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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2866_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 18. Anemia
367
Megaloblastic Anemia
This is a macrocytic anemia that results from impaired DNA
synthesis. The most common causes include the nutritional
deficiencies of folic acid (B9) or cobalamin (B12) [9].
Additionally, there are many medications that can cause
megaloblastic anemia through impaired absorption of either
B12 or folic acid.
Vitamin B12 Deficiency
Epidemiology
There many causes for vitamin B12 deficiency. Since we cannot synthesize it on our own, it is important that we obtain it
in our diet. This essential nutrient is found in animal products
such as meats, seafood, dairy products, and eggs. Many foods
such as cereals are also fortified with vitamin B12. It has
therefore become very uncommon for people to develop
vitamin B12 deficiency due to lack of dietary intake, especially in developed countries. The people at most risk include
those who adhere to a strict vegan or vegetarian diet. The
average person is able to store 2–3mg of B12, and this is generally considered enough to maintain an individual for
3–4years [9].
While developing vitamin B12 deficiency solely due to
lack of dietary intake is rare, it is more common to develop
the deficiency due to a malabsorptive process. Malabsorption
can occur anywhere between the stomach and the terminal
ileum, the location where it is ultimately absorbed before
storing it in the liver. Common causes of malabsorption due
to pathology in the stomach include pernicious anemia, atrophic gastritis, chronic H2 blockers or proton pump inhibitor
use, and Helicobacter pylori infection. In the duodenum,
pathologic causes for malabsorbtion include small intenstinal bacterial overgrowth and pancreatic insufficency. In the
terminal ileum, malabsorption may be caused by ileal resection, ileitis such as in Chron’s disease, chronic metformin use,
and fish tapeworm infection from Diphyllobothrium latum.
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B. Cohen
Pathophysiology
As mentioned above, vitamin B12 deficiency may arise due to
many causes but is mainly due to either poor nutritional intake,
or more commonly due to a malabsorptive process. After we eat
food and it passes through the stomach into the small intestine,
B12 is bound by intrinsic factor, a protein that actively helps with
absorption of B12in the ileum. Alterations to gastric acid secretion from medications such as proton pump inhibitors and H2
blockers prevent B12 bound in food from being bound by intrinsic factor. In the terminal ileum, inflammation from Crohn’s
disease or infection from D. latum leads to poor absorption
locally in the terminal ileum and can also lead to deficiency.
History andPhysical Exam
Vitamin B12 deficiency may manifest with anemia, pancytopenia, jaundice, or neuropsychiatric symptoms, and therefore,
a complete history and physical exam are essential when diagnosing and determining the severity of illness associated with
B12 deficiency. Vitamin B12 plays a role in myelin basic protein, which is important to maintain the myelin that insulates
peripheral nerves, and thus, deficiency can lead to neuropathy.
The classic neurologic symptoms associated with vitamin B12
deficiency are known as subacute combined degeneration and
occur due to demyelination of the dorsal and lateral column
of the spinal cord. As the disease progresses, patients may
experience weakness, ataxia, spasticity, and ultimately paraplegia. Other symptoms include depressed mood, irritability,
dementia, cognitive slowing, visual disturbances from optic
atrophy, abnormal deep tendon reflexes, and glossitis. The
neuropsychiatric manifestations of vitamin B12 deficiency
may occur without the presence of anemia, and the absence of
anemia should not rule out this nutritional deficiency as a
cause for any of the above neuropsychiatric symptoms [9].
Laboratory Evaluation
• CBC
• Peripheral smear—presence of macrocytes and hyperseg-
mented neutrophils
Chapter 18. Anemia
369
• Intrinsic factor antibodies, parietal cell antibodies
• B12 and folic acid level
• Methylmalonic acid and homocysteine level
• Schilling test—no longer routinely done [3]
Diagnosis
In most cases, B12 levels should be checked when the CBC
reveals a macrocytic anemia. For the majority of patients, we
do not check folic acid levels, as a deficiency is very uncommon in patients with a routine diet in resource-rich areas and
is only of benefit in patients with poor oral intake or frequent
alcohol use [3]. The diagnosis of vitamin B12 deficiency can
sometimes be obscure. The normal value of vitamin B12 is
greater than 300 pg/mL, and when the level is higher than
this, it is considered to be 90% sensitive to rule out B12 deficiency. When patients have values less than 200pg/mL, that is
sufficient to diagnose a B12 deficiency. The evaluation can
become obscure when values range between 200 and 300pg/
mL. When this occurs, it is appropriate to assess for serum
methylmalonic acid (MMA) and serum homocysteine levels,
proteins that are intermediaries in the metabolism of vitamin
B12. In scenarios where both MMA and homocysteine levels
are normal, vitamin B12 deficiency is ruled out. Elevation in
both the MMA and homocysteine levels confirms a diagnosis
of vitamin B12 deficiency [10] (this would not rule out a
simultaneous folic acid deficiency). If MMA is normal and
homocysteine levels are elevated, this is more consistent with
a folic acid deficiency.
