ANEMIA: AN APPROACH TO DIAGNOSIS
"I want to say in a single sentence
what it takes books for other philosophers to say"- Frederich Nietzsche
General Principles
1.
Anemia is a sign, not a disease.
2.
Anemias are a dynamic process.
3.
Although the elderly are more prone to anemia, being elderly is
not a cause of anemia.
4.
The diagnosis of iron deficiency anemia mandates further work-up.
Initial Work-up
1. Good H & P-Ask about blood loss,
duration of anemia, family history of anemia, medication use etc. The exam
should include a careful search for splenomegaly, blood in the stool, etc...
2. A careful review of the peripheral smear
will often reveal many diagnostic clues, especially in the complex patient.
3. The reticulocyte count provides
insight into whether a marrow problem is involved or if the anemia is due to
blood loss or destruction.
4. Armed with the above knowledge one can then
order specific tests further to explain the etiology of the anemia.
5. Given the frequency of iron and B12
deficiency and the non-specificity of RBC indices, serum ferritin,
homocysteine, and methylmalonic acid should be checked in
all anemic patients.
6. A word should be mentioned about the RDW. Once touted at the diagnostic panacea for
anemia, more recent studies have shown it is of little help in the diagnosis of
thalassemia, iron, folate or B12 deficiency, myelodysplasia, or the
anemia of chronic disease (ACD).
Reticulocyte Count
The
reticulocyte count is a measure of the new cells the marrow is producing. Since
you turn over about 1% of your red cells daily, to maintain a steady hematocrit
your reticulocyte count should be 1%. The reticulocyte count has to be adjusted
for the hematocrit since a retic 1% at a hematocrit of 45% is the same as one
of 4.5% at a hematocrit of 10%. Several ways exist to do this:
Absolute retic count: % retic x red cell count (normal is 50 ‑
85,000/mm3)
Corrected: retic % x (patient’s hct/45)
Increased
reticulocytes (greater than 2‑3% corrected reticulocyte count or 100,000/mm3
total) are seen in blood loss and hemolytic processes, although up to 25% of
hemolytic anemias will present with a normal reticulocyte count due to immune
destruction of red cell precursors and/or folate deficiency. The key idea is
that if a patient has a hematocrit of 10% and a "normal" absolute
reticulocytes count this is abnormal given the situation. Retic counts are most
helpful if extremely low (<0.1%) or greater than 3% (100,000/mm3
total).
Anemia:
Etiologies
1.
Production defects:
A.
Nutritional deficiencies-Vitamin B12, folate or iron deficiency.
B.
Inflammation/chronic disease.
C.
Primary marrow disorders-pure red cell aplasia, myelodysplasia.
2.
Sequestration (hypersplenism)-usually associated with mild pancytopenia.
3.
Dilutional-common in hospitalized patients. A patient=s plasma volume increases with lying
down and when they quit smoking.
Possibly responsible for as much as a 3-6% drop in the hematocrit in the
first two days of hospitalization.
4.
Blood loss.
5.
Blood destruction.
IRON DEFICIENCY
In
adults the most common cause of iron deficiency is blood loss. In men and in post-menopausal women the
source of the blood loss is most often the gastrointestinal track with cancer
being found in 10-15%. Patients who have
had gastrectomies can have impaired iron absorption. Iron deficiency, especially refractory to
iron therapy, can be a clue to celiac disease that can be seen in up to 1:250
Caucasians. Finally, infection with helicobacter
pylori is being recognized as a cause of iron deficiency.
Iron Deficiency: Diagnosis
1.
RBC indices are of little diagnostic value unless the MCV is
below 70fl which is only seen in iron deficiency and thalassemia.
2.
Serum iron can be decreased in a variety of states including iron
deficiency, inflammation, and stress.
The serum iron level varies tremendously from morning to evening and
from day to day. The minuscule amount of iron in a multivitamin can falsely
elevate the serum iron for up to 24 hours.
3.
The total iron binding capacity is very specific for iron
deficiency (near 100%) but has poor sensitivity (less than 30%).
4.
