Nutritional anemia

IDA
• It’s importance:
-Carry O₂ as a part of Hgb.
-O2 is also bound by myoglobin in muscle
-Cytochrome system in the mitochondria
+Without iron, cells lose their capacity for electron
transport and energy metabolism. In erythroid
cells, hemoglobin synthesis is impaired, resulting
in anemia and reduced O2 delivery to tissue.
 Epidemiology

• Globally
-50% of anemia …IDA

-841,000 death annually

reported.

-Africa & parts of Asia bears

71%
Cycle
Internal iron exchange in human:

Absorbed
from diet- Circulating Release
1mg/day iron bound from
M;1.4mg/day to store(80%
F-1 transferin(6 ) RES-3
0-90 min
delivered to
BM. 2

Transferin interact with its receptor-BM release

iron
Iron in excess amount store as Ferritin- 4
 Stages of Iron Deficiency

1.Negative iron balance:

- Demand Vs Access(in which the demands for (or losses of) iron exceed the
body's ability to absorb iron from the diet. )
- Cause: blood loss, pregnancy , rapid growth spurts in the
adolescent, or inadequate dietary iron intake
- Iron deficit will be corrected by mobilization of store iron from RES.
- Iron stores—reflected by the serum ferritin level or the appearance
of stainable iron on bone marrow aspirations—decrease
- At this stage,as long as iron stores are present and can be
mobilized, the serum iron, TIBC ,&red cell morphology and indices
are normal.
 Conti…
2.Iron deficient erytheropoiesis
- iron store depleted(def. serum ferritin level is
<15µg/dl)
- Serum iron begins to fall.
- Gradually TIBC increase
- As long as the serum iron remains within the
normal range, hemoglobin synthesis is unaffected
despite the dwindling iron stores
- Once transferin saturation falls to 15-20% ;Hge
synthesis impaired.
- Lab. First appearance of microcytic cells.
 Conti…
3. IDA
- Transferin saturation 10-15%
- Gradually Hge & Hct begin to fall.
- When moderate anemia is present (hemoglobin 10–13 g/dL),
the bone marrow remains hypoproliferative.
- With more severe anemia (hemoglobin 7–8 g/dL), hypochromia
and microcytosis become more prominent, target cells and
misshapen red cells (poikilocytes) appear on the blood smear
as cigar- or pencil-shaped forms, and the erythroid marrow
becomes increasingly ineffective. Consequently, with severe
prolonged iron-deficiency anemia, erythroid hyperplasia of
the marrow develops, rather than hypoproliferation
 Causes of Iron Deficiency

Increased demand for iron and/or hematopoiesis

rapid growth in infancy or adolescence
pregnancy
erythropoietin therapy
Increased iron loss
chronic blood loss
menses
acute blood loss
blood donation
phlebotomy as treatment for polycythemia vera
Decreased iron intake or absorption
inadequate diet
malabsorption from disease (sprue, Crohn's disease)
malabsorption from surgery (post-gastrectomy)
acute or chronic inflammation
 Hook worm

• Ancylostoma duodenale causes infection in Mediterranean

countries, Iran, India, Pakistan, and the Far East.
• Necator americanus infects humans in North and South America,
Central Africa, Indonesia, islands of the South Pacific, and parts of
India.
• Hookworm eggs hatch in the soil to release larvae that mature into
infective larvae. Percutaneous larval penetration constitutes the
principal mode of human infection, although infections with A.
duodenale may also be acquired by the oral route. As few as three
larvae can suffice to produce infection ; thus, even brief exposures
by travelers to contaminated soil may be adequate for the
acquisition of hookworm infections.
• From the skin, larvae pass to the lungs. At about 8 to 21 days after
infection, larvae, like the larvae of Ascaris, cross from the pulmonary
vasculature, enter the airways, ascend the tracheobronchial tree to
the pharynx, and are swallowed. In the small intestine, the larvae
mature into adult worms. Adults attach to the mucosa and feed,
continually consuming blood and serum proteins.
• Following fertilization by adult male worms, gravid female adults lay
eggs within the bowel. Eggs become detectable in feces about six to
eight weeks following infection with N. americanus. Ancylostoma
duodenale larvae may persist within tissues before returning to the
intestine; as a result, egg laying can be delayed . Hookworms may
be long-lived, lasting for 17 to 18 years in one experimental human
infection with N. americanus .
 C/f

