Vitamin B12 & Folate

Closely linked in the support of DNA synthesis

B12 is present in two forms:
o Deoxyadenosyl B12 support conversion of 1-methyl-malonyl-CoA to succinyl-CoA
o Accepts methyl group from MTHF to support synthesis of methionine. This transfer provides the THF necessary
for sythesis of various folate coenzymes needed for purine and glycine synthesis and for conversion of
deoxyuridylater to thymidylate for DNA synthesis
A lack of eiterh vitamine interferes with DNA sythesis
o When MTHF is in short supply, THF cannot be generated to support other folate enzymes
o When B12 is lacking, there is no acceptors for the methyl group grom MTHF
o Causes a methylfolate trap = reduced avaibility of THF to support DNA synthesis

Cobalamin (B12)
Dietary Sources & Requirements

Synthesized solely by micro-organisms

The only source of humans is food of animal origin , e.g. meat, fish & diary products
vegetables, fruits & other foods of non-animal orgin are free from cobalamin unless they are contaminated by
bacteria
normal western diet contains between 5 30g of cobalamin daily
adult daily losses (mainly in the urine & feces) are between 1-3g
body stores are of the order of 2-3mg, sufficient for 3-4 yrs if supplies are completely cut of

Absorption

2 ways to absorb cobalamin:

1. Passive occurs through the buccal, duodenal & ileal mucosa; rapid but extremely inefficient (<1% of oral dose
is absorbed)
2. Active:

Occurs through the ileum and is effieceint for small oral doses of cobalimin & is mediated by gastric
intrinsic factor (IF)

IF produced in the gastric parietal cells of the fundus & body of the stomach, and its secretions parallels
that of HCL

Dietary cobalimin is released from protein complexes via enzymes in the stomach, duodenum & jejunum
combines with salivary glycoprotein (that belong to haptocorrins, HCs) in the intestine, HCs are digested by pancreatic trypsin
cobalamin transferred to IF IF:cobalamin passes to ileum where IF attaches to a specific receptor (cubulin) on the microvillus
membrance of the enterocytes cubulin & its ligand IF:cobalamin are endocytosised into the ileal cell where IF is destroyed after
6hr delay, cobalamin appears in the portal blood attached to transcobalamin (TC) II

Between 0.5-5.0g of cobalamin enter the bile each day. This bind to IF & a major proitn of biliary cobalamin is normally reabsorbed
together with cobalamin derived from sloughed intestinal cells.

Note: This is why B12 deficiency develops more rapidly in individuals who malabsorb cobalamin than it does in vegans, b/c
they still have an intact reabsorption of biliary cobalamin in enterhepatic circulation

Transport

Two main tranport protiens in human plasma:

o TC I closely related to other cobalamin-binding HCs in milk, gastric juice, bile, salvia & other fluids; derived
primarily from the specific granules in neutrophils. Does not enhance cobalamin entry into tissues. Glycoprotien
receptors on liver cells are involved in the removal of TC I from the plasma
o TC II Principal transport protein for delivery of B12 to tissue & liver; normally carries 20-30 ng of cobalamin
per liter of plasma & readily gives up cobalamin to marrow, placenta, and other tissues, which it enters by
receptors-mediated endocytosis

Folate
Dietary Folate

Folate is found in most foods; highest concentration found in liver, yeast, spinach, other greens and nute
(>100g/100g)

Total folate content in the average western diet = ~250g/day

Folate is easily destroyed by heating, particularly in large volume of water

Total body folate = ~10mg, the liver containing the largest store

Daily adult requirements = ~100g

o Thus stores are sufficient for only 3-4 months in normal adults

Absorption:

Folates are absorbed rapidly from the upper intestine

The absorption of polyglutamates is less efficient than for monoglutamates; on ave ~50% of food folate is absorbed

Polyglutamate is hydrolyzed to monoglutamate, and then converted to 5-methyltetrahydrofolate (5-MTHF) within the
small-intestinal mucosa

