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Case 6
Chief Complaint
Fatigue, depression, and ataxia
History and Physical Examination
A 75-year-old man is brought to the office by his son, who states that his father has been
increasingly lethargic over the last few months. His father’s mood has been erratic and
volatile, and he drinks quite a lot of alcohol. The patient complains of increasing
generalized weakness and fatigue. Over the last few weeks he has experienced worsening
ataxia. He denies fever, chills, or difficulty with thyroid regulation. His appetite is
unchanged and he maintains a balanced diet.
Vital signs are T 37.5 C (99.5 F), BP 140/85 mm Hg, and pulse 86/min. In general, the
patient appears mildly confused but is oriented to person, place, and time. Examination
shows a supple neck without adenopathy, a normal thyroid, and a clear chest. He has a
regular heart rate and rhythm with an S1 and S2. Skin tone appears normal, and his
abdomen is soft, nontender, with no hepatosplenomegaly. Neurologic examination shows
muscle strength that is somewhat diminished throughout; a decreased sensation in the
lower limbs with loss of position and vibratory sense; hyperreflexia in the lower
extremities; and an ataxic gait.
Differential Diagnosis
Vitamin B12 deficiency1.
331
Initial Management
Setting: outpatient or emergency department if symptoms severe
Diagnostic/Therapeutic Plan
Test Results
Assessment
Tertiary syphilis
2.
Central nervous system vascular disease (multiple strokes)
3.
Chronic alcoholism
4.
Thyroid disease
5.
Depression
6.
CBC
Thyroid function studies (T4, TSH)
BUN, creatinine
Head CT
VDRL or RPR
WBC 4,000/mm
3
(normal 4,500–11,000/mm
3
), hemoglobin 9.1 g/dL (normal 13.75–17.5
g/dL), platelets 190,000/mm
3
(normal 150,000–400,000/mm
3
), MCV 110 µm
3
(normal 80–
100 µm
3
), differential: 60% granulocytes
Hypersegmented neutrophils seen on smear
T4, TSH normal
BUN, creatinine normal
Head CT: mild diffuse atrophy
VDRL or RPR non-reactive
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The patient’s primary manifestations are neurologic: motor deficits, sensory deficits, and
ataxia. This makes primary motor neuron or muscle disease unlikely. The diffuse distribution
makes stroke less likely. Fatigue, motor weakness, and confusion can be seen with both hypo-
and hyperthyroidism in elderly patients, but no other signs of thyroid disease are present. The
neurologic findings could be consistent with both vitamin B12 deficiency and syphilis.
Macrocytic anemia can be caused by vitamin B12 deficiency, folate deficiency, alcoholism, or
liver disease.
Given the neurologic symptoms in this patient, combined with macrocytic anemia and
hypersegmented neutrophils, vitamin B12 deficiency, or alcoholism is the most likely cause.
Homocysteine levels are elevated in both folate and vitamin B12 deficiency, whereas
methylmalonic acid levels are increased only in vitamin B12 deficiency. Folate will partially
improve vitamin B12-induced anemia but do nothing for the neurological symptoms.
Basic Science Correlate
Why does B12 cause neurological symptoms and folate does not?
Why is the marrow hypercellular if there is a pancytopenia?
B12 is needed to form myelin
Any neurologic problem is possible but peripheral neuropathy is the most common
(dementia is least common)
B12 deficiency gives ineffective erythropoiesis
Cells are made in increased number, but they rapidly self-destruct as they leave the
marrow
Cell destruction increases indirect bilirubin and LDH but keeps the reticulocyte
count low
333
What is the mechanism of B12 deficiency?
Further Management Plan/Results
Borderline low
Present
High
Discussion
The Schilling test is rarely, if ever, necessary. It is performed to determine the etiology of the
vitamin B12 deficiency when antiparietal-cell and anti-intrinsic factor antibody levels are
normal.