• Cutaneous manifestations : a focal pruritic maculopapular eruption at

each of the sites of larval penetration (so-called "ground itch")
• Transpulmonary passage : a mild cough and pharyngeal irritation may be
experienced during the time larvae are migrating in the airways, eosinophilic
pulmonary infiltrates typical of Ascaris pulmonary involvement are rare.
• Acute gastrointestinal symptoms : including nausea, diarrhea, vomiting,
abdominal pain (usually midepigastric and often with postprandial
accentuation), and increased flatulence
• Chronic nutritional impact : Each adult N. americanus worm consumes
about 0.3 mL of blood per day and each A. duodenale consumes about 0.5
mL of blood per day.
- hookworms release a serine proteinase inhibitor capable of broad
spectrum inhibition of trypsin, chymotrypsin and pancreatic elastase that
may impair digestion and contribute to malnutrition
 C/P
 Easy fatigability ; pallor , palpitation; tachycardia

• Pregnancy
• Adolescent should alert possibility
of IDA
• Period of rapid growth
• Intermittent Hx of B/d loss
 Sever deficiency cause skin & mm
smooth tongue; Koilonychia;cheilosis
 Conti…
Dysphagia-b/c of formation of esophageal
web(Plummer–Vinson
syndrome)
Pica(craving for ice , clay)
LAB.Ix
- Serum iron level (N=50-150µg/dl)
- TIBC- (N=300-360µg/dl)
- Transferin saturation (25-50%)

- Serum ferritin(store) -N= 100µg/lt Male

30µg/lt Female
- MCV/MCH/MCHC microcytic ; hypochromic
 Evaluation of Bone Marrow Iron Stores

• Although RE cell iron stores can be estimated from the iron stain of a BM
aspirate or biopsy, the measurement of serum ferritin has largely supplanted
BM aspirates for determination of storage iron. The serum ferritin level is a
better indicator of iron overload than the marrow iron stain.
• However, in addition to storage iron, the marrow iron stain provides
information about the effective delivery of iron to developing erythroblasts.
Normally, when the marrow smear is stained for iron, 20–40% of
developing erythroblasts—called sideroblasts—will have visible
ferritin granules in their cytoplasm. This represents iron in excess of that
needed for hemoglobin synthesis. In states in which release of iron from
storage sites is blocked, RE iron will be detectable, and there will be few or
no sideroblasts.
• In the myelodysplastic syndromes, mitochondrial dysfunction can occur, and
accumulation of iron in mitochondria appears in a necklace fashion around
the nucleus of the erythroblast. Such cells are referred to as ringed
sideroblasts.
 Red Cell Protoporphyrin Levels

• Protoporphyrin is an intermediate in the pathway to heme synthesis.

• Under conditions in which heme synthesis is impaired,
protoporphyrin accumulates within the red cell. This reflects an
inadequate iron supply to erythroid precursors to support
hemoglobin synthesis.
• Normal values are <30 g/dL of red cells. In iron deficiency, values in
excess of 100 g/dL are seen. The most common causes of
increased red cell protoporphyrin levels are absolute or relative iron
deficiency and lead poisoning.
 Serum Levels of Transferrin Receptor Protein

• Because erythroid cells have the highest numbers of transferrin

receptors of any cell in the body, and because transferrin receptor
protein (TRP) is released by cells into the circulation, serum levels
of TRP reflect the total erythroid marrow mass. Another
condition in which TRP levels are elevated is absolute iron
deficiency.
• Normal values are 4–9 g/L determined by immunoassay. This
laboratory test is becoming increasingly available and, along with
the serum ferritin, has been proposed to distinguish between iron
deficiency and the anemia of chronic inflammation
DDX
+Severity & causes will determine the Rx
option
1. Red cell transfusion:
- Pts with CV instability,symptomatics
- continued & excessive b/d loss
- Not only correct anemia but transfused red cells
reutilized
2. Oral iron therapy
- Asymptomatic Pts
- Multiple preparation
• up to 300 mg of elemental iron per day is given, usually as three or
four iron tablets (each containing 50–65 mg elemental iron) given
over the course of the day. Ideally, oral iron preparations should be
taken on an empty stomach, since food may inhibit iron absorption.
• A dose of 200–300 mg of elemental iron per day should result in the
absorption of iron up to 50 mg/d.
• Goal of therapy in individuals with IDA is not only to repair the
anemia, but also to provide stores of at least 0.5–1 g of iron.
Sustained treatment for a period of 6–12 months after correction of
the anemia will be necessary to achieve this.
 Conti…
Tablet(iron content)
Preparation ,mg
• Ferrous sulfate • 325(65)
• Ferrous fumerate • 325(107)
• Ferrous gluconate • 325(39)
• Polysaccharid iron • 150(150)

