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Презентация на тему Iron Metabolism, Iron Deficiency and Overload

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2. IRON METABOLISMIron has the capacity to accept
3. Proteins of Iron Transport, Uptake and StorageTransferrin
4. Proteins of iron regulationIron Regulatory Proteins (IRP-1,
5. Iron MetabolismAdult man normally have 35-45mg/kg iron,
8. IRON METABOLISM Dietary Iron: Iron is
9. Regulation of Iron AbsorptionHumans have no physiologic
10. TRANSPORT PROTEINS DMT1 (Divalent Metal Transporter 1)
11. Hepicidin, Primary regulator Increased expression of hepicidin
12. Hepcidin A 25 amino
13. HEPICIDN25 Amino acid disulfide peptide.
14. OHepcidin lowers iron absorption in the intestine
15. Ferroportin The only cellular iron exporter in vertebrates. Present in macrophages, placenta and the hepatocytes.
16. Mechanism of action of hepicidin The major
17. Hepicidin RegulationSo when hepicidin levels are low
18. IRON DEFICIENCYIn 1997 Looker et al reported
19. Iron deficiency is the commonest cause of
21. Causes of Iron Deficiency Inadequate absorptionAntiacid or
23. Stages of Iron DeficiencyIron depletion - decrement
25. Clinical PresentationAsymptomaticSigns and symptoms of underlying disordersManifestations
27. Laboratory Evaluation
29. Differential Diagnosis of Microcytic Anemias With decreased
30. THERAPYTherapeutic trail of iron – confirms diagnosis
31. ORAL IRON THERAPYFerrous (Fe3+) iron salt supplying
32. Parenteral Iron TherapyMalabsorptionIntolerance to oral treatmentChronic uncontrolled
34. Iron Overload Accumulation of iron can
35. Disease States Hepcidin deficiency, physiological = Haemochromatosis Hepcidin excess – anaemia of chronic disease
37. The role of Hepcidin in hereditary hemochromatosisHereditary
38. Hereditary HemochromatosisAutosomal recessive disease Excessive absorption of
39. Iron OverloadThe clinical features of iron overload
40. Therapy Hemochromatosis without anemia – regular venesection,
41. Iron chelatorsDeferoxamine – parenteral use, excretion in
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IRON METABOLISMIron has the capacity to accept and donate electrons: Fe2+⮀Fe3+, this capability makes it useful component of cytochromes, O2-binding molecules.Iron can damage tissues by producing free radicals that attack cellular membranes, proteins, DNA.

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Iron Metabolism, Iron Deficiency and Overload

Iron Metabolism, Iron Deficiency and OverloadR. Fineman, MDRambam Medical Center, HaifaISRAEL

IRON METABOLISMIron has the capacity to accept and donate electrons: Fe2+⮀Fe3+, this

Proteins of Iron Transport, Uptake and StorageTransferrin – a transport protein, carries

Proteins of iron regulationIron Regulatory Proteins (IRP-1, IRP-2) are mRNA-binding proteins

Iron MetabolismAdult man normally have 35-45mg/kg iron, women have less.2/3 of body

Iron Metabolism, Iron Deficiency and Overload

IRON METABOLISM Dietary Iron: Iron is essential element and must be

Regulation of Iron AbsorptionHumans have no physiologic way for iron excretion and

TRANSPORT PROTEINS DMT1 (Divalent Metal Transporter 1) (Tranports from lumen into

Hepicidin, Primary regulator Increased expression of hepicidin leads to Decrease iron

Hepcidin A 25 amino acid polypeptide produced by liver

HEPICIDN25 Amino acid disulfide peptide.

OHepcidin lowers iron absorption in the intestine , lowers iron releasing from

Ferroportin The only cellular iron exporter in vertebrates. Present in macrophages, placenta and the hepatocytes.

