Iron metabolism

Normal intake is 0.2-0.4 mmol/day (10-20mg/day)

The body contains 50-70 mmol (3-4g) iron: 65%-70% in Haemoglobin 25% in Iron stores (Liver (Spleen (Bone marrow 5-10% in other haem proteins: Myoglobin, cytochromes, catalase, peroxidase 0.1% (4 mg) circulates in plasma

Some statistics

Body iron content: 60 mg/kg bdy wt in 50 mg/kg bdy wt in 1 mg (18 mol) iron required for each ml of red cells produced 20-25 mg of iron required for erythropoiesis each day Only 1 mg/day of the iron turnover is newly absorbed iron About 25% of body iron is found in iron stores

Overview of iron metabolism

Overview of iron transport

Stores: liver, bone marrow, spleen

Transferrin

Negative acute phase protein Capable of binding about 54mol/L of iron Transports iron at the concentration of about 18 mol/L (one third saturated)

Acute phase reactants

negative acute phase reactants

Physiological regulators of iron metabolism

The state of iron stores; states of iron deficiencyabsorption states of iron overload absorption Rate of erythropoiesis; increased rate of erythropoiesis absorption even though iron stores may be adequate or overloaded e.g. thalassaemia / SCD Oxygen tension in the mucosal cells

Local factors in the GI Tract influencing iron absorption

The iron must be released during digestion (iron in haem can be absorbed) Chemical state of the iron: Fe2+ is better absorbed than Fe3+ H+ /ascorbate keep iron in the Fe2+ state and therefore lead to better absorption

Local factors in the GI Tract influencing iron absorption

Complex formation Ascorbate forms soluble complexes with iron and facilitates absorption Organic phosphates (phytates) and inorganic phosphates form insoluble complexes and inhibit absorption

Iron excretion and sources of loss

Iron loss is mainly by desquamation of skin cells and intestinal mucosal cells: in both & (18-20mol /day, ~1 mg/day) Loss generally in by menstruation & pregnancy Losses in the urine are negligible

Regulation of iron loss from the body

Very limited and mainly intestinal Loss approximately doubled in iron overload Loss approximately halved in iron depletion

Biochemical tests in haematology

Plasma [iron].variable Total iron binding capacity (TIBC) in iron deficiency in iron overload Plasma ferritin.corresponds directly with the state of iron stores The soluble transferrin receptor (TfR)

Plasma [iron]1
exclude iron 12-24 h, 12 h fast, sample taken in the morning,

Diurnal fluctuation in plasma iron; higher values in the morning Day to day fluctuation even in healthy individuals Variation occurs with stage of menstrual cycle; low values just before and during the menstrual period

Plasma [iron]2
Pregnancy and oral contraception These may be associated with an increase in plasma [iron] In pregnancy, due to concurrent iron deficiency a low plasma [iron] is more commonly observed

Plasma [iron]: Charateristics3

Variable Changes in iron deficiency or overload occur relatively late Only gives an indication of the available iron stores when these are grossly abnormal Tends to be low in chronic inflammatory conditions and in neoplasia

TIBC: saturate all binding sites on transferrin / remove all unbound iron / measure [iron]

Shows smaller physiological variations than plasma [iron] in pregnancy & therapy with oestrogen containing contraceptives in iron deficiency in iron overload Alters in the opposite direction to plasma [iron] in the above 2 conditions

TIBC & % Saturation1

Low in: Protein losing states, infections, neoplasms and after trauma % saturation= plasma [iron] x 100 TIBC

TIBC & % Saturation2

Plasma[iron]=120 g/dl (50-150 g/dl) TIBC=300 g/dl (240-360 g/dl)

plasma [iron] x 100 = 120 x100 = 40% TIBC 300

TIBC & % Saturation3

Plasma[iron]=89 g/dl (50-150 g/dl) TIBC=295 g/dl (240-360 g/dl)

plasma [iron] x 100 = 89 x100 = 30.2% TIBC 295

Reference ranges

Serum iron: 50-150 g/dl (TIBC): 240-360 g/dl Percent saturation: 20-45% Serum ferritin 12-300 g/L

Plasma ferritin1
protein devoid of iron but in equilibrium with tissue ferritin positive acute phase protein

Correlates directly with the state of body iron stores regardless of whether they are decreased, normal or increased Ferritin is released from diseased tissues in liver disease, leukaemia, and certain other neoplastic and inflammatory disorders Behaves as an acute phase protein

Plasma ferritin2

Plasma [ferritin] is a more difficult assay than plasma [iron]. However, the test is becoming more widely available, and there are several circumstances where its measurement yields information which cannot readily be obtained by other means:

Plasma ferritin3 Use:

When a patient is suspected of having a mild degree of iron deficiency or iron overload. In patients with anaemia due to chronic infection; in these patients, hypochromic anaemia may be due to the primary condition or to associated iron deficiency.