Should be taken on empty

stomach
S/E-GI disturbance, abd.pain
N,V ,constipation
Elixir a preparation containg alcohol(ethanol) or glycerin w/ch is used as the
vehicle for bitter or nauseous drugs
 Response to Rx
Time after administration Response

• 12-24 hr • Replacement of IC iron

enzymes; subj.imp.(inc.
appitite,dec.irritability)
• Initial BM
• 36-48hr
response;erytheroid
hyperplasia
• 48-72hr • Reticulocytosis,peak at 5-7d
• 4-30days • Inc. Hge level
• 1-3mo. • Repletion of stores
 Expected response

• If pica is present, it will disappear almost as soon as oral iron

therapy is begun, well before there are any changes in the
peripheral blood. The patient will note an improved feeling of well-
being within the first few days of treatment.
• In patients with moderate to severe anemia, a modest
reticulocytosis will be seen, maximal in approximately 7 to 10 days.
Patients with mild anemia may have little or no reticulocytosis.
• The hemoglobin concentration will rise slowly, usually beginning
after about one to two weeks of treatment, and will rise
approximately 2 g/dL over the ensuing three weeks. The
hemoglobin deficit should be halved by about one month and should
return to normal by 6 to 8 weeks.
• if there is absence of response look for poor absorption & continue
blood loss;non compliance;confinding dx.
• if its poor absorption swith to parenthral theraphy
• Response-Inc. He 2 gm/dl in 2-3 weeks
• Typically, the reticulocyte count should begin to increase within 4–7
days after initiation of therapy and peak at 1–11/2 weeks. The
absence of a response may be due to poor absorption,
noncompliance (which is common), or a confounding diagnosis.
• A useful test in the clinic to determine the patient's ability to absorb
iron is the iron tolerance test. Two iron tablets are given to the
patient on an empty stomach, and the serum iron is measured
serially over the subsequent 2 hours. Normal absorption will result in
an increase in the serum iron of at least 100 g/dL. If iron deficiency
persists despite adequate treatment, it may be necessary to switch
to parenteral iron therapy.
 Conti…
• In absence of response look for:
-Poor compliance
-poor absorption
-misdiagnosis
3. Parenteral Iron therapy- iron dexteran
 Acqiured sideroblastic anemia
• Defect in heme synthesis,most commonly due to pyridoxine
dependent impairment in early steps of protoporphyrin synthesis.
• Eg. Patient taking INH, or alcholic patient , well known pyridoxin
antagonis
• C/F- microcytic hypochromic anemia simulating IDA
• Pecularity: microscopy- hypochromic & normochromic (dimorphic
RBCs population)
• Iron study: revels- increase serum iron level,& increased TIBC
• BM examination - ringed sideroblast*
• The myelodysplastic syndromes represent the third and least
common condition. Occasionally, patients with myelodysplasia have
impaired hemoglobin synthesis with mitochondrial dysfunction,
resulting in impaired iron incorporation into heme.
• The iron values again reveal normal stores and more than an
adequate supply to the marrow, despite the microcytosis and
hypochromia.(BM will show ringed sideroblast)
 Megaloblastic anemia
• It’s nuclear maturation defect which leads to defect in DNA
synthesis.
• Megaloblast , the morphologic hallmark of the syndrome, is
a product of impaired DNA formation which in turn is due to
deficiencies of vitamin B12 (cobalamin , Cbl) or folic acid
(FA). Other causes of impaired DNA or RNA formation, such
as antimetabolite drugs and myelodysplastic syndrome, can
also lead to megaloblastic anemia.
• Causes
-Cobalamin deficiency or abnormality in it’s metabolizem.
-Folate deficiency or abn. Metabolizem
-Treatment with Antifolate drugs eg.methotrixate
 Vit. B 12 deficiency

