Although the clinical effects of vitamin B12 and folic acid deficiencies can differ in
various organ systems, they are similar in their effects on the hematopoietic system.
Typically, macrocytic anemia develops slowly and can be identified by large, oval,
well-hemoglobinized RBCs; anisocytosis; and nuclear remnants. The reticulocyte
count is low and the bilirubin level is elevated. If biopsied, the bone marrow is
markedly hypercellular. Nuclear immaturity is present, but the megaloblasts have
normal maturation of the cytoplasm. Iron stores in the marrow are increased as a
result of the intramedullary hemolysis. Symptoms include fatigue; exaggeration of
preexisting cardiovascular or pulmonary problems; a sore, pale, smooth tongue;
diarrhea or constipation; and anorexia.
Deficiency and poor utilization of vitamin B12 are two mechanisms for the
development of megaloblastic anemia.
synthesized by microorganisms, but humans are incapable of doing so and must
in their diet. Animal protein and fortified foods provide the
majority of dietary vitamin B12
23 The typical Western diet contains 3.5 to 5 mcg/day
, an amount sufficient to replace the up to 1 mcg lost daily through
urine, sweat, and other body secretions.
is released from protein complexes and bound to
intrinsic factor, which protects it from degradation by GI microorganisms. Intrinsic
factor is essential for the absorption of vitamin B12
. Specific mucosal receptors in the
distal small ileum allow for attachment of the intrinsic factor–vitamin B12 complex.
is then transferred to the ileal cell and finally to portal vein blood.
is absorbed, it is bound to specific β-globulin transport proteins,
transcobalamins I, II, and III. Transcobalamin II is responsible for transporting
through cell membranes and delivering it to the liver and other
organs. In the liver, vitamin B12
hematopoiesis, maintenance of myelin throughout the entire nervous system and
production of epithelial cells.
Total body stores of vitamin B12
range from 2,000 to 3,000 mcg, approximately
50% of which is stored in the liver. Because body stores are extensive, 5 to 10 years
are required before symptoms of vitamin B12 deficiency develop.
PATHOGENESIS AND EVALUATION OF VITAMIN B12 DEFICIENCY
Vitamin B12 deficiency can result from decreased supply (reduced intake, absorption,
transport, or utilization) or increased requirement (greater metabolic consumption,
destruction, and excretion). Other causes of vitamin B12 deficiency include
inadequate proteolytic degradation of vitamin B12
intrinsic factor deficiency. In addition, the gastric mucosa may be unable to produce
intrinsic factor under conditions such as partial gastrectomy, autoimmune destruction
(e.g., Addisonian or juvenile pernicious anemia), or destruction of the gastric mucosa
Pernicious anemia can result in vitamin B12 deficiency.
chronic atrophic gastritis accompanied by reduced intrinsic factor and hydrochloric
acid secretion or acquired as a result of gastrectomy, pancreatic disease, or
malnutrition. Pernicious anemia occurs commonly in patients with thyrotoxicosis,
autoimmune thyroiditis, vitiligo, rheumatoid arthritis, or gastric cancer. Intrinsic
factor and parietal cell autoantibodies may be observed in the serum of patients with
The onset of the pernicious anemia is insidious. Patients generally do not feel well
for months and often complain of at least two of the following symptoms: weakness,
sore tongue, and symmetric numbness or tingling in the extremities. The neurologic
symptoms of vitamin B12 deficiency are associated with a defect in myelin synthesis
and often are described as peripheral neuropathy or nonspecific complaints (e.g.,
tinnitus, neuritis, vertigo, headaches).
In general, the serum vitamin B12
level reliably reflects vitamin B12
Falsely low vitamin B12 concentrations may be observed in patients with folic acid
deficiency, transcobalamin I deficiency, multiple myeloma, or pregnancy.
normal levels may be observed in patients with myeloproliferative, liver, or renal
disease. Measuring serum methylmalonic acid and homocysteine levels may also
differentiate between folate and vitamin B12 deficiency. Once vitamin B12
been instituted, serum levels of these chemicals decrease if true vitamin B12
The cause of vitamin B12 deficiency may be determined by the use of antibody
testing (antiparietal cells and anti-intrinsic factor antibodies).
pernicious anemia are not able to absorb vitamin B12 because intrinsic factor is not
available for binding. Some patients produce intrinsic factor but are still unable to
. Malabsorption, which occurs more commonly in the
elderly, can be caused by intestinal bacteria that usurp vitamin B12
chronic acid suppression therapy, pancreatic insufficiency, alcohol abuse, inadequate
from proteins, or lack of intrinsic factor receptors
secondary to ileal loops, bypass, or surgical resection.
