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dr. Dian Nugrahenny, M.Biomed.

Email: diannugr2407@gmail.com
 Iron deficiency anemia : 4A
 Anemia associated with chronic diseases : 3A
 Macrocytic (megaloblastic) anemia : 3A
 Hemolytic anemia : 3A
Treatment of choice:
 Orally administered iron supplements.
 Iron is essential to normal human physiology.
 Roles:
 An essential component of proteins involved in oxygen transport.
 Essential for the regulation of cell growth and differentiation.

 Storage: iron in the body is found in:


 Hemoglobin, protein in RBCs that carries oxygen to tissues.
 Myoglobin, protein that helps supply oxygen to muscle.
 Proteins, that store iron for future needs (ferritin) and that transport
iron in blood (transferrin).
 Enzymes, that assist biochemical reactions.
 Iron stores are regulated by intestinal iron absorption.
 Predominant sites of storage: reticuloendothelial system and
hepatocytes, some storage also occurs in muscle.
 80% of the iron in plasma goes to the erythroid marrow to be packaged
into new erythrocytes.

 Physiological losses of iron: limited.


⅔: excreted from GIT as extravasated red cells, iron in bile, and iron in
exfoliated mucosal cells.
⅓: accounted for by small amounts of iron in desquamated skin and in
urine.
Men: 1 mg/day, menstruating women: 0.5-2 mg/day.
 Two forms of dietary iron: heme and nonheme.

 Heme iron:
 Derived from hemoglobin.
 Found in animal foods that originally contained hemoglobin.
 Absorbed better than nonheme iron.

 Nonheme iron:
 Found in plant foods.
 Form of iron added to iron-enriched and iron-fortified foods.
 Most dietary iron is nonheme iron.
Milligrams
Food % DV*
per serving
Chicken liver, pan-fried, 3 ounces 11.0 61
Oysters, canned, 3 ounces 5.7 32
Beef liver, pan-fried, 3 ounces 5.2 29
Beef, chuck, blade roast, lean only, braised, 3 ounces 3.1 17
Turkey, dark meat, roasted, 3 ounces 2.0 11
Beef, ground, 85% lean, patty, broiled, 3 ounces 2.2 12
Beef, top sirloin, steak, lean only, broiled, 3 ounces 1.6 9
Tuna, light, canned in water, 3 ounces 1.3 7
Turkey, light meat, roasted, 3 ounces 1.1 6
Chicken, dark meat, meat only, roasted, 3 ounces 1.1 6

*DV = Daily Value. The DV for iron is 18 mg.


A food providing 5% of the DV or less is a low source while a food that provides 10–19% of the DV is a
good source. A food that provides 20% or more of the DV is high in that nutrient.
Milligrams
Food % DV*
per serving
Ready-to-eat cereal, 100% iron fortified, ¾ cup 18.0 100
Oatmeal, instant, fortified, prepared with water, 1
11.0 61
packet
Soybeans, mature, boiled, 1 cup 8.8 48
Lentils, boiled, 1 cup 6.6 37
Beans, kidney, mature, boiled, 1 cup 5.2 29
Beans, lima, large, mature, boiled, 1 cup 4.5 25
Ready-to-eat cereal, 25% iron fortified, ¾ cup 4.5 25
Blackeye peas, (cowpeas), mature, boiled, 1 cup 4.3 24
Beans, navy, mature, boiled, 1 cup 4.3 24
Beans, pinto, mature, boiled, 1 cup 3.6 21
Healthy adults absorb about 10-15% of dietary iron, but individual
absorption is influenced by several factors:

 Storage levels of iron.


Iron absorption increases when body stores are low.
When iron stores are high, absorption decreases to help protect against
toxic effects of iron overload.

 The type of dietary iron consumed.