5-MTHF is then rapidly transported to tissues to enter the intracellular metabolic cycle required for purine and
pyrimidine metabolism & DNA synthesis

both methylated and nonmethylated THF are absorbed by the liver, where they are stored as 5-MTHF polyglutamate.
The liver plays a role in providing constant supply of folate to tissues
o about 60-90g of folate enters the bile each day and is excreted into small intestines and then reabsorbed
o Note: any dysfunction to the livers ability to store & release folate inot gut or with rebsorption of folate can
rapidly disrupt supply to tissues
Macrocytic Anemia

Erythropoeitic Profile of Severe

Macrocytic Anemia

Severe (Hgb<8-10g/dL)

MCV (fL)

110-140

QuickTime and a
decompressor Macrocytic,
Film
are needed to see this picture.

QuickTime and a
decompressor
are needed to see this picture.

Anemia

Causes:
Megaloblastic vit B12 deficiency, folate deficiency, drugs
(methotrexate, azathioprine)
Non-megaloblastic reticulocytosis, myelodysplastic
syndromes, liver disease, alcoholism, hypothyroidism

Characteristic

Megaloblastic

Non-megaloblastic

Morphology

Large, oval, nucleated

RBC precursor

Large round RBC

Pathophysiolo
gy

Failure of DNA synthesis

resulting in
asynchronous
maturation of RBC
nucleus & cytoplasm

Reflects membrane
abnormality with
abnormal cholesterol
metabolism

Morphology

normochromic

Reticulocyte
index

<1

Marrow E/G
ratio
Morphology

>1:1
megaloblastic

Serum
Iron/TIBC

Increased/normal

% saturation

>50

Marrow iron
stores

Increased

Serum ferritin

Increased

Bilirubin/LDH

Increased/increased

Vitamin B12 Deficiency

General Considerations:

Vit B12 is involved in 2 enzymatic reactions:

o Conversion of methylmalonyl-coenzyme A (CoA) to succinly-Coa
o Methylation of homocysteine to methionine reaction required for synthesis of thymidine, a component of DNA
Because B12 is present in all animal products only people with unusual diets (vegans, fad dieters) receive
inadequate intake. Some special populations, such as pregnant women, require increased levels of vit B12

Pathogenesis

Diet strict vegan (rare)

Gastric mucosal atrophy of pernicious anemia, post-gastrectomy

Intestinal absorption
o Malabsorption (e.g. Crohns, celiac sprue, pancreatic disease)
o Stagnant bowel (e.g. blind loop, stricture)
o Resection of ileum

Rare genetic causes (e.g. transcobalamin II deficiency)

Pernicous anemia
o occurs when autoantibodies against parietal cells are produced, resulting in a lack of IF
o IF is required to stabilize B12 as it passes through the bowel
o Decreased IF lead to decreased ileal absorption of B12

May be associated with other autoimmune disorders (e.g. thyroid & adrenal deficiency)

Clinical Findings
Symptoms & Signs:

Common megablastic anemia symptoms: anemia, pallor, weight loss, glossitis, lightheadness, jaundice, and
abdominal symptoms
Neurologic symptoms are specific to B12 deficiency begins with parenthesis in hands and feet; disturbances in
vision, taste, smell, proprioception and vibratory sense can also occur. Untreated B12 deficiency can lead to posterior
spinal column demyelination, resulting is spastic ataxia and dementia mimicking that of Alzheimer disease.
Sometimes lead to psychotic depression and paranoid schizophrenia.
Sum of Neurological Symptoms:
o Cerebral (common, reversible with B12 therapy)

Confusion, delirium, dementia (possibly reversible)

o Cranial nerves (rare)

Optic atrophy
o Cord (irreversible damage)

Subacute combined degeneration:

Posterior columns decreased vibration sense, proprioception & 2-point discrimination

Pyramidal tracts spastic weakness, hyperactive reflexes

o Peripheral neuropathy (variable reversibility)