Vitamin B12 is found in abundance in fish, meat, and dairy products. It is protein-bound in
food, and in the acidic environment of the stomach, pepsin cleaves it to free product, which is
then bound by intrinsic factor in the proximal ileum and is absorbed in the distal ileum. People
usually have vast stores of the vitamin. Strict vegetarians over years may develop a deficiency.
Vitamin B12 deficiency can also be seen with small-bowel bacterial overgrowth, Crohn’s
disease, celiac sprue, and ileal or gastric resections, resulting in malabsorption.
Pernicious anemia is an auto-immune disorder
Antibodies are made to intrinsic factor and parietal cells
B12 level
Anti-intrinsic factor antibody
Methylmelonic acid level
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The most common cause is pernicious anemia, and its incidence increases with advanced age.
It is found in 5–10% of patients age >65. It is an autoimmune process, which is characterized
by autoantibodies against gastric parietal cells and intrinsic factor. Patients first develop
achlorhydria, which is associated with gastritis that spares the antrum. The patients
subsequently develop vitamin B12 malabsorption. Deficiency develops slowly over time
(usually 3–6 yrs) if absorption stops abruptly.
CCS NOTE
CT scan of the head is always a good diagnostic test for unexplained change in mental
status or memory.
The disease is characterized by macrocytic anemia with associated hypersegmented
neutrophils. It may also present with pantocytopenia. In addition, there are neuropsychiatric
symptoms such as fatigue, weakness, paresthesia of the extremities, loss of vibratory and
position sense, ataxia, dementia, and psychosis. Neurologic symptoms may precede
hematologic ones. Patients with vitamin B12 deficiency and neuropsychiatric symptoms don’t
necessarily have macrocytosis or anemia. When vitamin B12 deficiency occurs with iron
deficiency, it can result in a mixed microcytic/macrocytic population of red cells yielding an
MCV that is normal. Serum gastrin levels are often high because the antrum is spared by the
gastritis, and gastrin-producing cells do not have normal feedback inhibition from acid
secretion.
CCS NOTE
335
Office-based cases require the clock to be moved forward by several days to weeks in
“simulated” time.
Deficiency is suggested by low serum levels, although the condition may exist with low normal
levels. In this circumstance, an elevation of the methylmalonic acid level suggests a vitamin
B12 deficiency.
Another reason for an alteration in the Schilling test in the presence of vitamin B12 deficiency
is if intrinsic factor is present but vitamin B12 is not absorbed because the vitamin that is
bound to food cannot be released from the food due to achlorhydria. In this situation, both steps
of the Schilling test will show absorption because free vitamin B12 is used. Anti-intrinsic
factor antibodies are found in patients with pernicious anemia. Antiparietal cell antibodies are
less specific. Pernicious anemia often co-exists with other autoimmune diseases such as
thyroiditis, vitiligo, MGUS and Addison’s disease.
Basic Science Correlate
Vitamin B12 and folate are both necessary for the conversion of homocysteine to
methionine, whereas the conversion of methylmalonyl CoA to succinyl CoA is
dependent on vitamin B12 alone. The latter is thought to result in accumulation of
nonphysiologic fatty acids, potentially leading to neurologic changes.
Vitamin B12 is an essential cofactor in folate metabolism necessary for DNA synthesis.
Its absence results in megaloblastatic changes in the bone marrow, characterized by
asynchrony between nuclear and cytoplasmic maturation.
Why does treatment of B12 deficiency lead to low potassium levels?
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Follow-up Management and Prevention
Final Diagnosis
Pernicious anemia/vitamin B12 deficiency
As cells are made in the marrow at a very rapid rate, all available potassium is used
up.
