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Chapter 39 Megaloblastic Anemias 525

Clues for Distinguishing Cobalamin and Folate Deficiencies Etiopathophysiologic Classification of Cobalamin Deficiency
Although the megaloblastic manifestations of cobalamin and folate I. Nutritional cobalamin deficiency (insufficient cobalamin
deficiencies are clinically indistinguishable, certain distinct patterns intake)—vegetarians, poverty-imposed near-vegetarians,
in mode of presentation provide clues to the type and cause of defi- breastfed infants of mothers with pernicious anemia
ciency. In general, the cause of folate deficiency can be found in the II. Abnormal intragastric events (inadequate proteolysis of food
patient’s recent past (within 6 months), primarily discerned from the cobalamin)—atrophic gastritis, hypochlorhydria, proton pump
history and physical examination. In contrast, the cause of cobalamin inhibitors, H 2 blockers
deficiency can remain obscure until specific tests to define the cause III. Loss/atrophy of gastric oxyntic mucosa (deficient intrinsic factor
are carried out. In the past, by the time anemia was symptomatic, [IF] molecules)—total or partial gastrectomy, adult and juvenile
more than 80% of patients had neurologic manifestations, and in pernicious anemia, caustic destruction (lye)
50% this led to some incapacity. Perhaps as a result of widespread IV. Abnormal events in the small bowel lumen
use of multivitamins containing folic acid among patients and even A. Inadequate pancreatic protease (R factor–cobalamin not
in the food given livestock in the West, the hematologic expression degraded, cobalamin not transferred to IF)
of cobalamin deficiency is often substantially attenuated, leading to 1. Insufficient pancreatic protease—pancreatic insufficiency
pure neurologic presentations. Studies highlight the apparent inverse 2. Inactivation of pancreatic protease—Zollinger-Ellison
correlation between hematologic and neurologic presentations such syndrome
that in a third of patients with cobalamin deficiency, the earliest signs B. Usurping of luminal cobalamin (inadequate binding of
are often purely neurologic, and symptoms related to paresthesias and cobalamin to IF)
diminished proprioception may cause the patient to see the physician. 1. By bacteria-stasis syndromes (blind loops, pouches of
Based on the multiple potential causes (see box on Etiopathophysi- diverticulosis, strictures, fistulas, anastomosis), impaired
ologic Classification of Cobalamin Deficiency or box on Etiopathophysi- bowel motility (scleroderma), hypogammaglobulinemia
ologic Classification of Folate Deficiency), the warning that “what the 2. By Diphyllobothrium latum (fish tapeworm)
mind does not know, the eyes do not see” is a caveat that cannot be V. Disorders of ileal mucosa/IF-cobalamin receptors (IF-cobalamin
taken lightly; failure to recognize cobalamin deficiency as the cause of not bound to IF-cobalamin receptors [cubam receptors])
neurologic disease and treatment of cobalamin deficiency with folate, A. Diminished or absent cubam receptors—ileal bypass/
or misdiagnosis of megaloblastosis as erythroleukemia represent resection/fistula
significant extremes of deviation from the dictum primum non nocere. B. Abnormal mucosal architecture/function—tropical/nontropical
Areas of overlap in the symptoms of cobalamin or folate deficiency are sprue, Crohn disease, tuberculous ileitis, amyloidosis
related to megaloblastosis (i.e., common cardiopulmonary and some C. Cubam receptor defects—Imerslund-Gräsbeck syndrome
gastrointestinal manifestations). Although pure folate deficiency in the D. Drug-effects—metformin, cholestyramine, colchicine,
alcoholic with thiamine deficiency (i.e., Wernicke encephalopathy) neomycin
and peripheral neuropathy is almost indistinguishable from and may VI. Disorders of plasma cobalamin transport (transcobalamin
mimic cobalamin deficiency, the remaining neurologic manifestations [TCII]-cobalamin not delivered to TCII receptors)—congenital
are uniquely characteristic of cobalamin deficiency. Folate deficiency TCII deficiency, defective binding of TCII-cobalamin to TCII
in adults has not been unequivocally shown to give rise to neurologic receptors (rare)
