iron Flashcards
What is the Fenton reaction?
Ferrous iron plus hydrogen peroxide produces damaging, highly reactive hydroxyl radicals plus ferric iron
What are the two storage forms of iron?
Ferritin and haemosiderin
Main site of absorption of iron
Duodenum and proximal jejunum
Main storage site of surplus iron
Hepatocytes
Most iron in the body is found in…
Erythrocytes and macrophages
Main role of hepcidin
Regulator of iron absorption and macrophage iron release
Where is hepcidin synthesized?
Hepatocytes
In what forms does hepcidin circulate?
Free, and bound to alpha-2 macroglobulin
What is ferroportin?
The main exporter of iron from within cells to the blood stream
How does hepcidin regulate iron release/absorption?
By binding to ferroportin, which causes its internalisation and degradation
Where is ferroportin found?
On the basolateral surface of jejunal enterocytes and on macrophages
What is the role of hephaestin and ceruloplasmin in iron metabolism?
They are multicopper oxidases that catalyse the oxidation of Fe 2+ to Fe 3+ for loading onto transferrin. Hephaestin does this from enterocytes and ceruloplasmin does this from macrophages and hepatocytes.
The erythroid progenitor cells uptakes which form of iron:
a) hepcidin bound
b) ferroportin bound
c) transferrin bound
d) hephaestin bound
c) transferrin bound
Where does heme synthesis occur?
In the mitochondria of the erythroid progenitor cell
How many subtypes of hereditary haemochromatosis are there?
6
What is the classical hereditary haemochromatosis phenotype? How many of the subtypes have this classical phenotype?
Normal Hb
Increased ferritin and transferrin saturation
Tissue iron overload
5/6 of the subtypes have this classical phenotype
What is the most common genotype for hereditary haemochromatosis?
Homozygous C282Y (cysteine to tyrosine at position 282) mutation of the HFE gene on chromosome 6
Briefly describe the pathogenesis of hereditary haemochromatosis.
Insufficient hepcidin cause increased ferroportin causes excessive iron absorption which exceeds the needs of the body. Deposition of Fe in parenchymal organs eg liver and pancreas
Benefits of early diagnosis and therapy for hereditary haemochromatosis
Prevent the development of tissue damage
Reduce morbidity and mortality
Provide long-term survival similar to the general population
Improve mental wellbeing
Therapy for hereditary haemochromatosis
Phlebotomy - 1 unit (500mL) blood/week until serum ferritin 50-100 ug/L
How is therapeutic phlebotomy for hereditary haemochromatosis monitored?
Measure serum ferritin every 10-12 phlebotomies (approx 3 monthly) until target of 50-100 ug/L is reached. May need to monitor more closely when approaching target to ensure iron deficiency does not develop.
Carrier frequency of HFE gene mutation?
1 in 10
Prevalence of hereditary haemochromatosis (HFE gene C282Y homozygotes) in a Caucasian population?
1 in 200
Second most common mutation of HFE gene after C282Y? What kind of disease is this gene mutation associated with?
H63D (his63asp). H63D homozygotes and C282Y/H63D compound heterozygotes are not considered disease-associated genotypes and rarely get clinically significant iron overload
In which proteins do mutations cause hereditary haemochromatosis?
Hepcidin
Ferroportin
Haemojuvelin
Transferrin receptor
What are the 6 subtypes of hereditary haemochromatosis and what genes are affected?
HH type 1 - HFE
HH type 2A - HAMP
HH type 2B - HJV
HH type 4 - TfR2
HH type 4A - SLC40A1 (LOF)
HH type 4B - SLC40A1 (GOF)
What is “ferroportin disease”
HH type 4A - SLC40A1 LOF results in iron overload restricted to reticuloendothelial system. Patients have high ferritin, normal transferrin saturations and, rarely, iron-restricted erythropoiesis with mild anaemia and intolerance of phlebotomy. Patients rarely develop iron-related disease symptoms. A diagnosis of exclusion (of other causes of hyperferritinaemia)
Causes of hyperferritinaemia
- Infection/inflammation
- Metabolic syndrome
- Renal insufficiency
- Malignancy
- Familial hyperferritinaemia-congenital cataract syndrome
- Aceruloplasminaemia
- Ferroportin disease
How is hereditary haemochromatosis diagnosed?
After identification of a patient with the typical biochemical pattern (increased ferritin and increased transferrin saturation), genetic testing, usually firstly of the HFE gene for the most common C282Y mutation eg by Sanger sequencing, followed by more extensive screening eg by next generation sequencing, if an HFE mutation is not found.
Typical pattern of laboratory investigations for hereditary haemochromatosis
Iron - high
Ferritin - >300 ug/L (M), >200 ug/L (F)
TF sats - >45%
Hb, MCV and MCH - high-normal
What does the HFE gene code for?
The HFE protein - this protein modulates the expression of hepcidin.
How does obesity cause iron deficiency?
Low-grade inflammation increases hepcidin production which reduces iron absorption and release from the reticuloendothelial system.
Causes of a high transferrin sats
Haemochromatosis
Recent oral iron supplement ingestion
Causes of an absurdly high ferritin (100000+)
Severe, acute liver failure
Haemophagocytic lymphohistiocytosis
Malignancy
HH
Adult onset Still’s disease
Juvenile arthritis
Chronically transfused states eg sickle cell
Your lab’s iron method
Iron released from transferrin under acidic conditions, which simultaneously reduces ferric iron to ferrous form. Ferrous iron complexes with ferrozine to produce a chromogen which absorbs at 57/658
Your lab’s transferrin method
Immunoturbidimetric
Transferrin sats calculation
Iron/TF × 1.2
Your lab’s ferritin method
Two site chemiluminescent immunoassay