Methylmalonic acid levels if the B12 level is normal or borderline
Injection of B12 as replacement
Potassium levels with B12 replacement
337
Case 7
Chief Complaint
Fatigue
History and Physical Examination
A 25-year-old woman comes to the office for a physical examination before starting a new
job. She states that she has been feeling fatigued, particularly at the end of the day. She
also notes palpitations with increasing frequency. Her menstrual cycle is regular, and lasts
7–8 days. She does not drink alcohol or smoke cigarettes, and is a vegetarian. Three
weeks ago she completed a course of trimethoprim/sulfamethoxazole for a UTI.
Laboratory studies reveal hemoglobin 9.6 g/dL. Blood pressure is 110/70 mm Hg and
pulse 100/min. She appears slightly pale. The heart has a regular rate and rhythm with
occasional irregular beats, and normal S1 and S2. Rectal examination shows guaiac-
negative stool. The remainder of the physical examination is unremarkable.
Differential Diagnosis
Iron deficiency anemia
1.
Folate deficiency
2.
Vitamin B12 deficiency
3.
Thalassemia
4.
Sulfa-induced bone marrow suppression
5.
Hemolytic anemia due to drugs or systemic lupus erythematosus
6.
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CCS NOTE
In the initial visit of an office-based case, perform a complete physical examination.
For acutely-ill patients in the hospital or emergency department, perform an
examination focusing on the area of the body that is the center of the chief complaint.
Initial Management
Setting: outpatient
Diagnostic/Therapeutic Plan
Test Results
Assessment
Myelodysplasia7.
CBC
MCV
Peripheral smear
Reticulocyte count
WBC 4,800/mm
3
(normal 4,500–11,000/mm
3
), hemoglobin 9.6 g/dL (normal 12–16 g/dL),
platelets 500,000/mm
3
(normal 150,000–400,000/mm
3
)
MCV: 70 µm
3
(normal 80–100 µm
3
)
Peripheral smear: RBC appear hypochromic and microcytic
Reticulocyte count: 1.0% (normal 1–2%)
339
The first issue to resolve in the evaluation of a patient with anemia is whether it is due to blood
loss, increased peripheral destruction of RBCs, or a failure of marrow production. There is no
clinical evidence of bleeding in the patient, and the lack of an elevated reticulocyte count in
response to anemia suggests a primary problem with marrow production of RBCs.
Folate deficiency is seen in patients with poor diets, particularly alcoholics. Folate is found in
leafy vegetables. Vitamin B12 deficiency can be seen in strict vegetarians but develops over
years. It is often seen in the setting of pernicious anemia, which is unusual in this age group.
Both folate and vitamin B12 deficiency produce macrocytic, not microcytic, anemia.
Trimethoprim/sulfa can have a suppressive effect on the marrow but often suppresses white-
blood-cell and platelet production as well. Sulfa drugs would be an unusual cause of an
isolated decrease in red-blood-cell production. Myelodysplasia is a stem cell disorder of the
marrow that affects all marrow cells. Anemia and dyserythropoiesis are seen.
The most likely cause of a microcytic anemia in an otherwise healthy young woman is iron
deficiency. Other potential etiologies include thalassemia, anemia of chronic disease, or
sideroblastic anemia. Iron deficiency results in an early elevation of the red cell distribution
width (RDW) and is often associated with an elevated platelet count.
Thalassemia presents with a normal RDW, a disproportionately low MCV, and the presence of
target cells on a peripheral smear. The diagnosis of iron deficiency is confirmed by
examination of the iron studies. Serum iron is low, and total iron binding capacity (TIBC; a
measure of iron binding sites available on circulating transferrin molecules) is high. This is in
contrast to chronic inflammatory disease, where serum iron is low but so is the TIBC because
of a defect in iron mobilization. Ferritin is the storage form of iron, and its level in the
circulation reflects the level of iron stores. A low ferritin confirms iron deficiency. Ferritin is
an acute-phase reactant, and a low-normal value can occur in an iron-deficient patient with an
active inflammatory state. This means that you can have iron deficiency anemia with a normal
ferritin level. In this situation, a bone marrow aspirate with direct examination of the iron
stores may be necessary.
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