 General consideration
• It’s belongs to family of Cobalamin.
• It serves as cofactor for two Rxn
1 -as methylcobalamin(conversion of homocystein to
methionin)
-it reduces the plasma concentration of homocysteine w/c
is probably toxic to endothelial cells; and, perhaps more
importantly, it demethylates (CH3)THF
-Demethylation is a critical step in DNA synthesis
2 -For conversion of methylmalonyl coA to succinyl coA
+this pathway might be important in myelin formation and in the
neurologic abnormalities seen with B12 but not FA deficiency
• 2nd rxn important for kreb`s cycle(ATP formation)
• Source : animal origin: all Vit B12 comes from diet & is
present in all foods of animal origin
• Daily absorption is 5mcg.
NB: cobalamin deficiency is characterized by elevations in
the serum levels of both homocysteine and
MMA(methylmalonyl coA ), while only homocysteine
levels are elevated in folate deficiency.
 absorption
• cobolamin initally combined with salivary glycoprotien w/ch is
digested by pancreatic trypsin & transferred to IF
• After being ingested , vit b12 is bounded to IF(Protien secreted by
gastric parietal cells) ; another cobalamin binding protien called R
factor compete with IF for vit b12 (w/c can`t be absorbed)
• The vit b 12 –IF complex travels through the intestine & absorbed in
the terminal ileum & transported through plasma & stored in liver
• Liver contain 2000-5000 mcg of stored vit B12.The body has
sufficent store of vit. B12 so that vit b 12 deficiency develops
more than 3 yrs after vit b 12 absorption ceases.
Ingesti
on of
vit B 12

IF
To terminal
ileume
Store in liver
2000-
5000mcg
 Causes
• Dietary deficiency (rare) except strict vegiterians
• its present in all foods of animal origin, extrimly rare
• Decreased production of IF
-Pernicious Anemia:most common cause(immunological destruction
of parietal cells in stomach w/ch produce IF)
-Gasterectomy
• Competition for vit B12 in gut:
-Blind loop syndrome(bacterial over growth)
-Fish tape worm(rare)-Diphyllobotherium
latum
• small bowel is the site of rapid motility so the organisms commonly
found are simply passing through. Interruption of this flow, as with a
stagnant segment (stricture, obstruction, diverticulum, blind loop),
results in colonic concentrations of bacteria with a predominance of
anaerobes. This bacterial overgrowth pattern may be responsible for
malabsorption and is best treated with antibiotics directed against
anaerobes. There is speculation that overgrowth may play a role in
irritable bowel syndrome
 Conti…

• Pancreatic insufficiency: cobolamin initally

combined with salivary glycoprotien w/ch is digested by
pancreatic trypsin & transferred to IF
• Decreased ileac absorption
-Surgical resection
-Crohn’s disease
 C/f
• Anorexia ,diarrhea ,Glossitis
• Sx of anemia
• Neurologic Sx:
-Paresthesia
-Next post. Column impaired(diff. in balance
loss of Position &vibration sense
progressive spastic &ataxic weakness
 Lab. Ix
• Elevated MCV
• Peripheral blood smear
Hyper segmented Neutrophils: >5% of peripheral neutrophils have ≥5
lobes of nucleus
Macrocytosis
• BM morphology
cytoplasm maturation with retarded nuclear development
• Coalmine serum level (N >240pg/ml)
Pts with low-normal or even normal serum Cbl values may be truly Cbl
deficient &respond to replacement Rx .Measurement of the serum
concentrations of the metabolic intermediaries homocysteine and
methylmalonic acid appears to be more sensitive for the diagnosis of
these deficiencies than serum vitamin levels , and is helpful in clarifying
the Dx when serum Cbl or folate concentrations are equivocal, or are low
in the pregnant subject
• Role of cobalamin in homocysteine and methylmalonic acid
metabolism. Panel A - Methylcobalamin is a cofactor in the
synthesis of methionine from homocysteine. Panel B -
Adenosylcobalamin is a cofactor in the synthesis of succinyl-CoA
from methylmalonyl-CoA. Tetrahydrofolate (THF) participates in
homocysteine but not methylmalonic acid (MMA) metabolism.

• cobalamin deficiency is characterized by elevations in the

serum levels of both homocysteine and MMA, while only
homocysteine levels are elevated in folate deficiency .
• Interdependent cofactor activity of cobalamin and folate in intracellular DNA synthesis
and metabolism. The + signs indicate enhancement, and the - signs indicate
inhibition. Demethylation of methyl-tetrahydrofolate (CH3-THF) to THF is a critical
step in DNA synthesis because THF is the substrate for the enzyme that converts
(THF)-1 to the polyglutamated form (THF)n. Only polyglutamated (THF)n participates
in purine synthesis.
 Schilling test

• Step 1: One µg of radioactive crystalline B12 is taken orally.