Plasma ferritin4 Use:

In patients with iron overload, to monitor progress and response to treatment either with chelating agents or with venesection.

Iron deficiency. The main causes are:

Deficient intake. Impaired absorption (intestinal malabsorptive disease, e.g. coeliac disease & abdominal surgery). Excessive loss (e.g. menstrual loss; 14% of menstruating women, gastrointestinal bleeding; oesophagitis, PU,
carcinoma, colitis, diverticulitis, haemorrhoids

).

Iron deficiency2

Chronic disease and infection, eg collagen disease, tumour Protein losing states: nephrosis and protein losing enteropathy In patients who develop iron deficiency, the sequence of events, in terms of development of abnormal test results, is as follows:

Iron deficiency3

Plasma [ferritin] falls....immediate Plasma TIBC increases..intermediate SolTfR increases.intermediate Plasma [iron] fallslate Anaemia becomes evident

Iron overload
This is much less common than iron deficiency. Raised plasma [iron] and fully saturated (decreased) TIBC are characteristic of iron overload, whatever the cause.

Iron overload. Causes:

Acute iron overload/ acute liver cell destruction Haemosiderosis due to: Increased intake and absorption: (Chronic iron overload) Parenteral administration of iron, blood transfusions. Haemolytic anaemias Idiopathic haemochromatosis.

The soluble transferrin receptor (solTfR)

Cells express TfRs on their surface Transferrin binds to TfR Transferrin-TfR is internalized into endosomes Iron is released into the cytosol Transferrin-TfR returns to cell surface Apo-transferrin dissociates from TfR

Plasma [TfR] or solTfR

Reflects total cellular TfR levels Cellular TfR up-regulated in iron deficiency Plasma [TfR] also in iron deficiency No acute phase up-regulation Direct relationship with rate of erythropoiesis and red cell turnover

End of Lecture

Thank you

Regulation of iron absorption & transport.

Iron for synthesis of heme, Fe-S centers & other non-heme iron proteins is obtained from:

the diet release of recycled iron from macrophages of the reticuloendothelial system that ingest old & damaged erythrocytes. Iron is significantly lost only by bleeding, including menstruation in females. Small losses occur from sloughing of cells of skin & other epithelia.

There is no mechanism for iron excretion.

transferrin with bound Fe extracellular space transferrin receptor

receptor-mediated endocytosis

Iron is transported in blood serum bound to the protein transferrin.

The plasma membrane transferrin receptor mediates uptake of the complex of iron with transferrin by cells via receptor mediated endocytosis.

Iron is stored within cells as a complex with the protein ferritin. The main storage site is liver.

The plasma membrane protein ferroportin mediates:

release of absorbed iron from intestinal cells to blood serum release of iron from hepatocytes (liver cells) and macrophages.

Control of dietary iron absorption and serum iron levels involves regulation of ferroportin expression.

Transcription of the gene for the iron transporter ferroportin is responsive to iron. Hepcidin, a regulatory peptide secreted by liver, induces degradation of ferroportin.

Hepcidin secretion increases when iron levels are high or in response to cytokines produced at sites of inflammation. Degradation of ferroportin leads to decreased absorption of dietary iron and decreased serum iron. Hepcidin is considered an antimicrobial peptide because by lowering serum iron it would limit bacterial growth.

Hereditary hemochromatosis is a family of genetic diseases characterized by excessive iron absorption, transport & storage.
Genes mutated in these disorders include those for: transferrin receptor a protein HFE that interacts with transferrin receptor hepcidin hemojuvelin, an iron-sensing protein required for transcription of the gene for hepcidin. E.g., impaired synthesis or activity of hepcidin leads to unrestrained ferroportin activity, with high dietary intake and high % saturation of serum transferrin with iron. Organs particularly affected by accumulation of excess iron include liver and heart.