Mechanism of action of hepicidin The major mechanism of hepicidin is THE

Hepicidin RegulationSo when hepicidin levels are low ,iron exporting cells have abundant

IRON DEFICIENCYIn 1997 Looker et al reported that 3% of American

Iron deficiency is the commonest cause of anemia world wild.The anemia of

Causes of Iron Deficiency Inadequate absorptionAntiacid or high gastric PhExcess bran,phytatesLoss of

Stages of Iron DeficiencyIron depletion - decrement of iron stores, no decline

Clinical PresentationAsymptomaticSigns and symptoms of underlying disordersManifestations common to anemia from all

Differential Diagnosis of Microcytic Anemias With decreased iron storesIron Deficiency Anemia

THERAPYTherapeutic trail of iron – confirms diagnosis of IDA if:Reticulocytosis starts 3-5

ORAL IRON THERAPYFerrous (Fe3+) iron salt supplying 150-200 mg elemental iron daily

Parenteral Iron TherapyMalabsorptionIntolerance to oral treatmentChronic uncontrolled bleedingRISKS – anaphylaxis (0.5-1%), severe

Iron Overload Accumulation of iron can occur in disorders associated with

Disease States Hepcidin deficiency, physiological = Haemochromatosis Hepcidin excess – anaemia of chronic disease

The role of Hepcidin in hereditary hemochromatosisHereditary hemochromatosis: -excessive intestinal iron absorption -Saturation of

Hereditary HemochromatosisAutosomal recessive disease Excessive absorption of Fe from GITHFE – the

Iron OverloadThe clinical features of iron overload from any cause are similar:

Therapy Hemochromatosis without anemia – regular venesection, each unit of blood removes

Iron chelatorsDeferoxamine – parenteral use, excretion in urine, side effects – deafness,

Слайды презентации

Слайд 2 IRON METABOLISM
Iron has the capacity to accept and

IRON METABOLISMIron has the capacity to accept and donate electrons: Fe2+⮀Fe3+,

donate electrons: Fe2+⮀Fe3+, this capability makes it useful component

of cytochromes, O2-binding molecules.
Iron can damage tissues by producing free radicals that attack cellular membranes, proteins, DNA.

Слайд 3 Proteins of Iron Transport, Uptake and Storage
Transferrin –

Proteins of Iron Transport, Uptake and StorageTransferrin – a transport protein,

a transport protein, carries iron in the plasma and

ECF to supply tissue needs.
Transferrin receptor – a glycoprotein on cell membranes, binds the transferrin-iron complex and is internalized as a vesicle.
Ferritin – iron storage protein.

Слайд 4 Proteins of iron regulation
Iron Regulatory Proteins (IRP-1,

IRP-2) are mRNA-binding proteins that coordinate expression of transferrin,

transferrin receptors and ferritin.
Hepcidin
Ferroprotin
DMT1 (Divalent Metal Transporter -
Tranports iron from lumen into the enterocytes)

Слайд 5 Iron Metabolism
Adult man normally have 35-45mg/kg iron, women

Iron MetabolismAdult man normally have 35-45mg/kg iron, women have less.2/3 of

have less.
2/3 of body iron is in haemoglobin in

erythron (RBC precursors in the marrow + RBC in blood)
Most of the remaining iron is found in hepatocytes and reticuloendothelial macrophages which serve as depots

Слайд 6

Слайд 7

Слайд 8 IRON METABOLISM
Dietary Iron:
Iron is essential

element and must be
precisely regulated.
On the

lumen side of small intestine iron is reduced from its ferric form (Fe3+) to ferrous form (Fe2+).
Ferrous iron is then transported in enterocytes by DMT1 (divalent metal transporter).

Слайд 9 Regulation of Iron Absorption
Humans have no physiologic way

Regulation of Iron AbsorptionHumans have no physiologic way for iron excretion

for iron excretion and regulation of absorption is crucial.
The

absorption takes place at gastrodeuodenal junction in acid environment.
There is no role for transferrin in intestinal absorption of iron.
Hepsidin, Ferriprotin, DMT-1

Слайд 10 TRANSPORT PROTEINS
DMT1 (Divalent Metal Transporter 1)

(Tranports from lumen into the enterocytes)

FERROPORTIN1
(Transports

from enterocytes to circulation)

Слайд 11 Hepicidin, Primary regulator
Increased expression of hepicidin leads

to
Decrease iron absorption and release.
Mutation :Hemochromatosis

Increased expression: Iron deficiency
Hepicidin mRna expression is increased by erythropoetin, hypoxia & inflammation.
Also binds to ferroportin.

