8/8/2019 Iron Aug 2010 JS

1/56

Iron

Metabolism

John Santangelo

8/8/2019 Iron Aug 2010 JS

2/56

8/8/2019 Iron Aug 2010 JS

3/56

Extravascular Pathway for RBC Destruction

Hemoglobin

Haem

Fe2+

Recycled

Globin

Phagocytosis & Lysis

Amino Acids

ferrous (Fe+2) is

more readily

absorbed in the

small intestine

than the ferric (Fe

+3) form, which is

not very soluble.

Bilirubin

Excreted

8/8/2019 Iron Aug 2010 JS

4/56

8/8/2019 Iron Aug 2010 JS

5/56

The History of Iron

The importance of dietary iron has been recognizedfor centuries.

In 4000 BC the Persian physician, Melampus, gave

iron supplements to sailors to make up for the ironlost from bleeding wounds.

In the 17th century, chlorosis was treated with iron.

It wasnt until 1932 that the value of iron therapy

was proven.

8/8/2019 Iron Aug 2010 JS

6/56

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 inFerric (Fe+3) andferrous (Fe+2) forms.

Heme contains the iron bound to the porphyrin

ring, called a metalloporphyrin.

8/8/2019 Iron Aug 2010 JS

7/56

ferrous (Fe+2) is more readily

absorbed in the small intestinethan the ferric (Fe +3) form, which

is not very soluble.

8/8/2019 Iron Aug 2010 JS

8/56

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 hypatocytes (liver), spleen,

bone marrow;

8/8/2019 Iron Aug 2010 JS

9/56

Storage and Excretion

StorageIron 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.

ExcretionNot 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 ofBlood contains 0.5 mg iron.

8/8/2019 Iron Aug 2010 JS

10/56

Functions of Iron

Cofactor for enzymesHeme 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

8/8/2019 Iron Aug 2010 JS

11/56

Interactions

Vitamin C- Improves iron absorption. Ascorbic acid forms a

chelate with nonheme iron, which remains soluble in the smallintestine 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 deficiencyanemia.

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 withoutfood can

inhibit the absorption of Zinc.

Solution: Dont take supplemental iron on a empty stomach.

8/8/2019 Iron Aug 2010 JS

12/56

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, spinich).

Solution: Avoid consumption of phytates with the iron

containing meal.

8/8/2019 Iron Aug 2010 JS

13/56

Dietary iron1-2 mg/day

Liver1000 mg

Spleen600 mg

Plasma transferrin3 mg

Slough mucosal cell1-2 mg/day

Myoglobin300 mg

utilization

Bone marrow300 mg

Erythrocyte1800 mg

utilization

8/8/2019 Iron Aug 2010 JS

14/56

Iron absorptionIron absorption

Fe+++

Fe++

Fe++

Fe++

ferritin

Fe+++ - transferrin

Promote absorption

-Fructose

-Vitamin C

-Heme iron

-Amino acidInhibit absorption

-Phosphate

-Phytate

-Tannin-Soil clay

HCl

Ferrous Fe++

More readily

absorbed

8/8/2019 Iron Aug 2010 JS

15/56

Common diseases

Iron deficiency

Iron overload

Anaemia of chronic disease

Vegetarian groups

Iron Functions

Oxygen carriers

Haemoglobin

Oxygen storage

Myoglobin

8/8/2019 Iron Aug 2010 JS

16/56

8/8/2019 Iron Aug 2010 JS

17/56

8/8/2019 Iron Aug 2010 JS

18/56

Iron Toxicity

Iron can damage tissues (Haemachromatosis)

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

8/8/2019 Iron Aug 2010 JS

19/56

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%

8/8/2019 Iron Aug 2010 JS

20/56

Iron Transport in Blood

Red cells

As haemoglobin

PlasmaBound to Transferrin

Carries iron between body locations

eg between gut, liver, bone marrow, macrophages

Iron taken up into cells by transferrin receptors

8/8/2019 Iron Aug 2010 JS

21/56

The serum contains about 0.1% of body iron

Over 95% of iron in serum bound to transferrin

Serum iron is a routine blood testMeasures all serum iron (not in red cells)

Low levels:

Iron deficiency

Other: Random variation; acute or chronic inflammation;

pre-menstrual.

High levels:

Iron OverloadOther: Random variation, OCP, pregnancy, recent iron

ingestion.

8/8/2019 Iron Aug 2010 JS

22/56

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.

8/8/2019 Iron Aug 2010 JS

23/56

Iron Loss

Physiological

Cell loss: gut, desquamation

Menstruation (1mg/day)

Pregnancy, lactation

Pathological

Bleeding

Gut, menorrhagia, surgery, gross haematuria

8/8/2019 Iron Aug 2010 JS

24/56

8/8/2019 Iron Aug 2010 JS

25/56

Iron Deficiency

Laboratory changes:

Low iron (poor specificity)Low ferritin (excellent specificity)

Elevated Transferrin (TIBC)