Absorption of heme iron from meat proteins is efficient, ranges from 15%
to 35%.
Absorption of nonheme iron in plant foods ranges from 2% to 20%.
Nonheme iron absorption is significantly influenced by various food
components:
 ↑ absorption: meat proteins and vitamin C.
 ↓ absorption: tannins (in tea), calcium, polyphenols, phytates (in
legumes and whole grains), and some proteins in soybeans.
Males Females Pregnancy* Lactation
Age
(mg/day) (mg/day) (mg/day) (mg/day)
7 to 12 months 11 11
1 to 3 years 7 7
4 to 8 years 10 10
9 to 13 years 8 8
14 to 18 years 11 15 27 10
19 to 50 years 8 18 27 9
51+ years 8 8

*Iron deficiency anemia of pregnancy is responsible for significant morbidity,


such as premature deliveries and giving birth to infants with low birth weight.
Iron deficiency anemia can be associated with:
 Low dietary intake of iron.
 Inadequate absorption of iron, e.g. deficiency vit. C, chronic
malabsorption, gastrointestinal disorders (inflammation of the small
intestine).
 Inability to use stored iron, e.g. deficiency vit. A (vit. A is needed to
mobilize iron from its storage sites).
 Excessive blood loss.
Indications:
 Diet alone cannot restore deficient iron levels to normal within an
acceptable timeframe.
 Clinical symptoms of iron deficiency anemia.
Hb levels are below normal,
Serum ferritin < 15 µg/L (female) and < 12 µg/L (male).

Goals:
 To supply sufficient iron to restore normal storage levels of iron, and
 To replenish hemoglobin deficits.

Forms: ferrous (Fe2+) and ferric (Fe3+).


 Ferrous iron salts (ferrous fumarate, ferrous sulfate, and ferrous
gluconate) are the best absorbed forms of iron supplements.
 Elemental iron is the amount of iron in a supplement that is available for
absorption.
 The small intestine regulates absorption, and with increasing doses of
oral iron, limits the entry of iron into the bloodstream.

 It is recommended to take daily iron supplement in two or three equally


spaced doses.

Doses of ferrous sulfate:


 Adult patient:
300 mg (60 mg iron) orally 2-3 times daily for three months.
 Pediatric patient:
3-6 mg/kg/day orally divided in 3 doses suggested, depending
on severity of anemia.
Side effects:
 Gastrointestinal disturbances such as nausea, vomiting, constipation,
diarrhea, dark colored stools, and/or abdominal distress.

Minimize side effects:


 Starting with half the recommended dose and gradually increasing to the
full dose.
 Taking the supplement in divided doses.
 Taking the supplement with food.

Iron from enteric coated or delayed-release preparations may have fewer


side effects, but is not as well absorbed and not usually recommended.
Monitoring:
 Measure hemoglobin levels, reticulocyte count (levels of newly formed
red blood cells), serum iron, total iron binding capacity, and serum
ferritin.

 In the presence of anemia, reticulocyte counts will begin to rise after a


few days of supplementation.
 Hemoglobin usually increases within 2 to 3 weeks of starting iron
supplementation.
Adult men and postmenopausal women
 Iron deficiency is uncommon  take iron supplements without
prescription  greater risk of iron overload: excess iron in the blood and
stored in organs such as liver and heart.

Hemochromatosis
 Genetic disease, affects 1 in 250 individuals of northern European.
 Absorbs iron very efficiently  excess iron  organ damage such as liver
cirrhosis and heart failure.
 Not diagnosed until excess iron stores have damaged an organ.

Individuals with blood disorders that require frequent blood transfusions are
also at risk of iron overload and are usually advised to avoid iron
supplements.
 Very little iron is excreted from the body  iron accumulate in body
tissues and organs when normal storage sites are full  potential for iron
toxicity.

 Signs and symptoms of severe poisoning: occur within 30 minutes:


abdominal pain, diarrhea, or vomiting of brown or bloody stomach
contents containing pills, pallor or cyanosis, drowsiness, hyperventilation
due to acidosis, and cardiovascular collapse.
 Death can occur within 6-24 hours.

 In children, death has occurred from ingesting 200 mg of iron.


 It is important to keep iron supplements tightly capped and away from
children's reach.
 When oral iron therapy fails, parenteral iron administration (e.g. Iron
dextran) may be an effective alternative.

 Indications:
 Iron malabsorption, severe oral iron intolerance, and as a routine
supplement to total parenteral nutrition.

 The rate of response to parenteral therapy is similar to that which follows


usual oral doses.