When choosing a treatment option for B12 deficiency, it is
important to identify the cause and severity of the deficiency
and the anemia. The scenarios where correction is urgent
include the patients with symptomatic anemia or Hb<8g/dL,
neuropsychiatric or neurologic symptoms, or in the presence
of a malabsorptive process such as pernicious anemia. In these
scenarios it is recommended to initiate treatment promptly
with intramuscular cyanocobalamin. Treatment should consist
of intramuscular injections 1–2 times per week for 2weeks,
followed by weekly injections until clinical improvement is
seen, after which repeat CBC and reevaluation of symptoms
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B. Cohen
should be completed. If results show resolution of macrocytosis, anemia, and/or improvement in the neuropsychiatric or
neurologic symptoms, the patient should continue with oral
cyanocobalamin 1000 μg daily or monthly intramuscular
injections indefinitely. In less severe cases, patients can be
started on oral cyanocobalamin 1000μg daily [10].
Folic Acid Deficiency
Folic acid deficiency is less common than vitamin B12 deficiency. Folic acid is an essential part of DNA synthesis, and so
deficiency leads to megaloblastic anemia. It presents similarly
to vitamin B12 deficiency, although the neuropsychiatric
symptoms are less common, and it does not cause subacute
combined degeneration. The most common cause for folate
deficiency is due to medication side effects or alcohol use
disorder. In resource-rich countries, many grains are enriched
with folic acid, and therefore, it is very difficult to develop a
deficiency due to poor intake [2]. In contrast with B12 deficiency, folic acid deficiency can develop quickly after about
3–4months if a person is cut off from all sources of folate.
Deficiency may also arise in the presence of rapid turnover of
erythrocytes, such as in hemolytic anemia. Common medications that cause folic acid deficiency include methotrexate,
trimethoprim, and phenytoin. Patients taking these medications should also be taking folic acid supplementation [10].
Diagnosis is made on lab testing demonstrating low folic
acid levels. Peripheral smear will show similar findings to
vitamin B12 deficiency, with macrocytosis and hypersegmented neutrophils. When the diagnosis is uncertain, MMA
and homocysteine levels may be evaluated, and lab testing
will show normal MMA and elevated homocysteine levels.
Treatment of folic acid deficiency, regardless of cause, is with
supplementation of 1mg of folic acid daily. Patients with alcohol use disorder should be counseled on strategies to decrease
or cease their alcohol consumption [10]. In cases of severe
deficiency due to medication side effect, the patient should
have a discussion with their provider about whether or not to
continue the medication or to pursue alternative therapies.
Chapter 18. Anemia
371
Hyperproliferative Anemia
This group of anemias is typically more complicated to treat.
The causes include sickle cell diseases, hemolytic anemias,
and rapid blood loss. In cases other than rapid blood loss,
patients should be evaluated by a hematologist.
Hemolytic Anemia
In healthy individuals, an erythrocyte lives for about 90days,
during which about 1% of erythrocytes are destroyed per day.
Hemolytic anemia is the process where there is premature
destruction of erythrocytes. When erythrocytes are destroyed,
the body responds with a reticulocytosis, increasing production of immature RBCs to help replace those that were
destroyed. As the erythrocytes are destroyed, lactate dehydrogenase (LDH) is released. In addition, haptoglobin, a
protein that binds free hemoglobin, decreases, as it is consumed. The remaining free hemoglobin is also metabolized
into unconjugated bilirubin. Thus, the hallmarks of hemolytic
anemia are elevated serum LDH and unconjugated bilirubin
and decreased or undetectable serum haptoglobin.
