Iron

Metabolism
John Santangelo

Extravascular Pathway for RBC Destruction

ferrous (Fe+2) is more readily absorbed in the small intestine than the ferric (Fe +3) form, which is not very soluble.

Phagocytosis & Lysis

Hemoglobin

Bilirubin
Unconjugated (fat soluble)

Haem

Globin

Fe2+
Conjugated Water soluble

Amino Acids

Excreted

Recycled

The History of Iron The importance of dietary iron has been recognized for centuries. In 4000 BC the Persian physician, Melampus, gave iron supplements to sailors to make up for the iron lost from bleeding wounds. In the 17th century, chlorosis was treated with iron. It wasnt until 1932 that the value of iron therapy was proven.

Iron Exists in several oxidation states.

There are 2 forms of iron: Heme; animal Non-heme; plants In the human body and food, iron exists in Ferric (Fe+3) and ferrous (Fe+2) forms. Heme contains the iron bound to the porphyrin ring, called a metalloporphyrin.

ferrous (Fe+2) is more readily absorbed in the small intestine than the ferric (Fe +3) form, which is not very soluble.

Iron in human body

Total iron in human body ~3.8 g (men), ~2.3 g (women); Iron is localized mostly in cells;

1-2 mg are taken up from food (10 % absorption); 1-2 mg are released with skin and gut tissues. Fe metabolism is conservative;

Transferrin is the major Fe binder in blood plasma. Most ferritin is found in hepatocyte's (liver), spleen, bone marrow;

Storage and Excretion

Storage
Iron is delivered by transferrin to the liver, bone marrow and spleen. Primary storage form of iron is Ferritin in cells and tissues. Secondary storage form of iron is Hemosiderin (protein). Stored more in the liver, then bone marrow and spleen.

Excretion

Not needed iron as ferritin it is excreted with the mucosal cells that are shed off into the lumen of GI tract every 2-3 days. Most iron is lost from the GI Tract,, then skin, kidney. Small amount lost in urine. During menstrual cycle lost iron accounts for 17.5mg per cycle.

Every mL of Blood contains 0.5 mg iron.

Functions of Iron
Cofactor for enzymes Heme dependent enzymes used in:-Oxygen transport and storage -Electron transport, energy metabolism and detoxification of drugs -Antioxidant -Defense mechanism by binding free iron to ensure bacteria does not use it to grow fight infection. -DNA synthesis and cell replication -as amino acid metabolism. -Thyroid hormone production Non heme dependent enzymes used in:-Neurotransmitters, and pro-oxidant functions -Regulation of intracellular iron by levels of transferrin receptors present

Interactions
Vitamin C- Improves iron absorption. Ascorbic acid forms a chelate with nonheme iron, which remains soluble in the small intestine therefore increasing intestinal absorption of non heme iron. Vit. C rich foods should be eaten at the same meal as iron source. Vitamin A- Deficiency in vitamin A may intensify iron deficiency anemia. Low plasma retinol concentrations are associated with decreased iron. Combination of Vit. A and iron, together, seems to improve anemia Copper- Required for iron transport to the bone marrow for RBC production. Zinc- Iron and zinc supplements taken together without food can inhibit the absorption of Zinc. Solution: Dont take supplemental iron on a empty stomach.

Interactions
Calcium- Decreases the absorption of iron when consumed together. Solution: Avoid consuming calcium rich foods at the same time of a meal containing iron. Coffee and Tea- Decreases iron absorption by 60% ! Tannins (polyphenols) bind to iron affecting iron availability. Solution: Do not consume coffee/tea at the time of meal containing iron or just after. Phytates- Interferes with iron absorption. Phytates bind minerals such as iron, forming a complex that is insoluble and therefore poorly absorbed, (Found in maize, whole grains, legumes, spinach). Solution: Avoid consumption of phytates with the iron containing meal.

utilization
Dietary iron 1-2 mg/day

utilization
Bone marrow 300 mg

Myoglobin 300 mg

Plasma transferrin 3 mg

Erythrocyte 1800 mg

Liver 1000 mg

Slough mucosal cell 1-2 mg/day

Spleen 600 mg

Iron absorption
Promote absorption -Fructose -Vitamin C -Heme iron -Amino acid

Ferrous Fe++

Fe+++
Fe++ Fe++
Fe++ ferritin HCl

More readily absorbed

Inhibit absorption

-Phosphate
-Phytate -Tannin

-Soil clay

Fe+++ - transferrin

Common diseases Iron deficiency Iron overload Anaemia of chronic disease Vegetarian groups Iron Functions Oxygen carriers Haemoglobin Oxygen storage Myoglobin

What do you see? A Foetus

Iron Toxicity
Iron can damage tissues (Haemochromatosis) Catalyzes the conversion of hydrogen peroxide to free-radical ions Free-radicals can attack: cellular membranes Proteins DNA Iron excess possibly related to cancers, cardiac toxicity and other factors

Iron distribution
35 45 mg / kg iron in adult male body Total approx 4 g Red cell mass as Haemoglobin - 50% Muscles as Myoglobin 7% Storage as ferritin - 30% Bone marrow (7%) Reticulo-endothelial cells (7%) Liver (25%) Other Haem proteins - 5% Cytochromes, Myoglobin, others In Serum - 0.1%

Iron Transport in Blood

Red cells As Haemoglobin Plasma Bound to Transferrin Carries iron between body locations eg between gut, liver, bone marrow, macrophages Iron taken up into cells by transferrin receptors

The serum contains about 0.1% of body iron Over 95% of iron in serum bound to transferrin Serum iron is a routine blood test Measures all serum iron (not in red cells) Low levels: Iron deficiency Other: Random variation; acute or chronic inflammation; pre-menstrual.