 Acute hypersensitivity, including anaphylaxis, can occur in 0.2% to 3% of


patients.
Clinical use:
 To selectively bind iron in transfusion-related iron-overload
 Improves life expectancy for patients receiving regular blood transfusion

Drugs:
 Desferrioxamine (DFO, Desferal)
Rapid renal excretion and poor absorption in the gut  requires
continuous intravenous infusion or daily intramuscular injections.
 Deferiprone (Ferriprox) and deferasirox (Exjade)
Longer half life than DFO  Effective oral administration.
 Mainly excreted in the urine but up to one-third is also
excreted in the stools.
 It is usually given over 8–12 hours, 5–7 nights per week
using a battery operated pump.

 Side-effects: deafness, retinal damage, bone abnormalities


and growth retardation, especially in children with
relatively low serum ferritin levels.
 Patients should have auditory and funduscopic
examinations at regular intervals.
 Deferiprone is used alone or in combination with desferrioxamine.
 Alone it is less effective than desferrioxamine.
 The two drugs have an additive or even synergistic action on iron
excretion.
 Compliance is usually better.
 Side-effects: arthropathy, agranulocytosis or severe neutropenia,
gastrointestinal disturbance.
 People with chronic infectious, inflammatory, autoimmune, or malignant
disorders may develop anemia, but may not respond to iron
supplements.

 Research suggests that inflammation may over-activate a protein


involved in iron metabolism.
 This protein may also inhibit iron absorption and reduce the amount of
iron circulating in blood, resulting in anemia.
 Anemia in chronic diseases is an adaptive physiologic response?
 Free iron have roles in oxidative stress.

 Meta-analysis:
Treatment of mild and moderate anemia in chronic diseases
(cardiovascular diseases, renal failure, cancer) with transfusion of packed
RBC or administration of erythropoietin-stimulating agents  harmful:
worsen clinical outcomes, higher mortality.

(Zarychanski and Houston, 2008)


 Perfusion with saline containing ferrous sulphate 
50x increases in lipid peroxidation (Erichsen et al., 2003)
due to release of ROS via the Fenton reaction:
H2O2 + Fe2+ → OH. + OH- + Fe3+ (Halliwell and Gutteridge, 1999).

 Hydroxyl radical (OH.) is very reactive  oxidative damage to lipids, DNA,


and proteins  diseases (Loh et al., 2009).

 Recent studies suggest that iron stores influence insulin sensitivity.


AGEs formation produces ROS by metal-catalyzed reactions.
AGEs bind transition metals, potentiating their toxic effects, including
insulin resistance (Fernández-Real et al., 2005).
 With anemia or hypoxemia, the synthesis rapidly increases by one
hundredfold or more, serum erythropoietin levels rise, and marrow
progenitor cell survival, proliferation, and maturation are dramatically
stimulated.

 This finely tuned feedback loop can be disrupted by kidney disease,


marrow damage, or a deficiency in iron or an essential vitamin.
 With an infection or an inflammatory state, erythropoietin secretion, iron
delivery, and progenitor proliferation all are suppressed.
 Epoetin alfa produced using engineered Chinese hamster ovary cells, is
nearly identical to the endogenous hormone.
 Available preparations: HEMAPO, EPOGEN, PROCRIT, and EXPREX for
intravenous or subcutaneous administration.
 Intravenously injected: half-life of 4 to 8 hours.
 The effect on marrow progenitors is sufficiently sustained that it need
only be given three times a week to achieve an adequate response.

 Novel erythropoiesis-stimulating protein (NESP) or darbapoetin alfa


(ARANESP) has longer circulatory survival of the drug to 24 to 26 hours.
 Epoetin alfa has been approved for use in the treatment of anemias
associated with AIDS (especially those with zidovudine-induced anemia),
cancer chemotherapy (Hb levels < 10 g/dl), and certain chronic
inflammatory conditions.

 Darbapoetin alfa has been approved for use in patients with anemia
associated with chronic kidney disease.