Слайд 12 Hepcidin
A 25 amino

acid polypeptide produced by liver cells
An acute phase protein
The

major hormonal regulator of iron homeostasis
Inhibits Fe release from macrophages, intestinal epithelial cells and from placenta
Interaction with transmembrane Fe transporter ferroportin (decrease)
Inflammatory cytokines IL-6, TNF induce hepcidin
Iron deficiency, hypoxia and ineffective erythropoesis Decreased hepcidin

Слайд 13 HEPICIDN
25 Amino acid disulfide peptide.

Слайд 14 O
Hepcidin lowers iron absorption in the intestine ,

OHepcidin lowers iron absorption in the intestine , lowers iron releasing

lowers iron releasing from hepatocytes and macrophages

Serum iron is decreased.

Слайд 15 Ferroportin
The only cellular iron exporter in vertebrates.

Present in macrophages, placenta and the hepatocytes.

Слайд 16 Mechanism of action of hepicidin
The major mechanism

Mechanism of action of hepicidin The major mechanism of hepicidin is

of hepicidin is THE REGULATION OF TRANSMEMBRANE IRON TRANSPORT.

It binds to FERROPORTIN ,forms hepicidin-ferroportin complex ,which is degraded in the lysosomes and iron is locked inside the cells (mainly enterocytes, hepatocytes and macrophages).

Слайд 17 Hepicidin Regulation
So when hepicidin levels are low ,iron

Hepicidin RegulationSo when hepicidin levels are low ,iron exporting cells have

exporting cells have abundant ferroportin and thus releases iron

into plasma. When hepicidin concentration increases it binds to ferroportin and thus iron is retained in the cells.

Слайд 18 IRON DEFICIENCY
In 1997 Looker et al reported that

3% of American toddlers, 2-5% of American teenage

girls are iron deficient.
More than half billion people worldwide have adverse effects as a result of iron deficiency.

Слайд 19
Iron deficiency is the commonest cause of anemia

Iron deficiency is the commonest cause of anemia world wild.The anemia

world wild.

The anemia of iron deficiency is caused by

defective synthesis of hemoglobin resulting in red blood cells that are smaller than normal (microcytic), and contain reduced amounts of hemoglobin (hypo chromic).

Слайд 20

Слайд 21 Causes of Iron Deficiency
Inadequate absorption
Antiacid or high

Causes of Iron Deficiency Inadequate absorptionAntiacid or high gastric PhExcess bran,phytatesLoss

gastric Ph
Excess bran,phytates
Loss of enterocytes
Bowel resection
Celiac disease
Inflammatory bowel disease
Intrinsic

RBC defect

Increased loss or requirement
Growth, pregnancy, lactation
GIT loss
Genitourinary loss
Pulmonary loss
Other – trauma, excessive phlebotomy, large vascular malformation

Слайд 22

Слайд 23 Stages of Iron Deficiency
Iron depletion - decrement of

Stages of Iron DeficiencyIron depletion - decrement of iron stores, no

iron stores, no decline in functional iron compound.
Iron deficient

erythropoesis – occurs when iron stores are exhausted and lack.
Frank Iron Deficiency Anemia.