The iron saturation (Fe/TIBC x 100) can be decreased below 16
percent in both anemia of chronic disease and iron deficiency and is of
little help in distinguishing between the two.
5. In the normal patient the serum ferritin
is directly correlated with iron stores. This relationship holds true even in
inflammatory states although the curve is "shifted to the left." That is, for a given level of storage iron in
a patient with an inflammatory state the serum ferritin is higher. A ferritin
level of greater than 100ng/ml rules out iron deficiency anemia in most
patients. One good rule of thumb is that in patients more than 65 years of age
a ferritin below 50 ng/ml is associated with iron deficiency. The measurement of the serum ferritin is the
most useful and cost‑effective test of iron stores.
The
most efficient approach to detecting iron deficiency is to perform a serum
ferritin. If it is more than 100 ng/dl,
this eliminates iron deficiency. Very
low values are diagnostic of iron deficiency.
Although laboratories will often state that ferritins of over 12-36
ng/dl are in the "normal range" it is important to remember that many
older patients may be iron deficiency with ferritin in the 50-80 ng/dl
range.
Oral iron is the best treatment option. To avoid GI upset it is best to start with 1
ferrous sulfate pills per day. Taking the pills with vitamin C aids in iron
absorption. Rare patients may require intravenous iron. The newer iron
preparations such as iron sucrose or iron gluconate are safer than iron
dextran. One drawback of the newer preparations
is that multiple doses may be needed to fuller replete iron stores.
With
effective iron therapy, the reticulocyte count should rise in one week and the
hematocrit should increase by two weeks. Unless the cause of the blood loss is
obvious, all patients with iron deficiency should undergo a gastrointestinal
evaluation. In older patients studies
show that 50% will have an identifiable source of blood loss and that 10-15% of
iron deficiency patients will have colon cancer. In patients with iron deficiency that is resistant
to iron therapy one should check anti-glidian and anti-endomyoseil antibodies
to check for celiac disease and for h. Pylori.
Recently achlorhydria due to anti-parietal cell antibodies has been implicated
in refractory iron deficiency.
Microcytic Anemia: Differential Diagnosis
1.
Iron Deficiency. The lack of iron
results in decreased hemoglobin available to the developing red cell. Thus, the erythrocytes produced are
underhemoglobinized which result in smaller cells. The earliest sign of iron deficiency is
decreased iron stores. This stage has a
normal CBC and indices, although one can see microcytic/hypochromic cells on
the smear. The anemia gradually evolves
into the classic microcytic- hypochromic anemia. Diagnosis is made by showing decreased iron
stores on bone marrow examination. Biochemically
the diagnosis is established by a high TIBC or a low ferritin. The major diagnostic difficulty is
distinguishing iron deficiency from anemia of chronic disease.
2. Anemia of Chronic Disease. (anemia of defective iron utilization). In patients with inflammatory states iron is
sequestered in the RE system and is unavailable for use by the developing red
cell (defective iron utilization). Thus
at the erythrocyte level the defect is identical to iron deficiency and
therefore results in production of underhemoglobinized red cells. This can result in a microcytic/hypochromic
anemia. Increase production of the
protein hepcidin is response for the multiple changes in iron metabolism seen
in inflammation. Additional factors
including shorten red cell survival and decreased levels of erythropoietin add
to the hypoproliferative state. The
inflammatory state also leads to a decreased serum iron and decreased
TIBC.
Recently
the spectrum of diseases associated with anemia of chronic disease has
expanded. Besides the classic association
of temporal arteritis (may be a presenting sign), rheumatoid arthritis, cancer
etc., anemia of chronic disease has been found in patients with
non-inflammatory medical conditions such as congestive heart failure, COPD and
diabetes. Patients with anemia of
chronic disease can have hemoglobins decreased into the lower 20% range and
many (20-30%) will have red cell indices in the microcytic range.