• Step 2: Gastric acid and pepsin free vitamin B12 from food proteins.
This step is not required when crystalline B12 is utilized as the test
dose. B12 attaches to "R" binders (R) produced by the stomach,
which have a higher affinity for B12 than intrinsic factor (IF), also
produced by the stomach.
• Step 3: Pancreatic proteases degrade the "R" binders, allowing
formation of the B12-IF complex, the specific form absorbed by the
terminal ileum.
• Step 4: One hour after the test dose, a 1000 µg "flushing" dose of
non-radioactive B12 is given to saturate B12 binders
(transcobalamines).
• Step 5: If present, bacteria in "blind loops" in the duodenum or
jejunum preferentially utilize vitamin B12, allowing none to be
available at the site of absorption.
• Step 6: With blood and tissue B12 binding sites blocked by the
"flushing" dose, the B12/IF complex is absorbed by the terminal
ileum, and the B12 is excreted in the urine
• (step 7), which is assayed for its content of radioactivity. The test
can be repeated with the addition of missing factors (eg, intrinsic
factor, pancreatic extract), or following the use of nonabsorbable
antibiotics (blind loops and/or bacterial overgrowth present), or
gluten-free diet (celiac disease)
• Identify the underlying cause
• Cobalamine 1000mcg/daily= 1 mg
- Given every 3-7 days(twice wkly) for 6 doses then monthly
- Folic acid 5 mg daily for 3-4 months
• Response
-Reticulocytosis occur(5-7days)
-Hematology picture normalize 2mo.
-CNS Sx reversible if it’s short duration(<6mo)
 Folic acid Deficiency
 General consideration
• It’s present in most fruits & vegetables.

• Daily requirement - 50-100mcg/day.

• Total body store ≈5000mcg;enough to

supply for 2-3mo.
 Causes
• Dietary deficiency
• Decrease absorption(rare)-drugs
• Increase requirement- Pregnancy
-chronic hemolytic A.
-Exfolative skin ds
• Inhibition of reduction to active form-
Methotrexate;Trimetoprim
• Deitary: by far the most common cause- alcholic person who don`t eat
fresh fruits & vegitable;those over cooks there food are candidate for folate
deficiency.
• Decrease absorption-rarely seen b/c absorption occur from entire GIT;
tropical spru, drugs like phentoin, cotrimoxazol,sulfasalzin

• During thymidylate synthesis, folate becomes oxidized to inactive

dihydrofolate polyglutamate. Regeneration of active tetrahydrofolate
requires the enzyme dihydrofolate reductase, which is inhibited by
methotrexate
• Trimetoprim- is a weak inhibitor of dihydrofolate reductase and in high dose
has been implicated in megaloblastic pancytopenia.
• Alcohol abuse produces a sharp fall in serum folate within two to
four days by impairing its enterohepatic cycle and inhibiting its
absorption Thus, alcoholics on a low folate intake can develop
megaloblastosis within 5 to 10 weeks. This period is shorter than the
4 to 5 months required in normals in part because alcoholics start
with lower stores due to previous dietary habits.

• (during thymidylate synthesis) Folate ---oxidized------DHF

polyglutamate(inactive form)---DHF Reductase-----THF (active form)
 C/F
• Similar to vit B12 except neurologic abn.

LAB. Ix
• Similar to Vit. B12
• Serum Vit. B12 level normal
• RBC folate level <150 ng/ml is diagnostic
• Folic acid 1mg/d orally
• Response:
-Rapid improvement &sense of wellbeing
reticulocytosis in 5-7 days.
-Total correction of hematologic abn. Within 2 mo.
• Folic acid can partially reverse some of the hematologic
abnormalities of Cbl deficiency, although the neurologic
manifestations will progress for reasons that are not entirely clear.
Thus, it is important to rule out Cbl deficiency before treating a
patient with megaloblastic anemia with folic acid. If initiation of
treatment is urgently required, blood samples should be obtained
for the appropriate assays, and the patient should be treated with
BOTH folic acid and vitamin B12 until the test results are known.
END