Usually symmetrical, afecting lower limbs more than upper limbs

Laboratory Findings
B12 Deficiency Lab Results
Test

Results

Serum

Anemia often severe +/- neutropenia (low neutrophil levels) +/- thrombocytopenia (low platelet levels)
MCV >120 (macrocytic)
Low reticulocyte count relative to the degree of anemia
pancytopenia - due to dysfunction DNA synthesis afecting all cell lines

Serum B12
& RBC
Folate

Vit B12 levels = 100pg/mL. Caution: low serum B12 lead to low RBC folate because of failure of folate
polyglutmate synthesis in the absence of B12

Blood Film

- Oval marcocytes
- hypersegmented neutrophils - which are pathognomonic for megaloblastic anemia

Bone
Marrow

Schilling Test

You will get two doses of vitamin B12 (cobalamin). The first dose is radioactive and taken by mouth. The
second dose is not radioactive and is given as a shot 2 - 6 hours later.
If your body does not make intrinsic factor, you cannot absorb vitamin B12. The lack of intrinsic factor can
lead to low levels of vitamin B12 because of pernicious anemia, partial removal of the stomach
(gastrectomy), poor vitamin B12 absorption due to bowel disease, too much bacteria in the intestine, a
lack of enough enzymes being produced by the pancreas, or certain medications. The Schilling test is
most commonly used to evaluate patients for pernicious anemia.

Homocystei
ne Levels

Homocysteine or methylmalonic elevated levels; most useful where diagnosis is suspected by not
supported by other lab values
Note: elevated methylmalonic levels confirm B12 deficiency

Diferentiates between megaloblastic and myelodysplastic anemias

hypercelluarility
failure of nuclear maturation
elevated unconjugated bilirbrubin & LDH due to marrow cell breakdown

Treatment

Monthly parenteral treatment of vit B12 in doses of 100-1000mcg, administered daily or ervery other day for the first
few weeks; followed by maintainance doses every 1-3 months

Once B12 levels have been reestablished, oral therapy can be substituted

Folate administariona 1-5mg/daily

Folate Deficiency

General Considerations:

In contrats to B12 reserves (which can last 3-5yrs), folate reserves last only 4-5 months. The human body requires
about 75-100mcg/day of folic acid, which is present in leafy greens, vegetables, fruits, nuts, beans, wheat germ and
liver

Involved in the synthesis of thymidine

Pathogenesis

Decreased intake - occurs most frequently in alcoholics and patients with atypical diets

Malabsorption- small intestine microvilli convert the ingested complex folic acid molecule into absorbable one,
diseases of the small intestine (e.g. gluten enteropathy & Crohn disease) can cause deficiency

Drugs e.g. anticonvulsants and oral contraceptives can predispose to folate malabsorption; alcohol,

Other medications e.g. antineoplastic agents, trimethopri & certain antimalarial drugs; inhibit enzyme necessary
for the replenishment of intracellular folate & can afect folate levels; birth control pills

Increased demand pregnancy, patients with hemolytic anemia, exfoliative skin diseases, patients on dialysis
Clinical Findings
Symptoms & Findings

Midly jaundiced due to hemolysis of RBC secondary to inefective hemoglobin

Essentials of
synthesis
Diagnosis:

Overall only severely anemic pateitns have symtpoms (those of normal anemia);
macrocytic anemia
typically neurological symtpoms are absent unlike B12 deficiency
- reduced RBC or serum

Patients with folic acid deficiency often go undiagnosed, especially alcoholics who
folate - normal Vit B12
have very poor diet and maintain blood alcohol levels above 100mg/dL for extended
levels
periods
o Unless anemia is severe, the patient is relatively insensitive to its symptoms when compared to the other
problems associated with alcoholism
o If withdrawn for alcohol long enough, usually serum folate levels return and megaloblastic defect begins to
resolve

During pregnancy associated with high incidence of fetal developmental abnormalities, especially neural tube
defects
Laboratory Findings
Folate Deficiency Lab Results
Test

