Iron Deficiency and Iron Overload
Iron Deficiency and Iron Overload
Iron Metabolism: Iron in the body is used primarily for Haemogolobin synthesis. Normal
erythropoiesis requires 20-25 mg/day of iron.
Iron Stores: Body iron stores – 40-50mg Fe/kg. Stores are less in women than men. Most of the
iron in plasma comes from recycling of iron from aged red cells. Daily losses 1-2mg. Total body
iron in adult 3-4gm
Iron Balance
Is determined by the amount of iron entering and leaving the body.
Humans lack the ability to excrete excess iron.
Loss – shedding of intestinal cells, urine, nails, hair, skin, menstruation
Therefore physiological regulation is controlled by absorption.
If stores are reduced absorption will increase.
Increased Utilization – pregnancy, rapid growth in infancy and adolescence
Iron Absorption:
Absorption sites: Maximal absorption occurs in the duodenum and upper jejunum. Acidic gastric
juice reduces insoluble ferric iron to soluble ferrous state.
Absorption is regulated by mucosal cells of proximal SI. Physiologically iron absorption is
determined by (a) level of stores and (b) level of erythropoiesis.
Hypoxia may also increase iron absorption.
Intestinal mucosal cells regulate intake of iron.
Iron enters the cell via DMT1(divalent metal transporter)
Two pathways for iron to follow:
1. Transported via the basolateral transporter ferroportin
2. Stay in the enterocyte as ferritin(sloughed off eventually)
Iron transported to the blood is bound to transferrin and then goes mainly to red cells for
Hb synthesis. Transferrin saturation-20-45%
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Hepcidin: Hormone produced by hepatocytes. When the level is increased, hepcidin binds to
ferroportin which is internalized and degraded. Iron stays in the enterocyte, ferritin is synthesized
and it is lost when cells are shed.
Haem versus non-haem iron: Haem iron forms a small part of dietary intake but is highly
available for absorption.
Other dietary constituents do not affect absorption.
Majority of the dietary iron is non-haem (90%). < 5% available for absorption.
Absorption is determined by enchancers e.g. AA and vitamin C and inhibitors e.g. phytates and
phosphates.
Direct: (a) Bone marrow aspirate and biopsy good for iron deficiency but have limited
applicability in iron overload because it does not give information about parenchymal iron. Liver
biopsy is more useful in this situation.
Problems with direct methods: Invasive, not acceptable to patients, risk (liver biopsy).
Indirect: (a) Ferritin – most useful indirect estimate of iron stores. Limitations include the fact
that it is affected by inflammatory states, tumors. (acute phase reactant)
(b) Serum iron and total iron binding capacity and saturation can be used in combination to assess
iron status. (Fe, TIBC, Saturation). Limitations include intake of iron, dietary factors,
inflammatory states and pregnancy(TIBC) affecting the results making interpretation difficult.
(c) Serum transferrin receptor – increased in IDA. Not widely available.
(d) Red cell protoporphyrin - iron supply → iron incorporation into haem→
↑ Red cell protoporphyrin
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- Results reflect changes over weeks
Iron Deficiency
Decrease in total body iron.
Iron depletion – decrease in storage iron without decrease in functional iron.
Iron deficient erythropoiesis – decrease in haemoglobin production. May not
be recognizable morphologically, as cells may still be Normochromic and Normocytic.
Iron deficiency anaemia – Hypochromic and Microcytic.
Sequence of events
1. Depletion of iron stores
2. Negative iron balance -depletion of iron stores -increase in iron absorption
Serum iron normal
Serum ferritin low
BM iron absent
3. Iron deficient erythropoiesis
Further iron depletion → serum transferrin receptor sat decrease (because increase
transferrin and decrease serum iron) → iron deficient erythropoiesis →increase serum
TR.
Increase RBC protoporphyrin
MCV and MCH are normal
4. IDA
Further iron depletion → IDA
Hypochromic/Microcytic,
Low MCH and MCV
Low Reticulocyte count
Increase TIBC; low serum iron; low saturation
BM iron absent
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Hemorrhoids
Parasitic infestation
Malignant conditions
Colorectal cancer
Gastric cancer
Oesophageal cancer
(ii) Genitourinary tract
Malignancy
Uterine fibroids
(iii) Pulmonary
Haemosiderosis
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(c) Pica - Pagophagia
Side Effects
Nausea, vomiting, constipation and diarrhoea
Parenteral iron
Indications:
Malabsorption
Intolerance
Need is in excess of what can be taken orally
Non-Compliance
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Dialysis patients
Iron overload
Excess of total body iron
Lack of physiologic means of excreting excess iron
Epidemiology
US - genetic disorder (hereditary haemochromatosis)
- transfusion dependant anaemia (thalassemia)
Asia/India/Mediterranean – transfusion dependent anaemia
Africa – iron in brewed beverages
Genetics
Hereditary Haemosiderosis – AR
- gene on short arm of chromosome 6
Iron loading anaemias - Homozygous B thalassemia
- inherited sideroblastic anaemia
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Pattern and severity of organ damage dependent on:
(a) magnitude of body iron burden
(b) rate of loading
(c) distribution of iron load
(d) ascorbate status
Organs damaged – liver, pancreas, heart
Specific conditions
Juvenile Haemochromatosis
Rare
Late adolescence
Severe clinical course
Present with endocrine and cardiac dysfunction
Excess absorption of dietary iron
Erythroid hyperplasia with marked ineffective erythropoiesis
Thal. major and intermedia
Hb E – B thal.
Congential dyserythropoietic anaemia
PK deficiency
Sideroblastic anaemias
Excess iron in parenchymal cells.
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Chronic liver disease
↑ absorption of dietary iron ?cause
may be related to alcoholic induced folate and sideroblastic abnormalities with ineffective
erythropoiesis.
Iron in Kupffer cells rather than parenchymal cells.
Atransferriemia
Dietary iron absorbed
Little used for red cell production
Iron deposited in tissue
No marrow iron
Hereditary Haemochromatosis
↑ iron absorption
HLA – linked
↑ parenchymal iron
Scant BM iron
Present in middle age
Liver disease, BM, skin pigmentation, gonadal failure
Cardiac failure in 10-15% untreated homozygotes
Present when stores are 15-20gm
Incomplete expression heterozygotes
Gene – HFE (mutation)
Locus short arm of chromosome 6
Clinical Presentation
Increased skin pigmentation
Hepatic disease and hepatomegaly, cirrhosis
Diabetes mellitus
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Gonadal insufficiency (primary testicular failure)
Abdominal pain
Cardiac dysfunction
Arthropathy
Endocrine dysfunction (thyroid, parathyroid, adrenal)
Laboratory Evaluation
Ferritin – increased
Iron/TIBC – does not give degree of iron overload
Liver biopsy
SQUID(superconducting Quantum Interference device)
MRI
Therapy
Phlebotomy – if Hb is high enough
usually weekly initially
500ml = 200 – 250mg iron
Iron chelation – desferrioxamine, deferasirox
Used in transfusion iron overload
Prognosis
Cirrhosis and hepatocellular carcinoma – major causes of death
Diagnose early
Initiate treatment early
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