HEMOLYTIC AND NUTRITIONAL ANEMIAS: DR.

BEA GEPTE, MD MPH

I. INTRODUCTION
A. The red blood cell
- No nucleus
o Better vessel for exygen transport
o Loss of ability for protein synthesis
o Finite life span
- No mitochondria
o Cannot generate ATP through Kreb’s cycle
o Metabolism of glucose by anaerobic glycolysis (Embden-Meyerhof pathway) and
pentose phosphate pathway
- Importance of ATP
1. Maintenance of electrolyte gradients
o Accomplished by an energy (ATP)-dependent membrane mechanism, the cation pump
2. Initiation of energy production
o ATP is required for the initial reaction of glycolysis involving phosphorylation of glucose
to glucoe-6-phosphate
3. Maintenance of RBC membrane and shape
o Maintains phospholipid structure of the RBC membrane and the RBC’s biconcave shape
4. Maintenance of heme iron in the reduced (ferrous) form
o Oxidative potentials within the RBC are inactivated
o Protection of RBCs from the effects of oxidation ultimately depends on NADPH and
NADH
5. Maintenance of the levels of organic phosphates such as 2,3-diphosphoglycerate (2-3 DPG)
and ATP within the RBCs
o Have profound effects on oxygen affinity

B. Red Cell Life Span

- The average life span for a neonatal RBC is 60-90 days, approximately ½ to 2/3rd that of an
adult RBC
1. A rapid decline in intracellular enzyme activity and ATP
2. Loss of membrane surface area by internalization of membrane lipids
3. Decreased level so of intracellular carnitine
4. Increased susceptibility of membrane lipids and proteins to peroxidation
5. Increased mechanical fragility due to increased membrane deformability

II. HEMOLYTIC ANEMIAS

- Hemolysis is defined as the premature destruction of red blood cells (RBCs)
o Rate of destruction exceeds the capacity of the marrow to produce RBCs
o RBC survival is shortened
o Erythropoietin is increased  the stimulation of marrow activity  heightened RBC
production  increased percentage of reticulocytes in the blood
 Reticulocytes = young RBCs; can be seen in peripheral smear, presence of
these in per. smear gives the suspicion of haemolytic anemia with marrow
compensation
o The marrow can increase its output 2 to 3-fold acutely, with a maximum of 6 to 8-fold
in long-standing hemolysis
 Even if you hemolyze, you may not develop anemia for as long as your bone
marrow can compensate

A. General Principles
- Reticulocyte Count and Reticulocyte Index
o Ret index = reticulocyte count (in %) * (observed hematocrit/actual hematocrit) * (1/μ)
o Μ = maturation factor of 1-3 related to the severity of the anemia
Hct μ
36-45 1
26-35 1.5
16-25 2
< 15 2.5
o Normal retic. Index = 1, hemolysis = 2-3 or more
- General consequences of hemolysis
1. Erythroid hyperplasia resulting to the expansion of the medullary spaces at the expense of
the cortical bone
2. Increased billiary excretion of heme pigment derivatives and increased urinary and fecal
urobilinogen
3. Gallstones composed of calcium bilirubinate may be formed in children as young as 4 yrs
of age
o Usual gallstone formers: Fat, Female, Fourty (3 Fs!)
4. Elevations of serum unconjugated bilirubin and lactic dehydrogenase
5. Presence of free haemoglobin in the plasma and urine

- Hemolytic anemia
- Can be extravascular or intravascular
o Intravascular: RBCs do not have to pass through liver and spleen for them to
be destroyed
o Extravascular: RBC destruction happens in spleen or liver
- Classification of haemolytic anemias
1. Cellular – resulting from intrinsic abnormalities of the membrane, enzymes, or
haemoglobin
2. Extracellular – resulting from antibodies, mechanical factors, or plasma factors