Results

Serum

Hb levels variably depressed

MVC >120 (macrocytic)
pancytopenia - due to dysfunction DNA synthesis afecting all cell lines

Serum & RBC Folate

Levels

Depressed; RBC folate <150pg/L (thought to be more precise indicator)

Blood Smear

Abnormal RBCs
Hypersegemented neutrophils

Bone marrow

Erythiod hyperplasia & marked asynchrony in matureation between cyotplasmic

Test of &Vit
B12 &material
Folate Deficiency
components
nuclear

Homocysteine/methymal
onic

Test homocysteine
Vit
B12 in spite of normal
Folate methylmalonic acid level suggest folate
Elevated
levels
Deficiency
Deficiency
deficiency

Treatment:

Increase folate
vegetables,
liver)

Folate
o Total

Never give folate

megaloblastic
deficiency and
continue

Serum B12
(normal
>200pg/mL)

<100

>200

Serum Folate level

(normal>4ng/mL)

>4

<4

Serum
methymalonic acid
(normal
<270nM/L)

2-100 x normal

Normal

Serum
homocysteine
(normal <12nM/L)

2-20 x normal

2-10 x normal

intake through diet (green leafy

fruits, nuts, beans, wheat germ, &
Supplementation - 1-5mg/daily
corrections occurs within 6-8weeks
alone to individual with
anemia b/c it will mask B12
neurological degeneration will

Normal RBC Turnover

RBC survival is dependent on: (1) the strength of the cell membrane, (2) the metabolic pathways that supply the
high-energy phosphate needed to maintain the membrane and keep Hb in a soluble, reduced state

As RBCs age = metabolic pathways decay, oxidized Hb accumulates, and oxidized phospholipids appear on the
surface of the cell

Loss of flexibility interferes with the cells ability to move through the microvasculature and initiates the process of
removal by
the monocyteMeasurements of RBC Destruction
macrophages
system via
receptors
Indirect Measurements
Direct measurements
Role of the
Spleen
Changes in hematocrit
51Cr blood cell survival

Testing site
for cell flexibility
reticulocyte production index
ferokinetics
and viability
serum lactic dehydrogenase (LDH) CO excretion

Blood is
delivered by
Serum indirect bilirubin
Urobilinogen excretion
terminal
arterioles to the
spleenic RBC
pulp, where the
volume of plasma is reduced and the cell is subjected to a relatively hypoxic environment

To escape and reenter circulation, the RBC must then squeeze through a 2-5um opening in the sinusoidal wall this
traps rigid cells and lead to phagocytosis & destruction by reticuloendothelial cells lining sinusoids
Pathways of RBC Destruction

RBC destruction is meant to recover heme iron for new RBC production

Two forms of destruction:

(1) intravascular (RBC break down in the circulation)

o Free heme dissociated into - dimers that bind to haptoglobin or is oxidized to methemoglobin that then
dissociates to release the heme group for binding with albumin & hemopexin
o The binding step prevents immediate loss of the heme group by glomerular filtration and allows clearance by
hepatocytes. The liver then breaks down the heme group to recover iron and produce bilirubin

(2) extravascular (normal reticuloendothelial pathway)

o Destruction of senescent cells is primary extravascular pathway; RBC are phagoctyized by reticuloendothelial
cells, the membrane is disrupted, & Hb is broken down (some parts reused & others excreted)

Hemolytic Anemias
Pathophsyiology

Reduced erythrocyte lifespan, ranging from nearly normal to remarkably shortened.

In compensation for a reduced RBC lifespan, the bone marrow increases its output of erythrocytes, a response
mediated by increased production of erythropoietin. The limits of erythrocyte production in hemolytic states are
probably lower in infants than in adults.

As a result of increased RBC production in response to hemolysis, the reticulocyte count often exceeds 2 percent,
with an absolute reticulocyte count usually greater than 100,000/microL.