High levels: Iron Overload Other: Random variation, OCP (Ova,Cysts & Parasites), pregnancy, recent iron ingestion.

Ferritin
A routine blood test reflects iron stores Low serum levels Indicate Iron deficiency (high specificity)

High serum levels Iron overload Other - Ferritin may be increased in serum by: Tissue release (hepatitis, leukaemia, lymphoma) Acute phase response (tissue damage, infection, cancer) Interpretation Low levels always indicate Fe deficiency.

Iron Loss
Physiological Cell loss: gut, desquamation Menstruation (1mg/day) Pregnancy, lactation Pathological Bleeding Gut, menorrhagia, surgery, gross haematuria

Iron Absorption Regulation

Increased Low dietary iron Low body iron stores Increased red cell production Low haemoglobin Low blood oxygen content Decreased Systemic inflammation

Iron Deficiency
Laboratory changes: Low iron (poor specificity) Low ferritin (excellent specificity) Elevated Transferrin (TIBC) Low transferrin saturation Hypochromic, microcytic Anaemia

Microcytes & Hypochromia

Causes of Iron deficiency

Increased demand for iron Infancy and adolescence Pregnancy and lactation

Iron loss Bleeding Decreased iron intake or absorption Hepciden

In physiologic conditions Menstruation In pathologic conditions Surgery, Haemoglobinuria, Haemoptysis (coughing up blood) Gastrointestinal tract pathology
In therapeutic procedures Phlebotomy (removal of blood) In blood donation

Iron DeficiencyDecreased Iron Intake or Absorption

Vegetarians or malnutrition (low-cost diet) Malabsorption syndromes Sprue, Ulcrative colitis, and Crohns disease After gastric and intestinal surgery Intestinal parasitosis Helicobacter pylori infection Autoimmune atrophic gastritis

Iron Deficiency Clinical Manifestations Fatigue Decreased exercise tolerance Tachycardia Dermatologic manifestations Decreased intellectual performance Dysphagia Depression, increased incidence of infections Restless legs syndrome

Symptoms of anemia

Fatigue Dizziness Headache Palpitation Dyspnoea Lethargy Disturbances in menstruation Impaired growth in infancy

Symptoms of iron deficiency

Irritability Poor attention span Lack interest in surroundings Poor work performance Behavioural disturbances Pica Defective structure and function of epithelial tissue
especially affected are the hair, the skin, the nails, the tongue, the mouth, the hypopharynx and the stomach

Increased frequency of infection

Pica
The habitual ingestion of unusual substances
earth, clay (geophagia) laundry starch (amylophagia) ice (pagophagia)

Usually is a manifestation of iron deficiency and is relieved when the deficiency is treated

Iron Deficiency Clinical Manifestations Skin and conjuctival pallor

Koilonychia

Angular cheilosis
Burning tongue Glossitis Hair loss (alopecia areata)

Iron Deficiency Anemia (IDA)

Most common cause of anemia

Microcytic hypochromic anemia

MCV, MCH, MCHC are reduced blood film : small red cells (microcytic) : pale red cells (hypochromic)

Microcytic Hypochromic

Glossitis

Megaloblastic Anaemia (Pernicious Anaemia)

Hypersegmented Neutrophils and

Oval Macrocytes

Koilonychia
Spoon shaped fingernail that occurs in

Iron deficiency anaemia

Side effects of Iron Therapy Oral iron - GI irritation

Black Stools

- Diarrhoea
- Constipation

IV iron

- anaphylactoid - hypotension - muscle cramp

Iron DeficiencyDiagnosis
Microphotograph of bone marrow staining for iron. Iron is stained blue and it is mainly in the macrophages (lower left)

Iron requirements (RDA)

Category Infants Age (years) RDA Iron (mg) 0 0.5 0.5 1 Children 13 46 7 10 Males 11 14 15 18 19 24 25 50 51 + 6 10 10 10 10 12 12 10 10 10

Females

11 14 15 18 19 24 25 50 51 +

15 15 15 15 10 30

Pregnant Lactating 1st 6 months 2nd 6 months

15 15

Laboratory findings (2)

Iron metabolism tests

serum iron concentration total iron-binding capacity (TIBC) saturation of transferrin serum ferritin levels sideroblasts

Response to treatment
Less irritable & increased appetite within 24 hrs Bone marrow response by 48 hrs Increased reticulocyte count by 3rd day Increased Hb level by 2 months Body iron store repletion

Haemochromatosis
Also known as accumulating disease. This is a genetic disorder in which the intestine is not able regulate iron absorption. Result: iron absorption increases = build up of excess iron = organ damage. Most often seen in Caucasian males around age 20

Accumulation Iron accumulation in tissues causes damage/ failure to: Liver Heart Pancreas Skin May generate free radicals which can damage normal cells.

Too much Iron Haemochromotosis Uncontrolled Iron absorption leads to Iron overload

Iron accumulates in: 1. Liver 2. Heart

And causes:

1. Cirrhosis
2. Cardiomyopathy 3. Diabetes

3. Pancreas
4. Skin 5. Joints

4. Bronzing
5. Arthritis

It is Autosomal recessive

Autosomal recessive An abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from each parent is required to cause the disease. People with only one abnormal gene in the gene pair are called carriers, but since the gene is recessive they do not exhibit the disease. In other words, the normal gene of the pair can supply the function of the gene so that the abnormal gene is described as acting in a recessive manner. BOTH parents must be carriers in order for a child to have symptoms of the disease. A child who inherits the gene from one parent will be a carrier.

Iron study
1. Serum iron
2.Total iron binding capacity (TIBC) 3. %Transferrin saturation (% sat) 4. Ferritin

Normal

Iron Overload

Iron
Overload

Haemochromatosis
Rust In Peace

Guess who?

Princess Diana

Cowasaki