Signs, Symptoms, and Laboratory Findings
Significant laboratory findings include the following:
Poikilocytosis and anisocytosis on the blood smear
White blood cell (WBC) count, 4,000/μL
Intrinsic factor antibody positive
What signs, symptoms, and laboratory findings in C.L. are typical of pernicious anemia?
C.L.’s signs and symptoms are classic for pernicious anemia. This disease occurs
equally in both sexes (primarily in individuals of northern European descent), with
28 Pernicious anemia develops from a lack of gastric
intrinsic factor production which causes vitamin B12 malabsorption and, ultimately,
vitamin B12 deficiency. C.L.’s signs and symptoms of vitamin B12 deficiency include
painful red tongue, loss of lower extremity vibratory sense, vertigo, and emotional
instability. The elevated MCV suggests megaloblastic anemia.
Folate and iron are two other factors that can affect the MCV and should be
evaluated during the workup of a patient for anemia. In this case, C.L.’s folate and
iron levels are normal, but his serum vitamin B12
poikilocytosis and anisocytosis observed in the blood smear represents ineffective
erythropoiesis. Other cell lineages also may be affected in the bone marrow.
Erythroid hypercellularity, along with a decrease in the myeloid cells (leukocytes
and platelets), increases the erythroid to myeloid ratio in C.L. The patient’s low Hgb,
elevated MCV, low serum vitamin B12
levels, and presence of intrinsic factor
antibodies are compatible with the diagnosis of pernicious anemia, which is often
associated with atrophic body gastritis. The Schilling test, which confirms intestinal
, is no longer available in the United States.
CASE 92-2, QUESTION 2: How should C.L.’s pernicious anemia be treated? How soon can a response be
C.L. should receive parenteral vitamin B12
in a dose sufficient to provide the daily
requirement of approximately 2 mcg and the amount needed to replenish tissue stores
(about 2,000–5,000 mcg; average, 4,000 mcg). To replete vitamin B12 stores,
cyanocobalamin can be given IM in accordance with various regimens as shown in
Intramuscular or deep subcutaneous administration provides SR of
vitamin B12 with better utilization compared with rapid IV infusion. An oral tablet or
intranasal cyanocobalamin solution is also available for maintenance therapy, after
the patient has normalized blood counts.
Treatment with vitamin B12 should completely reverse the hematologic
complications of pernicious anemia.
22,23 The reticulocyte count increases within the
first week of treatment and the megaloblastic anemia resolves within 6 to 8 weeks.
Neurologic symptoms may worsen at first and then resolve over weeks to months.
Some symptoms may never resolve completely. Because the rapid production of
RBCs can increase potassium demand, serum potassium should be monitored and
potassium supplementation provided as necessary. Peripheral blood counts should be
obtained every 3 to 6 months to evaluate the adequacy of therapy. If maintenance
therapy is discontinued, pernicious anemia will recur within years, making patient
adherence vital to long-term success.
CASE 92-2, QUESTION 3: What factors affect the oral absorption of vitamin B12
therapy an effective alternative to parenteral therapy for C.L.?
that can be absorbed orally from a single dose or meal
ranges from 1 to 5 mcg; approximately 5 mcg of vitamin B12
23 The percentage of vitamin B12 absorbed decreases with
increasing doses: 50% of a 1 mcg dose and 5% of a 20 mcg dose. Overall, oral
therapy is considered safe and effective,
30 although because of lack of
long-term efficacy data, oral supplementation is not routinely used in the acute
treatment of vitamin B12 deficiency.
27 Oral therapy for pernicious anemia using high
dosages of oral cyanocobalamin may be indicated in certain patients, especially
those who refuse or cannot receive parenteral therapy.
lack of response with oral therapy places the patient at substantial risk for significant
neurologic damage. Patients receiving oral vitamin B12
more frequently to ensure adherence to therapy.
Partial or total gastrectomy often results in anemia, particularly pernicious anemia,
because the loss of intrinsic factor impairs oral vitamin B12 absorption. The
hematologic and neurologic abnormalities associated with vitamin B12 deficiency do
not develop until existing vitamin B12 stores are depleted (about 2–3 years).