B. Hereditary spherocytosis
- Epidemiology
o Prevalence of approx 1/5,000 in people of Northern European descent
o Most common inherited abnormality of the red blood cell (RBC) membrane
o 25% do not have a family history, mostly representing a new mutation
- Etiology
Protein Band on Gel Gene Proportion of Inheritance
Patients w/ HS
Ankyrin 2.1 ANK1 50-67% Dom and Rec
Band 3 3 AE1 (SLC4A1) 15-20% Mostly dom
β Spectrin 2 SPTB 15-20% Dom
α Spectrin 1 SPTA1 < 5% Rec
Protein 4.2 4.2 EPB42 < 5% Rec

- Clinical manifestations
o Severe anemia and hyperbilirubinemia in the newborn period requiring phototherapy
or exchange transfusions
o Asymptomatic
o Severe anemia with pallor, jaundice, fatigue, and exercise intolerance
 o Splenomegaly
o Pigmentary (bilirubin) gallstones may form as early as age 4-5 yrs
o Susceptible to aplastic crisis
- Laboratory findings
o Reticulocytosis
o Indirect hyperbilirubinemia
o Increased MCHC 36-38 g/dL
o Spherocytes usually account for > 15-20% of the cells when
hemolytic anemia is present
o Erythroid hyperplasia is evident in the marrow aspirate or
biopsy
o Marrow expansion may be evident on routine Xray
o Gallstones on UTZ
- Diagnosis
o The diagnosis if hereditary spherocytosis usually is
established clinically from the blood film, which
shows many spherocytes and reticulocytes, from the
family history, and from splenomegaly
o Osmotic fragility test
 Nonspecific
 Normal test result also may be found in 10-
20% of patients
o Cryohemolysis test
o Osmotic gradient ektacytometry
o Eocin-5-maleimide test
o DNA analysis
- Differential diagnosis
o Isoimmune haemolytic disease of the newborn
 Due to ABO and RH incompatibility
 Detection of antibody on an infant’s RBC using
a direct antiglobulin (Coomb’s) test
o Autoimmune haemolytic anemias
 Evidence of previously normal values for haemoglobin, hematocrit, and
reticulocyte count
o Rare causes of spherocytosis
 Thermal injury, clostridial septicaemia with exotoxemia, and Wilson disease
- Treatment
o Splenectomy (Recommended after age 5-6)
 Curative!
 Indications
1. Severe anemia
2. Reticulocytosis
3. Hypoplastic or aplastic crises
4. Poor growth
5. Cardiomegaly
o Partial splenectomy also may be useful in children younger than age 5 and can provide
some increase in haemoglobin and reduction in the reticulocyte count, with potential
maintenance of splenic phagocytic and immune function
- Supportive care
1. Folic acid 1mg/day
2. Vaccination prior to splenectomy:
o Pneumococcus
o Meningococcus
o Haemophilus influenza type b.,
3. Prophylactic oral penicillin V
o Age < 5 yr, 125 mg twice daily
o Age 5 through adulthood, 250mg twice daily

C. Pyruvate Kinase deficiency

- No tests exist to diagnose this
- Pyruvate kinase: for ATP generation
- Homozygous for an autosomal recessive gene
- Marked reduction in RBC PK or production of an abnormal enzyme w/ decreased activity
o Decreased ATP  RBc’s cannot maintain potassium and water content  cells become
rigid  life span is considerably reduced
- Etiology
o Defect in the human PKLR gene located on chromosome 1q21
o 133 mutations are reported in this structural gene, which codes for a 574-amino acid
protein that forms a functional tetramer
- Clinical manifestations
o Severe neonatal haemolytic anemia
 Jaundice and enmia
 Kernicterus has been reported
o Mild, varies in severity, with haemoglobin values ranging from 8-12 g/dL
 Associated with some pallor, jaundice, splenomegaly
 Well-compensated hemolysis first noted in adulthood
o Severe form of the disease found among the Amish of the Midwestern United States
- Lab findings
o Polychromatophilia and mild macrocytosis elevated reticulocyte count
o Spherocytes are uncommon, but few speculated pyknocytes are found
o Normal non-incubated osmotic fragility
o Diagnosis relies on demonstration of a marked reduction of RBC PK activity or an
increase in the Michaelis-Menten dissociation constant (Km) for its substrate,
phosphoenolpyruvate
- Treatment
o Exchange transfusions may be indicated for hyperbilirubinemia in newborns
o Transfusions of packed RBCs are necessary for severe anemia or for aplastic crises
o Splenectomy for patients w/ recurrent and severe anemia 5-6 years of age (not
curative)