Diagnosis
is made by proving ample bone marrow iron stores with decrease sideroblasts
(iron containing red cell precursors). Biochemically anemia of chronic disease
remains a clinical diagnosis of exclusion. The key test is to rule out iron
deficiency. The serum erythropoietin level is inappropriately low vales when compared
with the hematocrit. The RDW (red cell destruction width) that appears on the
CBC report is of no value in differentiating anemia due to iron deficiency from
those associated with chronic disease. The serum iron is decreased in both
conditions and the TIBC is low in states where iron deficiency and chronic
disease co‑exists thus rendering these tests useless. The finding of an
elevated ferritin over 100ng/ml is an adequate demonstration of good iron
stores. In the older patient or one with back pain, one should also rule‑out
the presence of multiple myeloma by performing a serum protein electrophoresis.
In difficult cases one can resort to assessing bone marrow stores of iron. In the future assays of hepcidin levels will
be helpful.
There
is no specific therapy for the anemia of chronic disease except treating the
underlying disorder. Patients with low erythropoietin levels who are
symptomatic may response to erythropoietin injections with either erythropoietin
40,000/wk or darbopoeitin 300 ug/every 2-3 weeks but this has become
controversial in recent years. One
should insure there are adequate iron stores before starting growth factors.
3. Thalassemia.
In this disorder it is the defective production of hemoglobin that leads
to microcytosis. The main types are the
beta-thalassemia, alpha-thalassemia and Hemoglobin E.
Patients
who are heterozygotes for beta-thalassemia have microcytic indices with
mild (30ish) anemias. Homozygotes have
very severe anemia. Peripheral smears in
heterozygotes reveal microcytes and target cells. Diagnosis is established in by hemoglobin
electrophoresis that shows an increased HbA2. One should check iron stores since an
elevated HbA2 will not be present in patients with both thalassemia
and iron deficiency. Beta-thalassemia
occurs in a belt ranging from Mediterranean countries, the Middle East, India, and
Pakistan to Southeast Asia. Patients
with beta-thalassemia traits who are of child bearing age need to have their
spouse screened for beta-thalassemia and Hemoglobin E.
Alpha-thalassemia
also presents with microcytosis.
Patients with alpha-thalassemia will have normal hemoglobin electrophoresis. The diagnosis of alpha-thalassemia is made
by excluding other causes of microcytosis, a positive family history of
microcytic anemia, and a life-long history of a microcytic anemia. Exact diagnosis requires DNA analysis. Alpha-thalassemia is distributed is a similar
pattern to beta-thalassemia except it very high frequency in Africa (up to
40%). In patients of African descent the
finding of alpha-thalassemia requires no further evaluation. In patients from Asia of child bearing age
the spouse should be screened (if need be with DNA analysis) to assess the risk
of bearing a child with severe thalassemia.
Hemoglobin
E is actually an unstable beta-hemoglobin chain that presents in a similar
fashion to the thalassemia. It is
believed to be the most common hemoglobinopathy in the world. Hemoglobin E occurs in Southeast Asia,
especially in Cambodia, Laos and Thailand.
Patients who are heterozygotes are not anemic but are microcytic. Patients who are homozygotes are mildly
anemic with microcytosis and target cells.
The importance of Hemoglobin E lies in the fact that patients with both
genes for Hemoglobin E and beta-thalassemia have severe anemia and behave in a
similar fashion to patients with homozygote beta-thalassemia.
4. Sideroblastic Anemia. Defective
production of the heme molecule is the basis of this disorder. The deficit of heme leads to the underhemoglobinazation
of the erythroid precursors and microcytosis.
Sideroblastic anemia can be congenital, can be due to toxins such as
alcohol, lead, INH, or can be an acquired bone marrow disorder. The peripheral smear may show basophilic
stippling in lead poisoned patients, a dimorphic (macrocytic and intensely
microcytic red cells) in patient with acquired sideroblastic anemia, or
stigmata of a myelodysplastic syndrome.
Diagnosis is made by the finding of ringed sideroblasts on the bone
marrow iron stain. Iron studies in
patients with sideroblastic anemia usually show signs of iron-overload.
HEMOLYTIC ANEMIAS
The laboratory signs of hemolytic
anemias include:
1. Increased LDH (LDH1) ‑sensitive
but not specific.
2. Increased indirect bilirubin‑sensitive
but not specific.
