
- L-rich, low iron content, glycosylation slows clearance
- No role in iron transport or uptake but correlates with total stores
7
Q
What does low ferritin indicate?
A
Low ferritin indicates iron deficiency
8
Q
What causes High Ferritin?
A
High ferritin does not necessarily indicate iron overload. Caused by:
- Redistribution
- Increased ferritin synthesis
- Release of tissue ferritin
- Liver disease
- Chronic inflammation
- Malignancy
- Thyrotoxicosis
- Alcohol
- Familial hyperferritinaemia and cataract syndrome
9
Q
What should be considered with Ferritin >10,000 μg/L?
A
Consider:
- Still’s disease
- Haemophagocytic Lymphohistiocytosis
10
Q
What are investigations for a raised serum ferritin?
A
- Question alcohol intake and other risk factors for liver disease, transfusion history, family history of iron overload and the presence or absence of type 2 diabetes mellitus, obesity and hypertension, as well as for symptoms and signs that may point to an underlying inflammatory or malignant disorder
- Initial investigations: FBC & film, repeat ferritin, TSAT, inflammation markers (e.g. CRP), renal/liver/lipid profiles (abdominal u/s if LFT abnormal), glucose, consider hepatitis serology
- No evidence for therapeutic venesection in non-alcoholic fatty liver disease
11
Q
What should be done based on the ferritin levels?
A
- Ferritin <1000 μg/L, normal TSAT, otherwise well: (lifestyle adjustment), repeat in 3–6 months
- Unexplained persistent hyperferritinaemia (especially >1000 μg/L): refer to a hepatologist
12
Q
What are features of Transferrin?
A
- 80 kDa, 6% carbohydrate
- Reversibly binds 2x Fe3+ and 2x HCO3-
- 2x N-linked bi/tri-antenarry glycans
- Determines half-life
- Variants – serum/CSF, alcohol, polymorphisms, inborn errors
- Recycled approximately 500 times
13
Q
How is Serum Iron assessed?
A
- Predominantly reflects transferrin-bound iron = in-use iron binding capacity
- Requires a fasted sample otherwise if a patient has a large iron load in food, it will go up as a measurement otherwise even if the patient is low in iron
- Colorimetric, atomic absorption spectroscopy, ICP-MS
- (Abdominal x-ray if acute toxic ingestion suspected)
14
Q
How is Transferrin and Ferritin measured?
A
Specific immunoassay
15
Q
What is the Unsaturated Iron Binding Capacity (UIBC)?
A
- The unused iron binding capacity. Measures the unbound tranferrin
- Measured as the amount of Fe3+ taken up (by transferrin) at alkaline pH
- Fallen out of favour.
16
Q
What isTotal Iron Binding Capacity (TIBC)?
A
Total available iron if all binding sites (principally transferrin) fully saturated
Measured as iron concentration when sample saturated with added Fe3+
- If Calculated from UIBC
- TIBC = UIBC + [Iron]
- If Calculated from transferrin
- TIBC (umol/L) = transferrin (g/L) x 24.7
17
Q
How is transferrin calculated from TIBC?
A
Transferrin (g/L) =0.0007 x TIBC (ug/L)
18
Q
How is %transferrin saturation calculated?
A
- 100 x [Iron]/TIBC
19
Q
What causes secondary iron overload?
A
- Excess iron intake
- Dietary: Drinking beer brewed in iron containers
- Supplements or injections
- Transfusion-related siderosis
- Long-term dialysis
- Sideroblastic anaemia
- Ineffective erythropoiesis
- Porphyria cutanea tarda
20
Q
What causes Primary Iron Overload?
A
- Hereditary haemochromatosis: HFE, TFR2 & gain-of-function Ferroportin defects\
- African iron overload
- Juvenile haemochromatosis: Haemojuvelin (BMP coreceptor) & Hepcidin defects
- Neonatal haemochromatosis
- Acaeruloplasminaemia
- Hyperferritinaemia-catarract syndrome: Ferritin L-chain defects
- Erythropoietic protoporphyria: Mitoferrin defects
- Atransferrinaemia: Transferrin defects
- Macrophage-predominant iron overload:
- Ferroportin loss-of-function
- Anaemia with iron overload and sideroblasts: Glutaredoxin 5 defects
- Friedreich ataxia: Frataxin defects (mitochondrial iron chaperone)
21
Q
What is the pathogenesis of Hereditary haemochromatosis?
A
- Inherited progressive iron overload due to increased iron uptake 3-4 mg/day: positive iron balance 400-1000 mg/year
- Lipid peroxidation in the liver so cellular injury leading to fibrosis
- Iron deposition: Liver (90%), Endocrine glands, Joints, Heart
- Menstruation has positive effect.
22
Q
What is the classican triad of Hereditary Haemochromatosis?
A
- Pigmentation (‘bronzing’)
- Diabetes
- Cirrhosis
- Hypothyroidism
- Hypogonadism
- Cardiomyopathy
23
Q
What are common symptoms of Hereditary haemochromatosis?
A
- Fatigue
- Weight loss
- Weakness
- Arthralgia
- Oligo/amenorrhoea
- Erectile dysfunction
24
Q
What are investigations for Hereditary haemochromatosis?
A
- FBC, LFT, TSAT
- High transferrin saturation and serum ferritin
- (Liver biopsy, hepatic stored iron)
- MRI scan
- (Genetic testing): HFE gene defects have low penetrance. Only C282Y homozygotes generally develop clinical disease
- Exclude other causes of iron overload
25
What are the genetics of Hereditary Haemachromatosis?
HFE gene defects predominate: Very high prevalence in north European descent (polymorphisms)
1. **HFE C282Y:** HFE protein cannot bind B2-microglobulin
* HFE cannot stabilise in cell membranes
* Unregulated TFR-mediated intestinal iron uptake
2. **HFE H64D**
* HFE binds TFR but lacks high degree of inhibition
26
What the different variations of HFE gene defects?
**1 copy C282Y**
* Carrier of the C282Y variant; no increased risk of developing hereditary HC
* 25% of individuals may exhibit mild/moderate iron overload
* Complications due to iron overload are rare
* May be influenced by additional factors( genetic, environmental)
**1 copy C282Y, 1 copy H63D**
* Excludes the most common cause of hereditary HC
* May predispose to mild/moderate iron overload
* If iron overload, consider other contributing factors
* If severe iron overload, consider rare genetic causes
* Consider family testing for iron overload
**2 copies C282Y**
* Reported in approximately 90% of hereditary HC patients
* Investigate for iron overload
* Consider family testing for iron overload
27
What is the treatment for Hereditary Haemachromatosis?
**Reduce the amount of iron present**
* Therapeutic phlebotomy - weekly venesection and FBC
* Ferritin 20-30 μg/L and TSAT \<50% (monthly TSAT)
* Blood donation opportunity
* Iron chelation (desferrioxamine)
**Avoid alcohol**
**‘Minihepcidins’**