D. G6PD Deficiency
- High detection in Philippines due to inclusion in newborn screening: 1 in every 55 detected
- Most important disease in the hexose monophosphate pathway
o Remember, G6PD is needed to create NADPH, which is then used to reduce
glutathione which is an anti-oxidant (needed to remove oxidants from RBC for it to
survive)
- Responsible for 2 clinical syndromes:
o Episodic, haemolytic anemia induced by infections, certain drugs, or rarely, fava beans
(in Philippines, Dingdong nuts have fava beans!), and
o Spontaneous chronic nonspherocytic haemolytic anemia
- Affects more than 400 people worldwide
- “Balanced Polymorphism” – evolutionary advantage of resistance to falciparum malaria in
heterozygous females that outweighs the small effect of affected hemizygous males
- Etiology
o X-linked
o Inheritance of any of a large number of abnormal alleles of the gene responsible for
the synthesis of G6PD protein
o Milder disease is associated with mutations near the amino terminus of the G6PD
molecule, and chronic nonspherocytic haemolytic anemia is associated with mutations
clustered near the carboxyl terminus
- Inheritance of G6PD Deficiency
(X)Y – Deficient, symptomatic (X)(X) – Deficient, Sympomatic (X)x Carrier
- Episodic or induced haemolytic anemia
o Considerable variation in the defect is noted among various racial groups
o Example: The enzyme activity of RBcs containing the variant enzyme (G6PD B-) in
Americans of European descent is very low, often < 1% of normal.
A 3rd common mutant enzyme with markedly reduced activity (G6PD Canton) occurs in
approximately 5% of the Chinese population
o More than 100 distinct enzyme variants of G6PD are associated with a wide spectrum
of haemolytic disease
- Clinical manifestations
o Hemolysis develop 24-48 hours after a patient has ingested asubstance that has
oxidant properties of infection
o Favism
 Vicine and convicine hydrolyzed to divicine and isouramil producing hydrogen
peroxide and other reactive oxygen products
o The degree of hemolysis varies with the inciting agent, the amount ingested, and the
severity of the enzyme deficiency
- Laboratory findings
o Abrupt fall in haemoglobin and hematocrit
o Tea colored urine
o Unstained or supravital preparations of RBCs reveal Heinz
bodies (precipitated hemoglobin)
o Fragmented and polychromatophilic cells (5-15%)
- Diagnosis
o Direct measurement of enzyme activity
 Affected persons is < 10% of normal
o Screening tests
 Decoloration of methylene blue
 Reduction of methemoglobin
 Fluorescence of NADPH (the principle behind newborn screening for G6PD)
o G6PD variants also can be detected by electrophoretic analysis
o DNA analysis  can detect carriers
o In Philippines, only screening is done
- Treatment
o Prevention of hemolysis constitutes the most important therapeutic measure
o Supportive therapy may require blood transfusions
- Chronic nonspherocytic haemolytic anemia
o Type of G6PD that requires constant transfusion
o Caused by enzyme variants, particularly those defective in quantity, activity or stability
o Gene defects located primarily in the region of the NADP binding site near the carboxyl
terminus of the protein
o Impairment of the regeneration of GSH as an oxidant “sump”
o Manifest as pallor, jaundice, splenomegaly requiring regular transfusions
E. Thalassemia
- Epidemiology
o 3% of the world’s population carries genes for β-thalassemia
o 5-10% of the population carries genes for α-thalassemia in Southeast Asia
o In the US, an estimated 2000 individuals have β-thalassemia
- Pathophysiology
o An imbalance in α - and β -globin chain production
o In bone marrow, thalassemic mutations disrupt the maturation of red blood cells,
resulting in ineffective erythropoiesis