3. Increased reticulocyte count‑specific
but not sensitive
4. Decreased haptoglobin‑specific
but not sensitive.
5. Urine hemosiderin‑presence of
any is specific but not sensitive.
The indirect bilirubin is proportional to the
hematocrit, so with a hematocrit of 45% the upper limit of normal is 1.00 mg/dl
and with a hematocrit of 22.5% the upper limit of normal for the indirect
bilirubin is 0.5mg/dl. Since tests for hemolysis suffer from a lack of
sensitivity and specificity, one needs a high index of suspicion for this type
of anemia.
Autoimmune hemolytic anemias (AIHA) are due to red cell destruction by
autoantibodies. AIHA may be idiopathic
or associated with malignancies, drugs or other autoimmune disorders. The major subgroups are Warm antibody
hemolytic anemia (IgG), Cold antibody hemolytic anemia (IgM) and Drug induced.
(See Table 1) In patients with AIHA one
usually sees microspherocytes on the peripheral smear and splenomegaly may be
present on exam. The diagnosis is established by the finding of a positive
direct antibody test (direct Coombs).
Not all patients with a positive direct antibody test will have
AIHA. The direct antibody test will
detect IgG and occasionally complement in patients with warm antibody disease. Cold antibody disease will only demonstrate
complement and not IgG.
Patients
with warm antibody disease should be started on prednisone 60 mg/day. In those who do not respond or require high
doses of prednisone splenectomy may induce remission in 50%. Many patients will require further
immunosuppression with rituximab, azathioprine, or cyclophosphamide. Treatment of cold antibody disease is
difficult as these patients will not respond to steroid or splenectomy. Rituximab has been reported to be effective
and should be the initial therapy for symptomatic patients. Drug induced
hemolytic anemia requires stopping the implicated drug. All patients with hemolysis can become folate
deficiency so folate replacement should be given to all.
Microangiopathic hemolytic anemias are due to mechanical destruction of red
cells. The most common associated
diseases are disseminated intravascular coagulation, thrombotic
thrombocytopenic purpura, hemolytic‑uremic syndrome, valvular disease, or the
presence of an artificial heart valve.
One sees schistocytes in the peripheral smear and an elevated LDH. The
exact cause of the microangiopathic hemolytic anemia is determined by the
history and laboratory testing.
Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia that is
due to a clonal proliferation of erythrocytes abnormally sensitive to the
action of compliment. Hemolysis may be more conspicuous at night leading to the
characteristic hemoglobinuria. Paints with Paroxysmal nocturnal hemoglobinuria
demonstrate the routine lab abnormalities of hemolysis. The diagnosis is made
by performing flow cytometry to demonstrate the lack of CD59. Patients are often pancytopenic and can
present with aplastic anemia. Patients
with PNH also have a high incidence of thrombosis including visceral vein
thrombosis.
CONGENITAL HEMOLYTIC ANEMIA
Three basic processes lead to congenital
hemolytic anemia: 1) membrane defects,
2) hemoglobin defects, or 3) enzyme defects.
One of the most common congenital causes
of hemolysis is hereditary spherocytosis. In this disease the red cell
membrane is abnormal leading to increased splenic destruction. Patients often
have a family history of gallstones. Another rare cause of hereditary hemolysis
due to membrane defects includes hereditary elliptocytosis. The diagnosis
of hereditary spherocytosis is made by finding that spherocytes are present on
the peripheral smear and splenomegaly is present on exam. The laboratory values
are consistent with hemolysis and the MCHC is elevated. The diagnosis is
established by the finding of increased osmotic fragility.
The
most common hemoglobin defect is sickle cell anemia. In this disease the abnormal hemoglobin leads
to destruction of the red cell.
Diagnosis is established by hemoglobin electorphoreisis. Patients may also have chronic hemolysis due
to unstable hemoglobins. These patients
will often have "Heinz" bodies present on a specially stain blood
smear and may have an abnormal hemoglobin electrophoresis.