findings. Coexistence of folate deficiency with neurologic disease VII. Metabolic disorders (cobalamin not used by cell)
should prompt investigations to rule out cobalamin and other nutrient A. Inborn enzyme errors—cblA to cblJ disorders (rare)
deficiencies arising from dietary insufficiency or malabsorption. B. Acquired disorders (cobalamin inactivated by irreversible
oxidation)—nitrous oxide

surface of the spinal cord (on cross section) a spongy appearance; later Etiopathophysiologic Classification of Folate Deficiency
there is secondary Wallerian degeneration of long tracts. Patchy I. Nutritional causes
demyelination usually begins in the dorsal columns in the thoracic A. Decreased dietary intake—poverty and famine,
segments of the spinal cord (Fig. 39.8) and then spreads contiguously institutionalized individuals (psychiatric/nursing homes)/
to involve corticospinal tracts. These lesions spread throughout the chronic debilitating disease, prolonged feeding of infants with
length of the cord and ultimately involve spinothalamic and spino- goat’s milk, special slimming diets or food fads (folate-rich
cerebellar tracts. There is also degeneration of the dorsal root ganglia, foods not consumed), cultural/ethnic cooking techniques
celiac ganglia, the Meissner plexus, and the Auerbach plexus. Although (food folate destroyed)
demyelination may also extend to the white matter of the brain, it is B. Decreased diet and increased requirements
unclear whether the peripheral neuropathy is caused by a distinct 1. Physiologic—pregnancy and lactation, prematurity,
hyperemesis gravidarum, infancy
lesion or results from spinal cord disease; the clinical manifestations 2. Pathologic
may be extremely varied. 15 a. Intrinsic hematologic diseases involving hemolysis with
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Vegetarians with cobalamin neuropathy in India had cognitive compensatory erythropoiesis, abnormal hematopoiesis,
impairment in nearly one-half of 36 patients; it was mostly global or bone marrow infiltration with malignant disease
with impaired recall and “serial sevens” (which are useful bedside tests b. Dermatologic disease—psoriasis
of attention); impaired naming was found among one-quarter of the II. Folate malabsorption
patients. Nearly one-half had abnormal evoked potential (using the A. With normal intestinal mucosa
oddball auditory paradigm), which revealed P300 latency that was 1. Drugs—sulfasalazine, pyrimethamine, proton pump
reversible in 3 months of cobalamin replacement; in one-fifth P300 inhibitors (via inhibition of proton-coupled folate
transporter [PCFT])
was unrecordable. Objective tests to document cobalamin neuropa- 2. Hereditary folate malabsorption (mutations in PCFTs) (rare)
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thy include nerve conduction studies and motor- and sensory- B. With mucosal abnormalities—tropical and nontropical sprue,
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evoked potentials, 103,104 visual pathway abnormalities, and magnetic regional enteritis
resonance imaging that shows T2 hyperintensity and atrophy. III. Defective folate transport across the choroid plexus into the
Among another cohort of patients with cobalamin neuropathy cerebrospinal fluid—cerebral folate deficiency (mutation or
from the United States, 65% had mild, about 25% had moderate, autoantibodies to folate receptors) (rare)
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and about 10% had severe neurologic deficits. Paresthesias or ataxia IV. Inadequate cellular utilization
were most commonly the first symptoms, and diminished vibratory A. Folate antagonists (methotrexate)
B. Hereditary enzyme deficiencies involving folate
sensation and proprioception in the lower extremities were the most V. Drugs (multiple effects on folate metabolism)—alcohol,
common objective early signs. Although multiple neurologic syn- sulfasalazine, triamterene, pyrimethamine, trimethoprim-
dromes were often seen in the same patient, the spectrum of objective sulfamethoxazole, diphenylhydantoin, barbiturates
signs could include loss of fine or coarse touch, decreased or increased