 During erythropoietin therapy, functional iron deficiency (normal ferritin


levels but low transferrin saturation) may develop resulting from the
inability to mobilize iron stores rapidly enough to support the increased
erythropoiesis  require supplemental iron to increase or maintain
transferrin saturation.
 The hematocrit is determined once a week (HIV-infected and cancer
patients) or twice a week (renal failure patients) until it has stabilized in
the target range.
 The risk of thrombotic events was higher in adults with ischemic heart
disease or congestive heart failure receiving epoetin alfa therapy with the
goal of reaching a normal hematocrit (42%) than in those with a lower
target hematocrit of 30%.
 The higher risk of cardiovascular events may be associated with higher
hemoglobin or higher rates of rise of hemoglobin.
 The hemoglobin level should NOT exceeding a target level of 12 g/dl.
 Serious thromboembolic events have been reported during hemodialysis.
 Hypertensive encephalopathy and seizures have occurred in chronic
renal failure patients.
 Headache, tachycardia, edema, shortness of breath, nausea, vomiting,
diarrhea, injection site stinging, and flu-like symptoms (e.g., arthralgias
and myalgias) also have been reported in conjunction with epoetin alfa
therapy.
 Patients with cancer of the head and neck randomized to receive
recombinant erythropoietin had a statistically significant increase in
likelihood of tumor progression during the duration of the study. This
finding is being evaluated by the FDA and warrants serious attention.
 Vitamin B12 and folic acid are dietary essentials.

 Deficiency of folic acid itself or deficiency of vitamin B12, which leads to


functional folate deficiency, affects cells that are dividing rapidly
(including the hematopoietic system) because they have a large
requirement for thymidine for DNA synthesis.
 Clinically, this affects the bone marrow, leading to megaloblastic anemia.

 Treatment of choices: vit. B12 and folic acid supplementation.


 Active forms of vit. B12: methylcobalamin, deoxyadenosylcobalamin.
 Methyl groups in methylcobalamin are contributed by the conversion of
methyltetrahydrofolate to tetrahydrofolate.

 Then, methylcobalamin acts for the conversion of homocysteine to


methionine.
 Methionine is required for the synthesis of phospholipids and myelin.

 Tetrahydrofolate is the substrate for a number of metabolic steps,


including DNA synthesis.

 Vit. B12 deficiency causes functional folate deficiency – the “Folate Trap”
Methionine synthase

deoxyuridine monophosphate (dUMP),


thymidine monophosphate (dTMP)
 Vitamin B12 needs intrinsic factor (a glycoprotein secreted by the stomach's
parietal cells) for absorption.

 Cause of deficiency:
Failure of the absorption of vit. B12 rather than dietary deficiency.
Result of failure of intrinsic factor secretion caused by autoimmune disease
(gastric atrophy  destruction of parietal cells) or from production of anti-
intrinsic factor antibodies.

 Clinical manifestation:
Megaloblastic anemia and neurological disorders (such as numbness and
tingling in the hands and feet).
Micrograms (mcg)
Food Percent DV*
per serving
Clams, cooked, 3 ounces 84.1 1,402
Liver, beef, cooked, 3 ounces 70.7 1,178
Breakfast cereals, fortified with 100% of the DV for
6.0 100
vitamin B12, 1 serving
Trout (fish), rainbow, wild, cooked, 3 ounces 5.4 90
Salmon, sockeye, cooked, 3 ounces 4.8 80
Trout (fish), rainbow, farmed, cooked, 3 ounces 3.5 58
Tuna fish, light, canned in water, 3 ounces 2.5 42
Cheeseburger, double patty and bun, 1 sandwich 2.1 35
Haddock (fish), cooked, 3 ounces 1.8 30
Breakfast cereals, fortified with 25% of the DV for
1.5 25
vitamin B12, 1 serving

Noted: Natural food sources of vitamin B12 are limited to animal foods
Age Male Female Pregnancy Lactation
0–6 months* 0.4 mcg 0.4 mcg
7–12
0.5 mcg 0.5 mcg
months*
1–3 years 0.9 mcg 0.9 mcg
4–8 years 1.2 mcg 1.2 mcg
9–13 years 1.8 mcg 1.8 mcg
14+ years 2.4 mcg 2.4 mcg 2.6 mcg 2.8 mcg

* Adequate Intake
 Vitamin B12 is available for injection or oral administration.

 Oral route of administration:


 Have limited value in the treatment of patients with deficiency
of intrinsic factor or ileal disease.
 Not effective in the patient with a marked deficiency of vit. B12
and abnormal hematopoiesis or neurological deficits.