Enzyme
deficiencies such as glucose‑6‑phosphate dehydrogenase deficiency are
also important causes of hereditary hemolytic syndromes. The same population at
risk for thalassemia is also at risk for G‑6‑PD deficiency. It is sex linked
and thus only affects males. This defect is in the hexose monophosphate shunt
and renders the RBC to be unable to withstand oxidative stress. Most people
with this disease have hemolysis only with such stressors as infections and
intake of oxidative drugs. There are two
main subtypes‑African (A‑) and Mediterranean that tends to be more severe. Such
drugs as dapsone, pymethroprine, pyridium, and sulfamethoxazole may provoke
severe hemolysis in these patients.
MACROCYTOSIS
An
increased MCV can be due to many reasons but careful review of the patient's
history and blood smear can narrow the diagnostic possibilities. The differential can be divided into two
broad categories based on RBC morphology.
Round
macrocytosis-due to abnormal lipid composition of the erythrocyte
membrane. Common etiologies include:
1. Alcoholism.
2. Liver Disease.
3. Renal Disease.
4. Hypothyroidism ("myxedema of the
red cell").
Oval
macrocytosis (macroovalocytes) is a sign of problems with cell DNA replication. The developing red cell has difficulty in
undergoing cell division but RNA continues to be translated and transcribed
into protein leading to growth of the cytoplasm while the nucleus lags
behind. Often one or more cell divisions
are skipped leading to a larger than normal cells. Common causes are:
1. Drug effect including
cytotoxic chemotherapy (AZT now most common etiology of increased MCV).
2. Megaloblastic Anemias-Folate
Deficiency or Vitamin B12 deficiency - Patients will have
hypersegmented neutrophils on review of the peripheral smear.
3. Myelodysplasia - Patients have
often hyposegmented neutrophils and abnormal platelet morphology.
Patients
with RBC autoantibodies or cold agglutinins can have a spurious increase in the
MCV due to red cell clumping in the automatic counters. Patients with increased reticulocyte counts
can also have an increase MCV due to the large size of the reticulocyte (MCV =
160).
ABSORPTION
AND METABOLISM OF VITAMIN B12 AND FOLATE
Folate-The
body stores very little folate (four weeks) and maintenance of folate stores is
dependent on an adequate dietary intake.
Folate is found in green leafy vegetables, fruits and liver. Folate is absorbed in the small bowel and
circulates in a free form or loosely bond to albumin.
Vitamin
B12- In contrast to folate the body stores copious amounts of
vitamin B12 (2-6 years). This
is fortunate as the absorption of vitamin B12 is complex and can be
interrupted by a variety of mechanisms.
Vitamin B12 is synthesized by microbes and the major dietary
source is animal protein. When animal
protein is ingested, vitamin B12 is freed from the protein and binds
to "R proteins". The R
protein-vitamin B12 complex travels to the duodenum where pancreatic
enzymes destroy the R protein. This
allows intrinsic factor (IF) to bind to vitamin B12. This IF-vitamin B12 complex is
absorbed only in the last 1-2 feet of terminal ileum. Vitamin B12 binds to
transcobalamin II and is delivered to tissues.
VITAMIN
B12 AND FOLATE- METABOLIC PATHWAYS
Both
vitamin B12 and folate are key components in the synthesis of DNA
due to their role in conversion of uridine to thymidine. When methyltetrahydrofolate loses a methyl
group to form tetrahyrodrofolate, vitamin B12 "shuttles"
the methyl group to homocysteine converting it to methionine. Tetrahydrofolate is eventually converted to
methylenetetrahydrofolate required for thymidine synthase. Vitamin B12
other role is a cofactor in the conversion of methymalonyl-CoA to succinyl-CoA.
CONSEQUENCES
OF VITAMIN B12 OR FOLATE DEFICIENCY
When
vitamin B12 or folate is deficient, thymidine synthase function is
impaired and DNA synthesis is interrupted.
As described above this leads to megaloblastic changes in all rapidly
dividing cells. The inability to
synthesized DNA leads to ineffectual erythropoiesis. There is often erythroid hyperplasia in the
marrow but most of these immature cells die before reaching maturity. This process, intramedullary hemolysis, leads
to the classic biochemical picture of hemolysis-raided LDH and indirect
bilirubinemia. The LDH level is often in
the 1,000's in patients with megaloblastic anemia. The lack of DNA synthesis affects the
neutrophils leading to nuclear hypersegmentation. The anemia is of gradual onset and is often
very well tolerated despite low hematocrits.