When a chronic hemolytic process is present, hyperplasia of the erythropoietic marrow elements occurs, with
reversal of the myeloid-to-erythroid ratio from the normal 3:1 to 1:1 or less.

In the severe, chronic hemolytic processes of childhood (eg, thalassemia major, congenital spherocytosis, sickle cell
disease), hypertrophy of the marrow may expand the medullary spaces, producing bony changes, particularly in the
skull and hands

Diagnosis

Measured directly by determining erythrocyte survival, or indirectly via the presence of increased levels of the
metabolic products of hemolysis (eg, increased indirect bilirubin, increased lactate dehydrogenase, reduced
haptoglobin).

Alternatively, a hemolytic process may be inferred, in a non-bleeding patient, by documentation of the increase in
the erythrocyte production (eg, presence of reticulocytosis) that usually accompanies hemolytic states.

Elevations of unconjugated bilirubin often occur in children with hemolytic anemias. However, overt clinical jaundice
may be absent or may be missed.
o

Total bilirubin levels in excess of 5 mg/dL are unusual if hepatic function is normal.

The increased excretion of bilirubin pigments that occurs in patients with chronic hemolysis also may lead to the
production of pigmented gallstones that may develop in early childhood

In any hemolytic state, hemoglobin is released into the plasma, where it combines irreversibly with serum
haptoglobin. The large hemoglobin-haptoglobin complex is then rapidly cleared from the circulation by the liver.
Because the synthetic and binding capacities of haptoglobin are limited, serum levels of haptoglobin in hemolysis
usually are either decreased (<20 mg/dl) or absent.

Radioactive sodium chromate (51Cr) most often is used as a erythrocyte

tag in adults, whereas non-radioactive techniques using biotin are
available for use in neonates and children. A shortened erythrocyte
survival is likely when the 51Cr RBC half-life is reduced below 20 days

Investigations for Hemolytic Anemia

Test

Results

Blood
Tests

reticulocyte
haptoglobin (<20 mg/dl)
unconjugated bilirubin
urobilinogen
LDH

Blood
Film

RBC fragements, free Hb in

serum,
methemalbuminermia
(heme+albumin),
hemoglobinuria
(immediate),
hemosiderinuria (delayed)

51Cr
/biotin

(normal: 28 to 37 days). However, employing such survival studies in

clinical practice is necessary.
Classification

HA a result of an intrinsic abnormality of the erythrocyte or an extrinsic

abnormality acting on a normal erythrocyte.

Intrinsic hemolytic anemia generally result from inherited abnormalities of:

RBC half-life is reduced

below 20 days (normal: 28
to 37 days)

Erythrocyte membrane spherocytosis, elliptocytosis

Intracellular enzymes pyruvate kinase deficiency, G6PD deficiency

hemoglobin synthesis thalamassemias, hemoglobinopathies

Extrinsic hemolytic anemia usually is acquired and results from forces or agents that immunologically, chemically, or physically
damage the erythrocyte.
o

Immune hemolytic transfusion reaction, autoimmune HA, drugs (penicillin), cold agglutinins

Non-immune microangiopathic HA, paroxysmal nocturnal hemoglobinopathies, hypersplenism, infections (Malaria)

Thalassemia
Definition:

Congenital disorders of hemoglobin synthesis (microcytic anemia)

Characterized by deficient synthesis of one or more hemoglobin polypeptide chains ( or ) that leads to
microcytosis

Clinical manifestations & treatment depends on specific gene and number of alleles afected

Common Features:
o Increasing severity with increasing number of alleles involved
o Hypochromic microcytic anemia
o Basophilic stippling; target cells on blood film

Defects may be in any of the Hb genes:

o Normally 4 genes in total, 2 on each copy of chromosome 16
o Normally 2 genes in total, 2 on each copy of chromosome 11
o Fetal hemoglobin HbF (2:2) switches to adult forms HbA (2:2) and HbA2 (2:2) at 3-6 months of life