Low transferrin saturationHypochromic, microcytic Anaemia

8/8/2019 Iron Aug 2010 JS

26/56

8/8/2019 Iron Aug 2010 JS

27/56

Causes of Iron deficiency

Increased demand for iron

Infancy and adolescence

Pregnancy and lactation

Iron loss

Bleeding

Decreased iron intake or absorption

Hepciden

8/8/2019 Iron Aug 2010 JS

28/56

In physiologic conditions

Menstruation

In pathologic conditions

Surgery,

Haemoglobinuria,

haemoptysisGastrointestinal tract pathology

In therapeutic procedures

Phlebotomy

In blood donation

8/8/2019 Iron Aug 2010 JS

29/56

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 pyloriinfection

Autoimmune atrophic gastritis

8/8/2019 Iron Aug 2010 JS

30/56

Iron Deficiency

Clinical Manifestations

Fatigue

Decreased exercise tolerance

Tachycardia

Dermatologic manifestations

Decreased intellectual performance

Dysphagia

Depression, increased incidence of infectionsRestless legs syndrome

8/8/2019 Iron Aug 2010 JS

31/56

Symptoms of anemia

Fatigue

Dizziness

Headache

Palpitation

Dyspnoea

Lethargy Disturbances in menstruation

Impaired growth in infancy

8/8/2019 Iron Aug 2010 JS

32/56

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

8/8/2019 Iron Aug 2010 JS

33/56

Pica

The habitual ingestion of unusual

substances

earth, clay (geophagia)

laundry starch (amylophagia)

ice (pagophagia)

Usually is a manifestation of iron deficiencyand is relieved when the deficiency is

treated

8/8/2019 Iron Aug 2010 JS

34/56

Iron Deficiency

Clinical Manifestations

Skin and conjuctival pallor

Koilonychia

Angular cheilosis

Burning tongue

Glossitis

Hair loss (alopecia areata)

8/8/2019 Iron Aug 2010 JS

35/56

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)

8/8/2019 Iron Aug 2010 JS

36/56

Microcytic Hypochromic

8/8/2019 Iron Aug 2010 JS

37/56

8/8/2019 Iron Aug 2010 JS

38/56

8/8/2019 Iron Aug 2010 JS

39/56

Megaloblastic Anaemia

(Pernicious Anaemia)

Hypersegmented Neutrophilsand

Oval Macrocytes

8/8/2019 Iron Aug 2010 JS

40/56

8/8/2019 Iron Aug 2010 JS

41/56

Koilonychia

Spoon shaped fingernail that occurs in

Iron deficiency anaemia

8/8/2019 Iron Aug 2010 JS

42/56

Oral iron - GI irritation

- Diarrhoea

- Constipation

IV iron - anaphylactoid

- hypotension

- muscle cramp

Side effects of Iron Therapy

Black Stools

8/8/2019 Iron Aug 2010 JS

43/56

Iron DeficiencyDiagnosis

Microphotograph

of bone marrow

staining for iron.

Iron is stained

blue and it is

mainly in themacrophages

(lower left)

8/8/2019 Iron Aug 2010 JS

44/56

Females 11 14 15

15 18 15

19 24 15

25 50 15

51 + 10

Pregnant 30

Lactating 1st

6

months

15

2nd

6

months

15

C ategory Age (years) R DA Iron(mg)

Infants 0 0.5 6

0.5 1 10

Children 1 3 10

4 6 10

7 10 10

M ales 11 14 12

15 18 12

19 24 10

25 50 10

51 + 10

Iron requirements (RDA)

8/8/2019 Iron Aug 2010 JS

45/56

Laboratory findings (2)

Iron metabolism tests

serum iron concentration q

total iron-binding capacity (TIBC)o

saturation of transferrin q

serum ferritin levels q

sideroblasts q

8/8/2019 Iron Aug 2010 JS

46/56

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

8/8/2019 Iron Aug 2010 JS

47/56

Hemochromatosis

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

8/8/2019 Iron Aug 2010 JS

48/56

Accumulation

Iron accumulation in tissues

causes damage/ failure to:

Liver

Heart

Pancreas

Skin

May generate free radicals which

can damage normal cells.

8/8/2019 Iron Aug 2010 JS

49/56

Too much Iron

Haemochromotosis

Uncontrolled Iron absorption leads to Iron overload

1. Liver2. Heart

3. Pancreas

4. Skin5. Joints

Iron accumulates in: And causes:

1. Cirrhosis

2. Cardiomyopathy

3. Diabetes

4. Bronzing

5. Arthritis

It is Autosomal recessive

8/8/2019 Iron Aug 2010 JS

50/56

Autosomal recessive

An abnormal gene on one of the autosomal chromosomes (one

of the first 22 "non-sex" chromosomes) from each parent isrequired 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 havesymptoms of the disease. A child who inherits the gene from

one parent will be a carrier.

8/8/2019 Iron Aug 2010 JS

51/56

Iron studyIron study

1. Serum iron

2.Total iron binding capacity (TIBC)

3. %Transferrin saturation (% sat)

4. Ferritin

8/8/2019 Iron Aug 2010 JS

52/56

Normal

Iron Overload

8/8/2019 Iron Aug 2010 JS

53/56

Iron

Overload

8/8/2019 Iron Aug 2010 JS

54/56

Haemochromatosis

Rust In Peace

8/8/2019 Iron Aug 2010 JS

55/56

Guess who?

PrincessDiana

8/8/2019 Iron Aug 2010 JS

56/56

Cowasaki