o In β -thalassemias, there is an excess of α -globin chains relative to β or γ -globin
chains
 α -globin tetramers (α 4) are formed, and these inclusions interact with the red
cell membrane and shorten red cell survival
 The γ -globin chains are produced in increased amounts, leading to an
elevated Hb F (α2γ2)
 The δ -globin chains are also produced in increased amounts, leading to an
elevated Hb A2(α2 δ 2) in β -thalassemia
o In α -thalassemia, there are relatively fewer α -globin chains and an excess of β and γ
-globin chains
 These excess chains form Bart’s haemoglobin (γ 4) in fetal life and Hb H (β 4)
after birth
 Prenatally, a fetus w/ α-thalassemia may become symptomatic because HbF
requires sufficient α-globin gene production, whereas postnatally infants with
β-thalassemia become symptomatic because Hb A requires adequate
production of β-globin genes
- Homozygous β -thalassemia (thalassemia Major, cooley anemia)
o Severe anemia requiring regular transfusions (6 mos of life)
o Classic findings: typical facies (maxillary hyperplasia, flat nasal bridge, frontal
bossing), pathologic bone fractures, marked hepatosplenomegaly and cachexia
o Spleen may become so enlarged that it causes mechanical discomfort and secondary
hypersplenism
o Hemosiderosis
o Laboratory findings
 Severe hypochromic anemia
 Numerous nucleated red cells
 Microcytosis
o Treatment
 Blood transfusion
• Promotes general health and well-being and avoids the consequences
of ineffective erythropoiesis
 Chelation
• Measurement of the iron level by liver biopsy is the standard method
for accurately determining the iron store
o But in practice, serum ferritin is usually measured instead
 Bone marrow transplantation has cured > 1,000 patients who have
thalassemia major
• Most success has been in children younger than 15 years of age
without excessive iron stores and hepatomegaly who have HLA-
matched siblings
• But in Philippines, splenectomy is done (especially if the child is of
older age) to reduce transfusion dependence; HOWEVER it does not
cure thalassemia
o This is done to prevent enlargement of spleen, since enlarged
spleens trap more RBCs
- α -thalassemia
o Deletion of 1 a-globin gene (silent trait)
  No alterations are noted in the mean corpuscular volume and mean
corpuscular hemoglobin
 Individuals with this deletion are usually diagnosed after the birth of a child
with a 2-gene deletion, or Hb H (β4)
 Newborn period: <3% Bart's hemoglobin is observed
 common in African-Americans.
o Deletion of 2 a-globin genes/a-thalassemia trait
 Present as a microcytic anemia
 hemoglobin analysis is normal, except during the newborn period, when Bart's
hemoglobin is commonly <8%, but >3%
 distinguished from IDA by history and trial tx of iron
o Deletion of 3 a-globin genes: called Hb H disease
 During the newborn period, the Bart’s haemoglobin level is commonly >25%
 At least 1 parent must have a-thalassemia trait
 Definitive diagnosis of Hb H disease requires DNA analysis
 Transfusion is not commonly used for therapy because the range of
hemoglobin is 7.0–11.0 g/dL, with a mean corpuscular volume of 51–73 fl.
o Deletion of all 4 a-globin genes
 Causes profound anemia during fetal life, resulting in hydrops fetalis
• There are no normal hemoglobins present at birth (primarily Bart’s
haemoglobin, with Gower-1, Gower-2 and Portland)
• If the fetus surivives, immediate exchange transfusion is indicated.
• Infants with α- thalassemia major are transfusion-dependent, and bone
marrow transplant is the only cure.
o Hb H Constant Spring
 Nondeletional a-globin mutation with a 2-gene deletion (-a/a, aCS)
 Results in more severe anemia than deletion type of α-globin thalassemia
 increased hepatosplenomegaly, increased jaundice, and a much more severe
clinical course