HbA constitutes 97% of adult Hb

HbA2 consitutes 3% of adult Hb

Beta-thalassemia results in an excess of alpha-globins, leading to the formation of alpha-globin tetramers that
accumulate in the erythroblast

Alpha-thalassemia results in an excess of beta-globins, which leads to the formation of beta-globin tetramers
called hemoglobin H
o Hemoglobin H can precipitate, causing damage to the red blood cell membrane and leading to red cell breakage
Epidemiology:

ThalasSEAmia
thal prevalent in Mediterranean SEA
Thal prevalent in South East Asia
(SEA)

Age

Congenital condition

Beta-thalassemia major causes severe anemia and jaundice from age 3-6 months

Alpha-thalassemia causes intrauterine death if all four chains are afected; other forms may not present until later
life

Beta-thalassemia minor is usually asymptomatic

Genetics

Inherited in an autosomal-recessive pattern

Inheritance of one defective gene causes the mild type of thalassemia; inheritance of two defective genes causes
the severe type of thalassemia

Two alpha-thalassemia phenotypes are recognized; one is characterized by thalassemia minor in the heterozygous
state and the other is marked by no clinical or hematologic abnormality in the heterozygous state

There are also two major types of beta-thalassemia: one with some residual beta chains (beta+ type) and another
with no beta chains (beta0 type)
Etiology:

Alpha-thalassemias

Most of the alpha-thalassemia syndromes result from gene deletions

The alpha-thalassemias result from mutations that cause decreased synthesis of structurally normal globin
Two alpha-thalassemia phenotypes are recognized, and are referred to as follows: alpha-thalassemia 1 and
alpha-thalassemia 2 (alpha+ thalassemia - low level of alpha chains)
o Hydrops fetalis has no alpha-globin gene (alpha0 thalassemia- no alpha chains)
o Hemoglobin H disease has one alpha-globin gene
Beta-thalassemias:
o Most of the beta-thalassemia syndromes result from nucleotide substitutions or deletions in genes that are
otherwise intact
o
There is only one beta-globin gene, of which there are two alleles (paternal and maternal)
o
Globin chain synthesis in the homozygous state reveals two major types of beta-thalassemia: beta+ type
(suboptimal beta chains present) and beta0 type (total absence of beta chains)
o The beta-thalassemia syndromes are caused by mutations of the expressed beta+ allele and nonexpressed
beta-0 alleles
o The mutations afect gene regulation or expression rather than gene deletion, and can result in decreased
synthesis of structurally normal globin
o In individuals with beta+ thalassemia, the amount of beta-globin messenger RNA in reticulocytes and bone
marrow normoblasts is decreased 3- to 10-fold
o
In patients with homozygous beta0 thalassemia, beta-globin synthesis is absent
o
o
o

Pathophysiology of thalassemia: how does defective hemoglobin cause disease?

Selective deficiency of one or more polypeptide chains causes decreased hemoglobin synthesis and imbalance
between alpha and nonalpha chain production

In the absence of complementary globin chains with which to bind, chains with normal synthesis form aggregates,
precipitate within the cytoplasm, damage cell membranes, and lead to premature cell destruction

In patients with alpha-thalassemia, the defect in alpha chain synthesis results in an accumulation of gamma chains
in the fetal and neonatal periods and of beta chains thereafter
o The excess of beta chains oxidize and precipitate with cell aging

In homozygous beta-thalassemia, a deficiency of beta chain synthesis results in an accumulation of alpha chains
o The free alpha chains aggregate to form insoluble inclusions in bone marrow erythroid precursors

In thalassemia syndromes there is often(1) ineffective erythropoiesis and (2) hemolysis, which lead to anemia
Clinical Presentation
Symptoms:

symptoms of anemia: tiredness, breathlessness, poor exercice tolerance

abdominal pain due to hypersplenism and splenic infarction may occur

right upper quadrant pai cause by gallstones may occur

Signs:

Thalassemia triat has no signs or symptoms, other form of thalaassemia may have:

Pallor, poor growth, inadequate food intake, spelnomegaly, jaundice, maxiallary hyperplasia, dental malocculusion,
systolic ejection murmur in the presence of sever anemia, pathologic fractures
Diagnostic Decision

Symptomatic Thalassemia Sydromes

Hydrops fetalis:
o In major thalassemia, daignosis is obvious from Hb electrophoresis
is a condition in the
o Alpha-thalassemia major syndrome:
fetus characterized by

Electrophoresis is normal in the absence of HbH disease

an accumulation of
o HbH Disease:
fluid, or edema
(subcutaneous tissue,

Severe anemia, often require blood transfusion

pleura, pericardium, or

Hb electrophoresis shows HbH

in the abdomen).

At birth, 20-40% Hb Barts is found (Hb Barts is deletion of all four alpha-globin
Sometimes leading to
genes = hydrops fetalis)
spontaneous abortion.
o Beta-Thalassemia Major Syndrome (cooleys syndrome):
It is a prenatal form of
heart failure, in which

Anemia & morphologic alteration of circulating erythrocytes are first detect at 6

the heart is unable to
weeks
satisfy the insatiable

Splenomegaly detected @ 8 weeks

demand for an

[Hb] slowly fall to 3-5 g/dL

unusually high amount

reticulocyte count is elevated (5-15%)

Absent or reduced Hb; Increased fetal Hb (HbF)

Asymptomatic Thalassemia Syndromes:

o Alpha-Thalassemia Minor:

Suspected in newbrons on the basis of a low MCV (<94) & an increase in Hb Barts

Failure to detect hb Barts does not exclude alpha-thalamessiam

In absence of a specific screening test, a definitieve diagnosis can be made only by demonstrating a
reduced rate of alpha chain synthesis in reticulocytes

Beta-thalassemia Minor ( Thalassemia Triat):

Diagnosis of heterozygous -thal is confirmed by:

Increase HbA2, RBC microcytosis, hypochromia, target cells, & basophilic stippling

50% of patients have mild elevation of HbF of 1-3%

Hb electrophoresis demonstrates a predominance of HbA, increased levels of HbA2 (3.4-8%)

In beta-thalassemia the major presentation is at age 3-6 months:

How long has your baby been unwell for? Intercurrent infection is a common cause of hemolysis in babies,
particularly those with glucose-6-phosphate dehydrogenase (G6PD) deficiency
Was your baby jaundiced at birth? May indicate G6PD deficiency or red cell membrane disorders such as
sperocytosis.
Did your baby have any bleeding at birth or from the cord stump? Consider coagulation disorders
Has your baby passed any blood or dark stools? Consider blood loss from the gut (e.g. intussusception, Meckel's
diverticulum)
Has your baby ingested anything unusual? Drugs are a common cause of hemolysis in babies, particularly those
with G6PD deficiency
Has your baby been growing well? Thalassemia major often presents with failure to thrive with severe anemia
and jaundice at around 6 months
Have you ever lost a baby in pregnancy? Fetal hydrops caused by complete failure to synthesis alpha chains
leads to death in utero

Lab Tests
Investigations
Test
CBC

Alpha thalassemia

Beta Thalassemia

Major: [Hb] = 2.5-6.5g/dL, microcytic = MVC (48-72), hypochromic = MCHC (230-320g/L),

reticulocyte count = elevated (5-15%)
Minor: [Hb] = variably , RBC count elevated, MCV = , MCHC = N/