Nevertheless, prophylactic vitamin B12 should be administered in this patient after
32 Because the vitamin B12 stores are not currently depleted,
maintenance therapy, as discussed in Case 92-2, Question 2, should be adequate for
) Supplementation Regimens for Macrocytic
Initial Supplementation Chronic Supplementation (lifelong)
Dose Frequency Route Dose Frequency Route
Adults 100 mcg Daily for 7 days,
100–1,000 mcg Daily or every other
Daily for 1–2 weeks Oral 1,000 mcg
IM, intramuscular; SC, subcutaneous.
QUESTION 1: P.G. is a 48-year-old female scheduled to have laparoscopic Roux-en-Y gastric bypass
(RYGB) surgery for morbid obesity with a body mass index (BMI) >40.
What forms of anemia would be expected to develop in P.G.?
When a RYGB procedure is performed, the stomach is decreased in size, and the
small intestine is manipulated creating a gastrojejunostomy and jejunojejunostomy.
This results in bypassing the duodenum and proximal jejunum where iron is
absorbed, resulting in iron deficiency anemia. The gastric pouch is no longer an
acidic environment which impairs iron bioavailability and functioning of iron
transport mechanisms. Patients are also recommended to avoid red meat which is a
common dietary source of iron. An acidic environment is also needed for the
bioavailability of vitamin B12
leading to decreased absorption. The diagnosis of
vitamin B12 deficiency following bariatric surgery is rare due to the large amount
stored in the body. Folate deficiency may occur from reduced dietary folate intake.
The majority of folate is absorbed from the upper third of the small intestine, but may
occur at any location. Iron deficiency anemia is the most common cause for anemia in
bariatric surgery patients; however, other micronutrient deficiencies may also
CASE 92-4, QUESTION 2: What prophylactic strategies might P.G. employ to prevent anemia?
Following bariatric surgery, patients will need to take lifelong multivitamin and
micronutrient supplementation.
34 Patients should take a high potency multivitamin
with 100% of the recommended daily value for at least 75% of the nutrients. It should
have a minimum of 18 mg iron, 400 mcg folic acid, selenium, and zinc.
should be instructed to take an additional 1 to 2 tablets per day of an iron salt, ferrous
sulfate, or ferrous fumarate to prevent iron deficiency anemia. In addition to a high
potency multivitamin, patients should take 350 to 500 mcg/day of oral
cyanocobalamin or receive 1,000 mcg injections monthly.
Folate is abundant in virtually all food sources, especially fresh green vegetables,
fruits, yeast, and animal protein. As a result of food fortification, the average
American diet provides 50 to 2,000 mcg of folate per day; however, excessive or
prolonged cooking (>15 minutes) in large quantities of water may reduce the folate
36 Human requirements for folate vary with age and depend on the
rate of metabolism and cell turnover but are generally 3 mcg/kg/day.
daily adult requirement of folate is 50 mcg but, because absorption from food is
incomplete, a daily intake of 200 mcg is recommended. Folate requirements are
increased in conditions in which the metabolic rate and rate of cellular division are
increased (e.g., pregnancy, infancy, infection, malignancies, hemolytic anemia). The
following are estimates of daily folate requirements based on age and growth
demands: children, 80 to 400 mcg; infants, 65 mcg; pregnant or lactating women, 600
Dietary folic acid is in the polyglutamate form and must be enzymatically
deconjugated in the GI tract to the monoglutamate form before it is absorbed. Once
absorbed, the inactive dihydrofolate must be converted to active tetrahydrofolate
(folinic acid) by dihydrofolate reductase.
In contrast to the large stores of vitamin B12
, the body’s folate stores are relatively
small (about 5–10 mg). Therefore, deficiency and subsequent megaloblastic anemia
can occur within 3 to 4 months of decreased folate intake.
Folate deficiency is most commonly associated with alcoholism, rapid cell turnover,
and dietary deficiency. In alcoholics, the daily intake of the folate contained in food
may be restricted or absent. In addition, enterohepatic recirculation of folate can
become impaired by the toxic effect of alcohol on hepatocytes. Folate deficiency may
also develop during the third trimester of pregnancy as a result of a marginal diet and
rapid fetal metabolism. Folate coenzymes are required for most metabolic pathways
(Fig. 92-2). Therefore, folate deficiency will develop in any condition of rapid
cellular turnover (e.g., hemolytic anemias, hemoglobinopathies, sideroblastic
anemia, leukemias, lymphomas, multiple myeloma) or a diet lacking in folate (e.g.,
food faddism or a weight-loss diet). Folate deficiency also can occur with chronic
hemodialysis, diseases that impair absorption from the small intestine (e.g., sprue,
regional enteritis), extensive jejunal resections, and drugs that alter folate
metabolism (e.g., trimethoprim, pyrimethamine, methotrexate, sulfasalazine, oral
contraceptives, anticonvulsants).