Слайд 24

Слайд 25 Clinical Presentation
Asymptomatic
Signs and symptoms of underlying disorders
Manifestations common

Clinical PresentationAsymptomaticSigns and symptoms of underlying disordersManifestations common to anemia from

to anemia from all causes: pallor, weakness, shortness of

breath etc.
Specific to iron deficiency: cognitive abnormalities, pica, koilonychia, blue sclera, Plumer-Vinson syndrome

Слайд 26

Слайд 27 Laboratory Evaluation

Слайд 28

Слайд 29 Differential Diagnosis of Microcytic Anemias
With decreased iron

stores
Iron Deficiency Anemia
With normal or increased iron

stores
Impaired iron metabolism
Anemia of chronic disease
Disorders of globin synthesis: thalassemia
Disorders of heme synthesis : sideroblastic anemia

Слайд 30 THERAPY
Therapeutic trail of iron – confirms diagnosis of

THERAPYTherapeutic trail of iron – confirms diagnosis of IDA if:Reticulocytosis starts

IDA if:
Reticulocytosis starts 3-5 days from therapy
Rise of Hb

10-21 days from therapy
Must make sure – compliance, stop blood loss, treat coexistent disease

Слайд 31 ORAL IRON THERAPY
Ferrous (Fe3+) iron salt supplying 150-200

ORAL IRON THERAPYFerrous (Fe3+) iron salt supplying 150-200 mg elemental iron

mg elemental iron daily divided in 3-4 doses
In children

3mg/kg/day
Ferrous sulfate most widely used
Continue treatment for 4-6 months or until ferritin >50μg/l

Слайд 32 Parenteral Iron Therapy
Malabsorption
Intolerance to oral treatment
Chronic uncontrolled bleeding
RISKS

Parenteral Iron TherapyMalabsorptionIntolerance to oral treatmentChronic uncontrolled bleedingRISKS – anaphylaxis (0.5-1%),

– anaphylaxis (0.5-1%), severe serum sickness, given IM –

local reactions and staining
DOSAGE – iron dextrane 50mg/l elemental iron, total dose calculated from iron body deficit to correct Hb, not stores

Слайд 33

Слайд 34 Iron Overload
Accumulation of iron can occur

in disorders associated with excessive absorption or chronic blood

transfusions

Слайд 35 Disease States
Hepcidin deficiency, physiological = Haemochromatosis
Hepcidin

excess – anaemia of chronic disease

Слайд 36

Слайд 37 The role of Hepcidin in hereditary hemochromatosis
Hereditary hemochromatosis:
-excessive

The role of Hepcidin in hereditary hemochromatosisHereditary hemochromatosis: -excessive intestinal iron absorption -Saturation

intestinal iron absorption
-Saturation of transferrin
-Iron deposition in vital organs

Слайд 38 Hereditary Hemochromatosis
Autosomal recessive disease
Excessive absorption of Fe

Hereditary HemochromatosisAutosomal recessive disease Excessive absorption of Fe from GITHFE –

from GIT
HFE – the gene involved, situated close to

MHC locus on chromosome 6 and associated with HLA-A3 and –B8
The consequence of mutation in HFE, it is not expressed on duodenal crypt cells and isn’t able to incorporate iron and seems iron deficient and absorbs more iron
Down regulation of hepcidin

Слайд 39 Iron Overload
The clinical features of iron overload from

Iron OverloadThe clinical features of iron overload from any cause are

any cause are similar:
- skin hyper pigmentation

- endocrine abnormalities: diabetes mellitus, gonadal, thyroid, pituitary and parathyroid dysfunction
- liver fibrosis, cirrhosis, hepatocellular carcinoma
- cardiomyopathy
- arthropathy

Слайд 40 Therapy
Hemochromatosis without anemia – regular venesection, each

Therapy Hemochromatosis without anemia – regular venesection, each unit of blood

unit of blood removes 200-250 mg of iron, with

monitoring of Fe, TIBC, Ferritin
Transfusional iron overload – with Fe chelators that cause to excretion of iron in urine or feces.

Слайд 41 Iron chelators
Deferoxamine – parenteral use, excretion in urine,

Iron chelatorsDeferoxamine – parenteral use, excretion in urine, side effects –

side effects – deafness, visual, growth, and bone abnormalities
Deferiprone

– oral, 3/d alone or with deferoxamine, urine exretion, more effective in cardiac iron deposition, side effects – arthropathy, agranulocytosis (1%)
Deferasirox (Exjade) – oral, fecal excretion side effects mild – skin rashes, transient liver enzymes elevation