Hb Electrophoresis

Peripheral Blood Smear

Normal except for the presence of HbH in

Hbh disease

Major: absent/ HbA, HbF, variable in

HbA2

HbH Disease: @ birth 20-40% Hb Barts

(later replaced by HbH); A2level

Minor: predominance of HbA, HbA2 levels,

N/ HbF levels

Abnormal RBC morphology with

microcytosis & hypochromia, basophilic
stippling,
% target
cells

Major: significant anisocytosis, hypochromic,

% target cells, basophillic stippling

Hematocrit

Minor : microcytosis, hypochromia,

anisocytosis, target cells, basophilic stippling,
no nucleated RBCs

Major: may fall less than 10% in beta-thal

Minor: reduced to 28-40% in both traits

Serum Ferritin,
transferrin & TIBC

Serum iron levels are increased

Transferrin is decreased in hemolytic anemias
Serum iron-binding capacity is decreased in hemolytic anemia

Serum Bilirubin
(indirect)

Normal (0-1.0mg/dL (2-18mcmol/L))

Increased unconjugated bilirubin levels due to hemolysis

Urine urobilin &

urobilinogen

Normal (not present)

Both Substances present

Treatment

General Measures
o Mild cases require no therapy

Avoid iron therapy for minors

Severe thalassemia: maintain a mean Hb of at least 9.3g/dL w/ regular transfusion schedule

Goals of transfusion therapy are correction of anemia, suppression of erythropoiesis, and inhibition of
increased gastrointestinal absorption of iron
o Folate supplementation: prevents megaloblastic arrest of erythropoiesis
o Iron Chelate Therapy (deferoxamine): for patients receiving tranfusions, this prevents iron-overload
Surgical Measures:
o Spelnectomy if hypersplenism causes marked increase in transfusion requirement (needs to be 4-6yrs old)

Anti-biotics should accompany post surgery regimen

Bone Marrow Transplantations:
o Can cure the disease; associated with significant mortality and morbidity
o
o

Back to the Case: SOAP

O:
acute respiratory distress - [Hb} thus O2-carrying
capacity
generalized swelling = signs of prenatal heart failure (?)
Apgar score 7 = A baby who scores a 7 or above on the test
at 1 minute after birth is generally considered in good health
Gestational age = 32 weeks; A fetus born prior to the 37th
QuickTime and a
week of gestation is considered premature and faces
decompressor
are needed to see this picture.
increased risk of morbidity and mortality.

is usually considered to be the age of an embryo or

fetus (or newborn infant) from the first day of the
woman's last menstrual period (LMP)

A full-term human pregnancy is considered to be 40

weeks (280 days), though pregnancy lengths between
38 and 42 weeks are considered normal.
HR 180 tachycardic; HR X SV = CO (needs to increase CO
to make-up for anemia
RR 40/min tacyhpnea; correlates with increased HR & CO
Large liver & spleen = due to increased hemolysis and engulfment of destroyed RBC
Hb 50g/L decreased; due to decreased production or/and increased hemolysis
WBC 15,000x10^9/L = increased; infection (?) or due to hemolysis (increasing erythropoiesis_
Neutrophils 5,00ox10^9/L = increased;
Platelets 570,000X10^9/L = increased;
MVC 67 = microcytic; typical of thalassemia
Many nucleated cells = sign of major thal syndrome vs minor
A: Since there is immediate presentation of thal anemia from birth, it would suggest alpha thal because fetal Hb would
be composed of :F. Thus a defect to -globin gene would present symptoms earlier than -globin gene mutations,
which takes 3-6months to gradually replace fetal globin synthesis
P: (1) blood transfusion, (2) iron chelate therapy,

Apgar Score
Apgar Sign

HR

Normal = >100bpm

<100bpm

Absent

Breathing

Normal rate & efort, good

cry

Slow or irregular, breathing,

weak cry

Absent (no breathing)

Grimace (responsiveness or
reflex irritability)

Pulls away, sneezes, or

coughs with stimulation

Facila movement only

(grimace with stimulation)

Abesnt 9 no respons to
stimulation_

Activity (muscle tone)

Active, spontaneous
movement

Arma and legs flexed with

little movement

No movement flopyy tone

Appearance (skin
coloration)

Normal colour all over

(hands and feet are pink)

Normal colour (but Hnads

and feets are bluish)

Bluish-gray or pale all over

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