F. Iron Deficiency Anemia

- General facts
o Most common hematologic disease of infancy and childhood
o About 1 mg of iron must be absorbed each day to maintain positive iron balance in
childhood required for growth and to replace losses
o A diet containing 8-10 mg of iron daily is necessary for optimal nutrition since
absorption of dietary iron is assumed to be about 10%
o Site of absorption: proximal small intestine
o Iron is absorbed 2-3 times more efficiently from human milk than cow’s milk
o Adolescents are also susceptible to iron deficiency
 High requirements due to the growth spurt
 Dietary deficiencies
 Menstrual blood loss
- Etiology
o Insufficient iron stores during infancy due to prematurity or perinatal hemorrhage
o Inadequate dietary iron is the cause among term infants (unusual before 6 mo and
usually occurs at 9-24 mo of age)
o Prolonged consumtion of large amounts of cow’s milk (>24 oz/day) and of foods not
supplemented with iron
o Intense physical activity
- Other causes of iron-def anemia
o Chronic blood loss
 GIT (milk protein–induced inflammatory colitis, peptic ulcer, Meckel
diverticulum, polyp, or hemangioma, inflammatory bowel disease, hookworm
infestation, Helicobacter pylori)
 Pulmonary hemosiderosis
 o Chronic diarrhea
o Cow’s milk-induced colitis
 Due to a protein-losing enteropathy
 Presents with edema and anemia
- Clinical manifestations and laboratory findings
o Pallor
o Pagophagia
o Plumbism
o Weight problems
o Irritability
o Anorexia
o Neurologic and intellectual dysfunction
o Low serum ferritin
o Low serum iron level
o Increased iron-binding capacity of the serum (serum transferrin)
o Low percent saturation (transferrin saturation)
o Accumulation of free erythrocyte protoporphyrins (FEP)
- Laboratory findings
o Microcytic, hypochromic RBCs with poikilocytosis
o Normal or moderately elevated reticulocyte percentage
but absolute reticulocytepercentage but absolute
reticulocyte counts indicate an insufficient response to
anemia
o Thrombocytosis
o Red cell hyperplasia in the bone marrow
o No stainable iron in marrow reticulum cells
- Differential diagnosis
Ferritin Iron TIBC %sat FEP
IDA low Low high low high
Thal Normal or Inc Normal or Inc normal normal normal
ACD Normal or Inc low low normal
Lead high
poisoning

o TfR is high in IDA and normal in ACD

o FEP non-complexed, non-heme protophorphyrin
- Treatment
o Iron therapy: 4-6 mg/kg of elemental iron in 3 divided doses
o Proper education in nutrition
o Time after iron administration
 12-24 hrs: replacement of intracellular iron enymes, subjective improvement,
decreased irritability, increased appetitie
 36-48 hr: initial bone marrow response; erythroid hyperplasia
 48-72 hr: Reticulocytosis, peaking at 5-7 days
 4-30 days: increase in haemoglobin level 1-2 g/L
 1-3 mo: repletion of stores
o Blood transfusion if necessary
o IV iron therapy if oral form cannot be tolerated
o Correction of underlying condition

III. MEGALOBLASTIC ANEMIAS

- Rare
A. General Characteristics
- Vitamin B12 or Folic acid deficiencies result in defective
synthesis of DNA and, to a lesser extent, RNa and
protein
- Ineffective erythropoiesis
 o RBCs are larger than normal at every stage of development and have an open, finely
dispersed nuclear chromatin and an asynchrony between the maturation of nucleus
and cytoplasm, with the delay in nuclear progression becoming more evident with
further cell divisions Folic acid deficiency
- RBCs are large (increased mean corpuscular volume [MCV]) and often oval
- Giant metamyelocytes and bands also are present in the marrow
- Hypersegmented neutrophils also are characteristic, with many neutrophils having >5 lobes