Often a mild pancytopenia is seen but thrombocytopenia can be severe.
Other
rapidly dividing tissues are influenced by the megaloblastic process. In the GI tract this can lead to atrophy of
the luminal lining and further malabsorption.
As
discussed further below, only vitamin B12 deficiency leads to
neurological damage. The mechanism is
unknown.
ETIOLOGIES
OF FOLATE DEFICIENCY
Decreased intake
Increased requirements-Patients who are pregnant, have
hemolytic anemia, or psoriasis have increased needs for folate that can cause
them rapidly to develop folate deficiency if intake is not kept up.
Malabsorption
Drugs - Patients with underlying mild folate deficiency are more
susceptible to trimethoprim/sulfa, pyrimethamine and methotrexate
toxicity. Oral contraceptive and
anticonvulsants lead to increase consumption of folate.
Alcohol- Alcohol affects several aspects of
folate metabolism. Alcoholics have a
poor intake of folate. In addition,
folate metabolism is interfered with leading to a functional folate
deficiency. Alcoholics have an inability
to mobilize folate stores and can have depleted tissue stores with normal serum
levels of folate.
ETIOLOGIES
OF VITAMIN B12 DEFICIENCY
Inadequate intake is rare but seen in very strict vegans
(no eggs or milk).
Abnormal gastric events include being unable to dissociated
vitamin B12 from food due to lack of stomach acid or enzymes. This is a recently recognized group of
patients that may compose a very large subset of patients with vitamin B12
deficiency. 10-30% percent of patients with
partial gastrectomy will develop vitamin B12 deficiency. The recent promiscuous use of H2
and proton pump blockers is leading to an increased incidence of patients not
absorbing vitamin B12.
Finally, infection with H. pylori is also associated with decreased B12
absorption.
Deficient intrinsic factor most commonly occurs due to destruction
of parietal cells by autoantibodies (pernicious anemia).
Abnormal small bowel events include pancreatic insufficiency, blind
loops syndromes (bacterial absorbing vitamin B12-IF complexes) and
patients infested with Diphyllobothrium latum.
Abnormal mucosal events including malabsorption syndromes and
surgical removal of the terminal ileum.
APPROACH
TO THE PATIENT WITH AN MEGALOBLASTIC ANEMIA
1. Recognizing that a megaloblastic
anemia is present.
2. Diagnosing vitamin B12
and/or folate deficiency
3. Determining the underlying cause.
4. Therapy
DIAGNOSING
VITAMIN B12 AND/OR FOLATE DEFICIENCY
When
a patient is believed to have a megaloblastic anemia or a process consistent
with vitamin B12 deficiency, one should draw a serum methylmalonic
acid, a serum homocysteine level (a more sensitive indicator of tissue stores
than serum or red cell folate) and since up to 30% of patients with
megaloblastic anemia have concurrent iron deficiency, a serum ferritin.
Recent data suggests that B12
levels may not be accurate especially in older patients. Many patients will
have low B12 levels but not tissue deficiency. Up to 15% of patients with normal B12
levels will have tissue deficiencies.
Measuring serum levels of methymalonic acid, a metabolic precursor that
is increased in B12 deficiency, is now the preferred method of
diagnosis especially in older patients.
Many patients who are B12 deficiency will also have elevated
serum homocysteine levels. Patients with
high homocysteine levels should have a methylmalonic acid drawn to insure that
they do not have B12 deficiency.
Folate deficiency
Like B12 levels, serum folate
levels do not reflect body stores of folate. Serum homocysteine levels are more
accurate.
|
|
B12 Deficiency
|
Folate Deficiency
|
|
Methymalanoic
acid
<0.4 umol/L
|
Elevated
|
Normal
|
|
Homocysteine
4-12 umol/L
|
Elevated
|
Elevated
|
DETERMINING
THE UNDERLYING CAUSE
In
most of patients with folate deficiency, one can determine the underlying cause
by history. The key concern in vitamin B12
deficiency is determining at which point in the complex pathway of vitamin B12
absorption the "lesion" is.
