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538 Part V Red Blood Cells

Similarities of Clinical Manifestations and Drugs That Perturb Folate Metabolism
TABLE Megaloblastic Sequelae of Folate and Cobalamin
39.6 Deficiency a Ethanol. Although beer has higher folate content than other alcoholic
beverages, alcoholism may lead to neglect of healthy dietary practices
System Manifestations in favor of alcohol. Patients who have one nutritious meal each day
tend to stave off the eventual development of folate deficiency. Alcohol
Hematologic Pancytopenia with megaloblastic marrow
consumption leads to a relatively rapid (2- to 4-day) fall in serum folate
Cardiopulmonary Congestive heart failure levels. Excess alcohol consumption is possibly the most common cause
Gastrointestinal Beefy-red tongue and added stigmata of of folate deficiency in the United States. 15
Trimethoprim and pyrimethamine bind to bacterial and parasitic
broad-spectrum malabsorption in folate dihydrofolate reductase with much greater affinity than to human
deficiency b
dihydrofolate reductase, but patients with underlying folate deficiency
Dermatologic Melanin pigmentation and premature graying appear to be more susceptible to the effects of these drugs. The mega-
loblastosis can be reversed by folinic acid (5-formyl-tetrahydrofolate
Genital Cervical or uterine dysplasia
[5-formyl-THF]; leucovorin).
Reproductive Infertility or sterility Methotrexate binds with high affinity to human dihydrofolate reduc-
Psychiatric Depressed affect and cognitive dysfunction tase and leads to trapping of folate as a metabolically inert form
(dihydrofolate). This leads to a true depletion of THF within hours
Neuropsychiatric c Unique to cobalamin deficiency with cerebral, and consequently to functional deficiency of 5,10-methylene-THF and
myelopathic, or peripheral neuropathic reduced thymidylate synthesis. Although megaloblastosis can develop
disturbances, including optic and autonomic rapidly, the toxic effects of methotrexate can be avoided by rescue with
nerve dysfunction 5-formyl-THF (leucovorin).
Sulfasalazine produces megaloblastosis in up to two-thirds of
a However, the neurologic spectrum of dysfunction in cobalamin deficiency is
distinct. Inadequate hemoglobinization (from inadequate iron stores or globin patients taking full doses (over 2 g/day) by decreasing absorption of
synthesis) can mask the expected erythroid megaloblastic morphologic findings folates and induction of Heinz body hemolytic anemia (i.e., increased
in the bone marrow and peripheral smear, and only specific therapy (i.e., iron) requirements).
can unmask classic megaloblastic manifestations (i.e., masked Anticonvulsants can induce neural tube defects (NTD), and consen-
megaloblastosis). Megaloblastic leukopoiesis is unchanged. sus guidelines have stressed the importance of ensuring that pregnant
b If folate deficiency is uncorrected for 2 to 3 years, cobalamin deficiency will women and children 251,252 with epilepsy be prescribed folates together
22
supervene. with anticonvulsants. Whereas folates protect against spontaneous
c Dorsal tract involvement is earliest manifestation in more than 70% of patients abortion, 253 folic acid supplementation of women receiving antiepileptic
with cobalamin deficiency. Neuropsychiatric manifestations are not associated drugs, which are known to interfere with folate absorption, also led to
with megaloblastosis in up to 30% of patients.