B. Folic Acid Deficiency

- Heat labile and water soluble
- Folic acid is absorbed throughout the small intestine
o Folate conjugase activity in the intestinal brush border aids the conversion of
polyglutamates to the monoglutamate and thereby enhances absorption
- Not biologically active
o It is reduced by dihydrofolate reductase to tetrahydrofolate, which is transported into
tissue cells and polyglutamated.
- Megaloblastic anemia occurs after 2–3 mo on a folate-free diet
- Clinical manifestations
o Anemia
o Irritable
o Inadequate weight gain
o chronic diarrhea
o Hemorrhages from thrombocytopenia in advanced cases
o Peak incidence: 4 – 7 months of life
o Very-low-birthweight infants
o May accompany kwashiorkor, marasmus, or sprue
- Etiology
o Inadequate folate intake
 decreased folate intake usually becomes manifest under clinical conditions
that have increased vitamin requirements e.g., pregnancy, growth in infancy,
chronic hemolysis
 weight-based requirements are higher in children than adults because of
children's increased needs for growth
 Goat's milk is deficient in folic acid
 Folate supplementation of at least 400μg/day is recommended from the start
of pregnancy to prevent neural tube defects and to meet growth needs of the
developing fetus
o Decreased folate absorption
 Malabsorption due to chronic diarrheal states or diffuse inflammatory disease
such as celiac disease or chronic infectious enteritis, and in association with
enteroenteric fistulas
1. May be caused by impaired folate conjugase activity.
2. Interferes with the enterohepatic circulation of folate, thereby enhancing
folate losses because of rapid intestinal passage
 Previous intestinal surgery
 Anticonvulsant drugs (e.g., phenytoin, primidone, phenobarbital) can impair
absorption of folic acid
o Congenital abnormalities in folate metabolism
 a very rare disorder that is due to an inability to form biologically active
tetrahydrofolate
 severe megaloblastic anemia in early infancy
 treated successfully with large doses of folic acid or folinic acid
 Deficiency of methylene tetrahydrofolate reductase has been described in
some patients with homocystinuria without hematologic abnormalities.
o Drug-induced abnormalities in folate metabolism
 Methotrexate - binds to dihydrofolate reductase and prevents formation of
tetrahydrofolate, the active form
 Pyrimethamine -used in the therapy of toxoplasmosis
  Trimethoprim
 Therapy with folinic acid (5 formyltetrahydrofolate) usually is beneficial.
- Laboratory Findings
o anemia is macrocytic (mean corpuscular volume >100 fL)
o reticulocyte count is low, and nucleated RBCs demonstrating megaloblastic
morphology
o Neutropenia and thrombocytopenia may be present in patients with long-standing and
severe deficiencies
o neutrophils are large, some with hypersegmented nuclei
o Serum folic acid levels are <3 ng/mL(N: 5–20 ng/mL)
o Levels of iron and vitamin B12in serum usually are normal or elevated
o Serum activity of lactate dehydrogenase (LDH), a marker of ineffective erythropoiesis,
is markedly elevated
o Bone marrow findings:
 hypercellular because of erythroid hyperplasia, and megaloblastic changes
 large, abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic
vacuolation
- Treatment
o When the diagnosis of folate deficiency is established, folic acid may be administered
orally or parenterally at 0.5–1.0 mg/day.
o If the specific diagnosis is in doubt, smaller doses of folate (0.1 mg/day) may be used
for 1 week as a diagnostic test, because a hematologic response can be expected
within 72 hr.
o Vitamin B12deficiency but may aggravate any associated neurologic abnormalities
o Transfusions are indicated only when the anemia is severe or the child is very ill.
o Folic acid therapy (0.5–1.0 mg/day) should be continued for 3–4 wk until a definite
hematologic response has occurred.
o Maintenance therapy with a multivitamin (containing 0.2 mg of folate) is adequate.