38,39 Few patients have inborn errors of folate
The evaluation of megaloblastic anemia must be thorough because indiscriminate
use of nondirected therapy can be dangerous. Large doses of folate can partially
reverse hematologic abnormalities caused by vitamin B12 deficiency; however, folate
cannot correct neurologic damage caused by vitamin B12 deficiency. Therefore,
folate deficiency must be differentiated from vitamin B12 deficiency before folate
therapy is initiated. Otherwise, progression of the neurologic sequelae of vitamin B12
QUESTION 1: D.H. is a malnourished-appearing woman in her second trimester of pregnancy who presents
Pertinent laboratory values include the following:
, 350 pg/mL (normal, 200–1,000)
WBC count, 2,000/μL with hypersegmented polymorphonuclear neutrophils (PMN)
As with most patients who are folate deficient, D.H. has more than one risk factor.
Cocaine and alcohol, together with multiparity complicated by anorexia, nausea, and
vomiting, could lead to poor nutrition. Alcohol has toxic effects on the intestinal
mucosa and interferes with folate utilization by the bone marrow. D.H. should be
asked specifically about her dietary habits and recent weight history. She may have a
folate-poor diet for financial reasons or because she is overcooking her food.
Alternatively, cocaine may be causing anorexia. The nutritional intake of people who
abuse alcohol and drugs is often poor. The diagnosis of folate deficiency is
plausible, considering folate deficiency can develop in a matter of weeks to months.
Figure 92-2 Intracellular metabolic pathways. Vitamin B12
and folic acid are both necessary for nucleic acid
D.H. be treated and monitored?
D.H.’s laboratory values reflect macrocytic anemia (Hct, 25.5%; MCV, 112 fL)
with pancytopenia (reduced number of RBCs, WBCs, and platelets). Serum vitamin
B12 concentrations reflect normal vitamin B12 stores, but folate stores are inadequate
as exemplified by the low RBC folate concentration, pancytopenia, and macrocytic
Serum folate concentrations generally reflect folate balance during the past 3
weeks although one balanced meal can raise serum levels and falsely elevate body
stores. Tissue folate stores are more accurately reflected by the RBC polyglutamated
folate content, which is approximately 10 to 30 times the corresponding serum folate
41 Hemolysis or vitamin B12 deficiency causes leakage of
monoglutamated folates from cells, thereby falsely elevating serum folate levels.
D.H. should be counseled regarding her nutritional and social habits. Because the
estimated total body folate store is only about 5 to 10 mg, 1 mg of folic acid given
daily for 2 to 3 weeks should be more than adequate to replace her storage pool of
folate. Higher dosages (up to 5 mg) may be needed, however, if absorption is
compromised by alcohol or other factors.
38 Once stores are replenished, D.H. should
continue folate supplements throughout her pregnancy and lactation period. She
should be reassessed after the course of therapy to determine response to therapy and
whether the cause of the folate deficiency has been corrected. Supplementation with
folic acid 1 mg/day may be required as long as risk factors are present. D.H.’s fetus
is unlikely to develop folate deficiency because maternal folate is preferentially
delivered to the fetus; however, sustained folate deficiency during pregnancy can
cause birth defects in the newborns (see Chapter 49, Obstetric Drug Therapy).
D.H.’s response to therapy can be monitored by several different parameters.
Although bone marrow aspirates are not obtained routinely, the RBC morphology
should begin to revert back to normal within 24 to 48 hours after therapy is initiated,
and hypersegmented neutrophils should disappear in the periphery in about 1 week.
Serum chemistry and hemogram studies should begin to normalize within 10 days.
The reticulocyte count should increase by day 2 to 3 and peak by day 10. Bilirubin
and LDH values should normalize in 1 to 3 weeks. Finally, the anemia should be
corrected in 1 to 2 months. Once anemia is corrected, 100 mcg
daily of folate as a nutritional supplement should be adequate for maintenance
treatment (independent of the patient’s pregnancy/lactation status).