The Schilling test is a test of vitamin B12 absorption. Patients are given radio labeled vitamin B12
orally and a large dose of vitamin B12 is given intravenously. The IV dose of vitamin B12
prevents binding any absorbed labeled vitamin B12 and this is
excreted. The amount of excreted vitamin
B12 reflects vitamin B12 absorption. The Schilling test is NOT a
test of vitamin B12 deficiency but a tool to decide the etiology of
the deficiency. The tradition Schilling
test is called "stage I.@
If less than 8% of the labeled vitamin B12 is excreted then
one can perform the Schilling test with a variety of diagnostic maneuvers to
pinpoint the lesion. This includes
giving intrinsic factor, pancreatic enzymes, or antibiotics.
The
Schilling test has several shortcomings.
One is it requires patient cooperation in collecting the 24-hour urine
sample. As noted above patients can have
secondary malabsorption due to vitamin B12 deficiency. Several drugs including "slow K"
will cause a false positive Schilling test.
Finally the classic Schilling test will not detect abnormalities in
patients with difficulties in dissociating vitamin B12 from
food. The "food" Schilling
test where labeled vitamin B12 is mixed with food has been proposed
to detect this common group of patient.
Patients
with pernicious anemia can be detected by assaying for autoantibodies but these
tests can lack diagnostic specificity.
Antibodies to IF are specific but not sensitive and antibodies to
parietal cells are sensitive but not specific for pernicious anemia.
VITAMIN
B12- NEUROLOGICAL CONSEQUENCES
Recently
it has become clear the patients can have neurological damage due to vitamin B12
deficiency without anemia. In fact as
many as 30% of patients with neurological disease due to vitamin B12
deficiency will have no or only subtle hematological symptoms. Patients with the most severe neurological
manifestation often have mild hematological disease. Thus it is appearing that vitamin B12
deficiency may exhibit two different types of disease states in humans -
hematological or neurological.
Neurological symptoms are reversible if found early but those present
for over a year slowly, if ever, improve.
The
neurological symptoms include:
< Paresthesias-most often in fingers and
toes. The most common symptom of vitamin
B12
deficiency.
< Diminished vibratory sense
< Gait ataxia
< Increases deep tendon reflexes
< Memory loss
< Personality change
< Orthostatic hypotension
VITAMIN
B12 AND THE ELDERLY
On
routine screening as many as 10-23% of elderly patients will have low vitamin B12
levels. One study found that 14.5% had
levels below 300 pg/ml with 56% of these patients having increased levels of
homocysteine and methylmalonic acid indicative of tissue vitamin B12
deficiency. The most common mechanism is
inability to absorb vitamin B12 from food. It is speculated the rapid rise in the use of
H2 blockers will increase this problem in this patient population.
Patients with dementia have lower levels of vitamin B12 then those
without but treatment with vitamin B12 is often not effective,
perhaps due to the long duration of the neurological damage. Studies are underway to examine the
relationship of vitamin B12 deficiency to neurological disease in
the elderly and the effects of early intervention.
B12 DEFICIENCY- THERAPY
For
severe deficiency B12 subcutaneous injections of 1000 ug should be
given. Long term management can consist
of either monthly B12 shots or oral therapy with 1-2 mg/day.
Patients who have had their bowel or stomach resected should receive routine B12
supplementation. There is increasing
evidence that oral B12 replacement at a dose of 1-2 mg/day is just
as effective as injections.
Myelodysplasia
The
myelodysplastic syndromes are a group of bone marrow diseases marked by various
cytopenias, morphologically abnormal blood cells, dysplastic bone marrow
changes and a propensity to evolve into acute leukemia. The changes on the peripheral smear can range
from very abnormal looking blood smears to subtle changes. Hallmarks on the peripheral smear are
pseudo-Pelger Huet cells (two-lobed neutrophils), macroovalocytes and hyposegmented
neutrophils. This is commonly a disease
of older patients and manifests itself as an anemia with normal iron, vitamin
B12, and folate studies. Often these
patients are misdiagnosed and treated ineffectually with iron or vitamin
shots. Another group of patients in whom
the myelodysplastic syndromes are common is patients who have undergone therapy
for malignancy. Diagnosis is by bone
marrow examination. Often cytogenetic
abnormalities will be present and aid in diagnosis and assessing prognosis. Therapy is very dependent on age and
underlying disease. Only bone marrow
transplant is curative but newer therapies can reduce transfusion requirements.