C. Vitamin B12 Deficiency

- Vitamin B12is derived from cobalamin in food (mainly animal sources) secondary to production
by microorganisms
- absorbed in the distal ileum via specific receptors for IF-cobalamin
- In the plasma, cobalamin binds to a transport protein, transcobalamin II (TC-II), which carries
the vitamin B12 to the liver, bone marrow, and other tissue storage sites.
- TC-II enters cells by receptor-mediated endocytosis, and cobalamin is converted to active
forms (methylcobalamin and adenosylcobalamin) important in the transfer of methyl groups
and DNA synthesis.
- TC I and TC III – no role in transport but reflects body stores
- In contrast to folate stores, older children and adults have sufficient vitamin B12 stores to last
3–5 yr.
- In young infants born to mothers with low vitamin B12 stores, clinical signs of cobalamin
deficiency can become apparent in the first 6–18 months of life.
- Etiology
o Inadequate Vitamin B12 Intake.
 may occur in cases of extreme dietary restriction (e.g., strict vegetarians or
vegans) in which no animal products are consumed.
 not common in kwashiorkor or infantile marasmus
 occurs in breast-fed infants whose mothers are vegans or themselves have
pernicious anemia.
 Maternal pernicious anemia may be manifest by reduced serum vitamin
B12with or without macrocytic anemia in the mother. This cause of childhood
megaloblastic anemia can appear in the first year of life.
o Lack of Intrinsic Factor - Congenital pernicious anemia
 rare autosomal recessive disorder due to an inability to secrete gastric IF or
secretion of functionally abnormal IF
 symptoms at around 1 yr of age
  weakness, irritability, anorexia, listlessness, tongue is smooth, red, and painful,
neurologic manifestations include ataxia, paresthesias, hyporeflexia, Babinski
responses, and clonus
o Lack of Intrinsic Factor - Juvenile pernicious anemia
 atrophy of the gastric mucosa, achlorhydria, and antibodies in serum against IF
and parietal cells
 additional immunologic abnormalities, cutaneous candidiasis,
hypoparathyroidism, and other endocrine deficiencies
 Parenteral vitamin B12should be administered regularly to these patients
 Gastric surgery can lead to intrinsic factor deficiency, and susceptible
individuals need lifelong parenteral vitamin B12supplementation.
o Impaired Vitamin B12 Absorption
 regional enteritis or neonatal necrotizing enterocolitis
 surgical removal of the terminal ileum
 overgrowth of intestinal bacteria within diverticula or duplications of the small
intestine by consumption of (or competition for) the vitamin or by splitting of
its complex with IF.
 fish tapeworm Diphyllobothrium latum infestation of the upper small intestine
 Lifelong parenteral administration should be used if there is evidence that
vitamin B12 is not absorbed.
o Impaired Vitamin B12 absorption - Imerslund-Grasbeck syndrome
 defects of the receptor for IF-B12in the terminal ileum
 autosomal recessive disorder is caused by defects in the CUBN gene on
chromosome 10p12.1, resulting in decreased expression of the IF-B12 receptor
cubilin
 parenteral treatment with vitamin B12 monthly corrects the deficiency
o Absence of Vitamin B12 Transport Protein
 rare congenital deficiency inherited as an autosomal recessive condition, with
failure to absorb and transport vitamin B12
 patients lack TC-II, but some have functionally defective forms
 serum vitamin B12 levels are normal because the storage forms of cobalamin,
TC-I and TC-III, are not affected
 usually manifests in the first weeks of life as failure to thrive, diarrhea,
vomiting, glossitis, neurologic abnormalities, and megaloblastic anemia
 diagnosis of this disorder is suggested by the presence of severe megaloblastic
anemia with normal serum vitamin B12 and folate levels and no evidence of
any other inborn errors of metabolism
 Tx: large parenteral doses of vitamin B12given twice a week for life
 Most children with this disorder die if treatment is not provided in infancy.
- Laboratory Tests
o Schilling test
 To confirm that absence of IF is the basis of the vitamin B12 malabsorption, IF
is given with a second dose of radioactive vitamin B12. Normal amounts of
radioactive vitamin should now be absorbed and flushed out in the urine.
 If vitamin B12 malabsorption results from absence of ileal receptor sites or
other intestinal causes, no improvement in absorption occurs with IF.
 The Schilling test result remains abnormal in patients with pernicious anemia,
even when therapy has completely reversed the hematologic and neurologic
manifestations of the disease.
- Treatment
o Parenteral administration of vit B12 (1 mg)
 reticulocytosis in 2–4 days, unless there is concurrent inflammatory disease
 physiologic requirement 1–5μg/day
 if with evidence of neurologic involvement, 1 mg should be injected
intramuscularly daily for at least 2 wk
 maintenance therapy is necessary throughout a patient's life: monthly IM of 1
mg of vit B12