Sickle cell anemia is an inherited, autosomal recessive Hgb disorder characterized
by a DNA substitution at the β-globin gene.
43 Hgb is a quaternary structure composed
of two α-globin chains and two β-globin chains (α2β2) in adults. During fetal
development, the γ-globin is the primary β-globin expressed, forming fetal Hgb (HbF
or α2γ2). Normally, the period from birth to approximately 3 to 6 months of age is
marked by the replacement of γ-globin with β-globin, giving rise to the adult form of
Sickle cell anemia results from a DNA substitution of thymidine for adenine in the
glutamic acid codon, forming a B6 valine instead of glutamic acid.
the inheritance of the sickle β-globin gene.
46 The Hgb produced from this substitution
has a more negative charge than normal HbA and in the deoxygenated state will
aggregate and polymerize, forming sickled RBCs.
44,45 Sickled RBCs are more rigid
and may become “lodged” when passing through the microvasculature, resulting in
In addition, the sickled RBC surface contains rearranged aminophospholipids,
which augment the ability of the RBC to initiate coagulation, adhere to vascular
endothelium, and activate complement. Abnormal interactions with other cell types
cause hemolysis and vaso-occlusion, producing several complications such as
anemia, pain, increased infections, and multi-organ damage.
much effort has been focused on neonatal diagnosis to reduce morbidity and mortality
in children younger than 3 years of age.
More than one inheritance pattern results in abnormal Hgb polymerization. Patients
with sickle cell anemia are homozygous, inheriting a sickle gene from each parent
(α2βS2), whereas patients with sickle cell trait are heterozygous and have inherited
the sickle cell gene from one parent and the HbA gene from the other parent
(α2βAβS). Other inheritance patterns include patients with a sickle cell gene and a
hemoglobin C (HbC) gene (in which glutamic acid is substituted for lysine B6
[α2βSβC]). Patients may also inherit the sickle cell gene and the β-thalassemic gene
(α2βSβSthal), in which case the clinical course is less severe than with patients
diagnosed with sickle cell anemia.
48 Hematologic abnormalities are more commonly
observed in patients with sickle cell anemia and less often in those with sickle cell
In patients with sickle cell disease, the WBC and platelet counts often are elevated,
but the WBC differential is normal.
44 The reticulocyte count can range from 5% to
15%, and the MCV may be elevated. If MCV values are within the normal range, iron
-thalassemia must be considered. Sickled cells may be visually
observed in poorly oxygenated blood of a patient with sickle cell anemia. In contrast,
a patient with the sickle cell trait should have normal RBC morphology and WBC,
reticulocyte, and platelet counts. Sickled cells are rarely observed. In patients with
-thalassemia, hematologic abnormalities vary depending on the amount
of HbA present. This form may be difficult to distinguish from sickle cell anemia;
RBC microcytosis may be the only differentiating parameter.
Clinical Course and Management
Part of efforts to improve outcomes in this population include routine screening for
sickle cell anemia or sickle cell trait in newborns in the United States. Therefore,
most patients are diagnosed during their first year of life. Families carrying sickle
cell trait or disease are referred for genetic counseling. Patients with sickle cell
disease are referred to a hematologist and multidisciplinary team for medical
Patients carrying the sickle cell trait experience milder symptoms than those with
sickle cell anemia. The kidney is commonly affected by microinfarction, which
occurs in the renal medulla and impairs the kidney’s ability to concentrate urine.
During pregnancy, an increased frequency of urinary tract infections and hematuria is
seen. However, vaso-occlusive events are uncommon and are usually caused by
Treatment of sickle cell anemia is largely directed toward prophylaxis against
infections and supportive management of vaso-occlusive crises. The clinical course
among patients with sickle cell disease is variable and difficult to predict. Some
patients experience a multitude of health problems. Organs such as the kidneys,
retina, spleen, and bones are frequent sites of vaso-occlusive events because these
sites have a relatively low pH and oxygen tension. Cardiac, pulmonary, neurologic,
hepatobiliary, obstetric/gynecologic, ocular, dermatologic, or orthopedic
complications can also occur. The management of these complications is organ
specific and primarily aimed at supportive interventions.
Sickle cell HbC disease is usually associated with few clinical complications.
These patients may have normal physical examination findings with only
splenomegaly. Patients are at risk for bacterial infections and, because of elevated
Hgb levels, they may experience ocular, orthopedic, and pulmonary vaso-occlusive
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