Hemolytic anemias are classified as being either intrinsic
or extrinsic [11].
Intrinsic Hemolytic Anemia
These are the hemolytic anemias that are caused by some
acquired, inherited, or congenital hemoglobinopathy, RBC
membrane defect, or enzyme deficiency [11]. Causes of
intrinsic hemolytic anemia include the following:
• Hemoglobinopathy
– Sickle cell anemia
– Thalassemia
• RBC membrane defect
– Hereditary spherocytosis
– Hereditary elliptocytosis
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B. Cohen
• Enzyme deficiency
– G6PD—glucose-6-phosphate deficiency
Sickle Cell Anemia
Epidemiology
Sickle cell anemia is the most common hemoglobinopathy. It
is estimated to affect approximately 100,000 Americans each
year. It is more prevalent in the African American community and estimated to occur in 1 out of 365 births.
Approximately 1in 13 births in the African American community has sickle cell trait. Finally, it is estimated to occur in
1 out of every 16,300 births in the Hispanic-American community [12]. It is theorized that sickle cell anemia is more
common in areas with malaria, as it provided a selective
benefit of protecting individuals from becoming infected with
the parasite that causes malaria.
Pathophysiology
Sickle cell anemia (SCA) is an autosomal recessive disease,
and so in order to have the disease, a person must inherit one
copy of the defective gene from each parent [13]. In SCA
there is a mutation in the beta-globin gene where the hydrophilic nucleotide glutamic acid is replaced with the hydrophobic nucleotide valine at the sixth position of the beta-globin
gene, resulting in hemoglobin S (HbS). When the HbS is
exposed to deoxygenated environments, polymerization of
HbS occurs leading to erythrocyte rigidity and distortion of
the erythrocyte membrane, creating the characteristic sickle
shape. The rate at which this occurs depends on the concentration of HbS and hemoglobin F (HbF). This sickling leads
to premature intravascular hemolysis, which causes vascular
injury and endothelial dysfunction. The hemolytic process
also depletes available nitric oxide, leading to vasoconstriction. This process also leads to release of inflammatory
mediators and overexpression of adhesion molecules, leading
to vaso-occlusion [14].
Chapter 18. Anemia
373
The main pathologies associated with sickle cell anemia are
vaso-occlusive crisis, hemolysis, and certain infections [14]:
• Hemolysis: The baseline hemoglobin levels are often lower
than the average adult due to the shorter life span of their
erythrocytes. The rate of hemolysis may increase during
times of increased stress such as during an infection, and
the patient with SCA will be more prone to vaso-occlusive
crisis. The most severe form of this is known as a hyperhe-
molytic crisis.
• Vaso-occlusive crisis: These episodes are often marked by
severe pain and can lead to infarction at different locations
in the body. The most severe complications of vaso-
occlusive crisis include acute chest syndrome, acute papil-
lary necrosis, both ischemic and hemorrhagic stroke, spinal
cord infarction, cholecystitis, acute coronary syndrome,
and pulmonary embolism. Patients with SCA often develop
chronic lifelong pain that may be difficult to treat. Many of
these patients may require opioid analgesia and it is
important to carefully monitor these patients for signs of
opioid addiction and withdrawal. Other complications
include osteoporosis, avascular necrosis, pulmonary hyper-
tension, and priapism.
• Infection: Patients with sickle cell anemia are at higher risk
for osteomyelitis. Patients will develop splenic infarcts and
are considered to have functional asplenia, putting them at
higher risk for infections from encapsulated bacteria such
as Streptococcus pneumoniae, Neisseria meningitis, and
Haemophilus influenzae type B and gram-negative organ-
isms such as Salmonella sp., Enterobacter cloacae,
Enterococcus faecium, and Pseudomonas aeruginosa.
Key History andPhysical Exam
For patients with SCA it is important to determine the severity of their illness. Each patient may present differently and
with a different level of disease burden. History should focus
on determining evidence of any complications due to SCA,
374
B. Cohen
and given the widespread effects across all organ systems, it is
important that a thorough review of systems is performed for
each patient. It is important to determine whether a patient’s
pain is adequately controlled or not. Understanding what
medications have been used and how often blood transfusions have been required may guide your treatment plan.