 Preparation of choice: cyanocobalamin, administered by


intramuscular or subcutaneous injection.
 Cyanocobalamin is administered in doses of 1 to 1000 µg.
 Anaphylaxis can occur after injection.
 An intradermal skin test should be performed.

 Water soluble!
 Excess vit. B12 will not result in greater retention of the vitamin,
and cleared rapidly from plasma into the urine.
 No adverse effects have been associated with excess vit. B12
intake from food and supplements in healthy individuals.
 The megaloblastic anemia that results from folate deficiency cannot be
distinguished from that caused by vitamin B12 deficiency, because of the
final common pathway of the major intracellular metabolic roles of the
two vitamins.

 Folate deficiency is rarely if ever associated with neurological


abnormalities.

 After deprivation of folate, megaloblastic anemia develops much more


rapidly than it does following interruption of vitamin B12 absorption (e.g.,
gastric surgery)  reflects the fact that body stores of folate are limited.
Food Μg % DV
*Breakfast cereals fortified with 100% of the DV, ¾ cup 400 100
Beef liver, cooked, braised, 3 ounces 215 54
Lentils, mature seeds, cooked, boiled, ½ cup 179 45
Spinach, frozen, cooked, boiled, ½ cup 115 29
*Egg noodles, cooked, enriched, ½ cup 110 28
*Breakfast cereals, fortified with 25% of the DV, ¾ cup 100 23
Great Northern beans, boiled, ½ cup 90 23
Asparagus, boiled, 4 spears 89 22
*Macaroni, cooked, enriched, ½ cup 84 21
*Rice, white, long-grain, enriched, cooked, ½ cup 77 19

* Items marked with an asterisk (*) are fortified with folic acid as part of the Folate
Fortification Program.
Males and Females
Age Pregnancy (μg/day) Lactation (μg/day)
(μg/day)
1–3 years 150 N/A N/A
4–8 years 200 N/A N/A
9–13 years 300 N/A N/A
14–18 years 400 600 500
19+ years 400 600 500

*1 DFE (Dietary Folate Equivalent) = 1 μg food folate = 0.6 μg folic acid from
supplements and fortified foods
Form of marketed folic acid:
 Oral tablets containing 0.4, 0.8, and 1 mg
pteroylglutamic acid.
 Aqueous solution for injection (5 mg/ml).
 In combination with other vitamins and minerals.
 Oral folic acid usually is not toxic.
 Even with doses as high as 15 mg/day, there have been no substantiated
reports of side effects.

 Folic acid in large amounts:


 May counteract the antiepileptic effect of phenobarbital, phenytoin,
and pirimidone, and
 Increase the frequency of seizures in susceptible children.
 Intake of supplemental folic acid should not > 1,000 μg/day to prevent
folic acid from masking of continued vit. B12 deficiency.
 This permit neurological damage due to vit. B12 deficiency to develop or
progress.

 Folic acid supplements can correct the anemia associated with vitamin B12
deficiency, but will not correct changes in the nervous system due to vit.
B12 deficiency.
A 12-year-old girl accompanied by her mother arrives at clinician’s office
with a chief complaint of pale. Patient also feels tired and sleepy easily at
school.
1 week ago, patient had heavy bleeding during her first menstrual period
(replace 3-4 pads/day) for 5 days.
Patient comes from poor family so that she does not eat regularly.

From physical examination, patient appears malnourished and pale, blood


pressure is 90/60 mmHg, pulse is 96 beats/min, conjunctiva is pale,
abdominal examination shows no hepatosplenomegaly.

From examination of patient's peripheral blood smear under a light


microscope, there are hypochromic microcytic red blood cells.
A 35-year-old woman arrives at clinician’s office with a chief complaint of
increasing fatigue over the last several months. Patient also feels tingling in
her feet.
Patient is a strict vegetarian and eats no animal products.
As a child, she had a portion of her terminal ileum removed.

From examination of patient's peripheral blood smear under a light


microscope, there are enlargement of red blood cells and hypersegmented
neutrophils.
1. Define the patient's problem
2. Specify the therapeutic objective
3. Verify whether your P-treatment is suitable for this patient (the most
effective, safe, suitable and cheap treatment)
4. Start the treatment (write the prescription)
5. Give information, instructions and warnings
6. Monitor (stop) the treatment