Aplastic
Anemia/Pure Red Cell Aplasia
Destruction
of the hemopoietic cells of the marrow by whatever means leads to the clinical
condition of aplastic anemia. The
patient with this condition presents with pancytopenia. A thorough history should be taken from the
patient to try to identify any possible drug or toxin exposure, although in
most patients the cause is unknown.
Splenomegaly is absent. The
peripheral smear shows a decreased number of normal red cells. Diagnosis is established by bone marrow
biopsy that reveals a hypocellular marrow.
Since paroxysmal nocturnal hemoglobinuria can initially present as
aplastic anemia, when marrow function recovers, a Ham's test should be
preformed. In young patients with aplastic anemia, bone marrow transplantation
is the treatment of choice. Since the prognosis
is worse in these patients if they had received transfusion, one should not
transfuse these patients unless absolutely necessary.
Pure red cell aplasia is the
condition where the red cell precursor are selective destroyed. Since this condition can be associated with
thymomas (and responsive to its removal), this should be sought with
radiographic studies. Parvovirus B19,
which is selectively toxic to the developing red cell, can cause a chronic
infection that leads to clinical picture resembling pure red cell aplasia in
susceptible patients. Parvovirus infection is also hazardous in patients
dependent on increased RBC production such as those with congenital hemolytic
anemia or sickle cell anemia. In those
patients parvovirus infection may lead to a dramatic "aplastic crisis.@
Anemia
and Alcoholism
Anemia
of complex etiologies is often present in the alcoholic patient. Alcohol has a direct toxic effect on the bone
marrow that leads to decreased red cell production. Folate metabolism is also interfered with
leading to functional folate deficiency.
This is aggravated by the poor dietary intake of folate by alcoholics
and impaired absorption of folate in these patients. The alcohol abusing patient may also have
increased blood losses due to gastrointestinal bleeding and trauma. Hypersplenism due to liver disease can be a
factor to the anemia. This group of
patients will often have coexistent inflammatory states that will lead to
defective iron use. Heavy alcohol use
can even lead to a sideroblastic anemia.
Diagnosis
of specific defects in the alcoholic can be difficult due to the myriad of
problems. The serum ferritin is a
dependable gauge of marrow iron stores.
Although the MCV may be normal, most alcoholics with folate deficiency will
have either macroovalocytes or hypersegmented neutrophils present on the
peripheral smears. Sources for blood
lost should be aggressively sought.
Often a bone marrow examination is required fully to explain the etiology(s)
of the anemia.
A Brief but Important Paragraph about
Copper
Copper
plays a key role in hematopoiesis.
Patients can become copper deficiency most commonly by:
1.
Lack of intact (anorexia, bariatric
surgery)
2.
Excessive zinc intake (Cu and Zn share the
same transporter)
a.
Eating to many coins (especially pennies)
b.
Too many Zn supplements
The
classic signs of copper deficiency are the following 4 findings
1.
Anemia – can be severe
2.
Neutropenia – can be severe
3.
Thrombocytopenia – very RARE
4.
Neurological findings – peripheral
neuropathy
Treatment
is by replacing copper and convincing the patient to stop eating coins.
Indications for a Bone Marrow Aspiration
and Biopsy
1. Pancytopenia.
2. Leukoerythroblastic blood smear
(presence of immature white cells and nucleated red cells).
3. Staging of the lymphomas and of small
cell lung cancer (not in the diagnosis of these diseases!).
4. Unexplained anemia.
5. Blood smear suggestive of
myelodysplasia or of leukemia.
6. Monoclonal gammopathy.
7. Anemia with a very low (less than
0.1%) reticulocyte count.
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