A full physical exam should be performed to evaluate for
any neurologic deficits, conjunctival pallor, tachycardia, jaundice, gait abnormalities, and dactylitis.
Laboratory Evaluation
• CBC
• Hemoglobin electrophoresis
• Reticulocyte index
• LDH, haptoglobin, unconjugated bilirubin
• Peripheral blood smear
Diagnosis
Diagnosis of sickle cell anemia is based on RBC morphology
on a peripheral blood smear along with clinical criteria of
hemolysis with a history of ischemic pain. The diagnosis is
confirmed with hemoglobin electrophoresis, which will show
elevated levels of HbS.
Treatment
The overall management of sickle cell anemia varies depending on the severity of the illness and each patient should be
managed with the help of a hematologist. For the severe
complications such as acute chest syndrome, stroke, transient
ischemic attack (TIA), spinal infarcts, hyperhemolytic crisis,
and severe infections, or in cases where pain cannot be controlled at home, patients should be referred to their local
hospital for further management.
For patients with less severe symptoms, outpatient management is recommended. All patients should be started on
folic acid supplementation, as the sickled erythrocytes have a
very short life span of 12–16days and the folic acid is needed
Chapter 18. Anemia
375
for erythrocytosis and the rapid turnover of RBCs. Pain management should focus on use of NSAIDs for mild to moderate pain control [15].
Studies have found that patients with higher levels of
fetal hemoglobin (HbF) have milder courses of disease and
decreased hospitalization and may have improved survival
[13]. In normal physiology, the fetus has high concentrations
of HbF but after birth this gene is turned off and the gene
for HbA, or in the case of patients with SCA, HbS, is turned
on. The medication hydroxyurea, which is used as a chemotherapy agent by halting the cell cycle between G1 and S
phases, also has the advantage of increasing HbF production
and is recommended for all patients with sickle cell anemia
who have had repeated complications from vaso-occlusive
crisis or have had painful crisis more than three times per
year [13].
In addition to hydroxyurea, it may sometimes be necessary
to give a blood transfusion, particularly if a patient is having
any of the more severe complications of a vaso-occlusive
crisis.
All patients with sickle cell anemia should receive appropriate pneumococcal and HiB vaccinations to protect against
these encapsulated organisms if they have not already
received them earlier in life.
Thalassemia
Epidemiology
Thalassemia is another common hemoglobinopathy. It is estimated that roughly 20% of the world population carries a
gene for alpha thalassemia, and 5.2% of the population has a
significant form of the disease, either beta-thalassemia or
alpha-thalassemia trait. Thalassemia is most prevalent in
African and Mediterranean countries, the Middle East, and
Southeast Asia. The most common form is the heterozygous
form of disease. The homozygous alpha-thalassemia causes
intrauterine demise and homozygous beta-thalassemia is
associated with a severe anemia diagnosed at early age [16].
376
B. Cohen
Pathophysiology
Thalassemia is a group of heterogenous hemoglobinopathies
that results in decreased production of either the alpha or
beta globin gene on the hemoglobin molecule. Hemoglobin is
a tetramer that is composed of two alpha and two beta globin
molecules. The beta globin molecule has two genes and the
alpha globin gene has four genes. The spectrum of the different thalassemia disorders is dependent on how many genes
are lost due to mutation. These mutations leads to a mismatch
in the alpha/beta globin ratio, cellular damage, and early
hemolysis [2].
Key History andPhysical Exam
When evaluating for possible thalassemia disorders, it is
important to obtain a complete social and family history. The
patient’s country of origin, or whether their parents have any
hemoglobinopathy, can help you determine whether it is
likely that a patient could have a thalassemia disorder. Since
the laboratory evaluation will show microcytic anemia, it is
important that your history and physical exam focus on ruling out causes for iron deficiency anemia.
Laboratory Evaluation
• CBC
• Iron studies
• Hemoglobin electrophoresis
• DNA sequencing
• Peripheral blood smear
Diagnosis andManagement
The evaluation for thalassemia often begins when pursuing
causes of microcytic anemia. Therefore, just like with iron
deficiency anemia, the evaluation should begin with checking
the CBC and iron studies. Patients with thalassemia will often
have a mild anemia and a very low MCV.In contrast to iron
deficiency anemia, the iron studies in these patients will not