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a significant reduction of spontaneous abortion. Now there are new
clinical data on phenytoin-induced gingival hyperplasia, which is a
cosmetically undesirable side effect that affects a large percentage of
multivitamins, liver pills, or injections (often given by a well-meaning patients, usually between 2 and 6 months of initiating therapy. A recent
family member or unregistered practitioner) is a common quick fix randomized controlled trial among children 6 to 15 years of age who
in many cultures. Family members are a good source for details on were initiated on phenytoin has provided incontrovertible evidence that
the patient’s dietary habits (food faddism, vegetarianism, alcohol taking folic acid 0.5 mg daily can largely prevent phenytoin-induced
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intake) and family history of medical problems (blood diseases, gingival hyperplasia ; whereas 88% in the placebo group developed
gluten sensitivity, autoimmune diseases). gingival hyperplasia, only 21% in the folic acid group developed this
side effect. The data from this paper provide more “ammunition”
A medical history of epilepsy or alcoholism with seizure disorder to encourage young women on antiepileptic drugs to keep taking
(anticonvulsant therapy) is important. Rarely, patients with auto- folic acid to prevent them from getting cosmetically unsightly gingival
immune hemolytic anemias may be lost to follow-up and return with hyperplasia (particularly if reducing the risk for having a baby with NTD
acute aplastic crises when they run out of folate. A surgical history is too nebulous a concept for them). The only caveat is that before
of total or partial gastrectomy, anastomosis, fistula, or bowel resection initiating long-term folic acid supplements, the cobalamin status must
can reveal the potential for perturbation of physiologic absorption be normalized.
(loss of IF, bypassing or loss of absorptive surface, blind loop syn- Although antineoplastics and antiretroviral antinucleosides such as
dromes). Surreptitious or accidental inhalation of nitrous oxide in an azidothymidine lead to megaloblastosis, the temporal sequence and
occupational setting (dental or anesthesiology professionals) and investigations to rule out cobalamin or folate deficiency should easily
lead to a correct causal assignment.
deliberate inhalation of nitrous oxide (nanging) using cartridges
attached to whipped cream dispensers or visits to “houses of laughter,”
where nitrous oxide can be inhaled for a small fee can be revealed
only on direct questioning. Visits to tropical countries and the because of burning, and even odynophagia, which may compromise
development of intermittent episodic diarrhea may give a clue to further food intake (seen in cobalamin and folate deficiencies). The
tropical sprue; prolonged (over 3 years) chronic gastrointestinal patient may volunteer that glossitis is relieved by multivitamin inges-
symptoms followed by insidious development of neurologic problems tion. Weight loss in cobalamin deficiency is not as severe as in folate
predicts a combined (folate followed by cobalamin) deficiency (see deficiency arising from intrinsic gastrointestinal disease. Episodic or
box on Drugs That Perturb Folate Metabolism). chronic diarrhea with steatorrhea is commonly caused by tropical
Systemic review of symptoms may range from none (i.e., inciden- sprue, although it may be brought on by gluten-containing foods.
tal increased MCV or PMN hypersegmentation) to severe (i.e., Although these symptoms may be accompanied by abdominal pain,
unstable angina from severe anemia). With slow development of pain in the absence of diarrhea could be caused by tabetic crisis
anemia, the patient often does not develop cardiopulmonary symp- (vomiting, abdominal rigidity, absence of leukocytosis, or fever)
toms until there is a 50% reduction in hemoglobin concentration, accompanying spinothalamic involvement in cobalamin-deficient
which leads to dyspnea on exertion, palpitation, and generalized myelopathy.
fatigue or lethargy. Only when the hemoglobin concentration is The patient with pernicious anemia may have two or three
below 5 g/dL does the patient develop dyspnea at rest and angina on semisolid bowel movements per day; although this may be construed
modest exertion or even at rest. Congestive heart failure is heralded as a normal pattern, it may represent a change since the last time the
by pedal edema, nocturia, orthopnea, and tender hepatomegaly. patient was well. Constipation may be related to obstipation arising
Upper gastrointestinal symptoms with anorexia associated with from involvement of the Meissner plexus and the Auerbach plexus
intrinsic gastrointestinal disease or anemia with heart failure must be within the gastrointestinal tract. Similarly, incipient loss of bladder
distinguished from symptoms arising from glossitis. The latter may or bowel control caused by cobalamin myelopathy may present with
lead to inability to wear dentures, or tolerate hot drinks or spicy foods urgency or nocturia.