Page 628 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 39 Megaloblastic Anemias 537

248
glutamine-rich protein found in wheat, barley, rye, and other grains) clefts, more information is required to confidently assign causality
15
and a related substance, gliadin. The intestinal lesion (i.e., villous with these conditions.
atrophy with hypertrophied crypts and lymphocytic and plasma cell
infiltrate of the lamina propria) is more florid than that seen in
tropical sprue but occurs to a greater extent in the proximal small Polymorphisms and Inborn Errors of Folate Metabolism
intestine with relative ileal sparing; as a result, cobalamin malabsorp-
tion is less common. The consequences of malabsorption are otherwise Several genetic polymorphisms involve genes that participate in one-
the same. Patients present between the ages of 30 and 50 years with carbon metabolism. These genetic polymorphisms merely reflect
intermittent or persistent diarrhea (abrupt in 20%), weight loss, variants that are more frequent than the expected 1% allelic variation
abdominal distention with discomfort, glossitis, and megaloblastic that could be found in any population. Whereas some polymorphisms
anemia. Iron deficiency may also be prominent. Diagnosis is estab- impinge on normal physiology of folate and explain abnormal labora-
lished by documenting the presence of sensitive and specific serum tory levels of folate, cobalamin, or metabolites, others may redistribute
antiendomysial antibodies IgA type or anti–tissue transglutaminase folate toward thymidylate synthesis and be “DNA protective.” Pre-
antibodies, malabsorption, and jejunal biopsy. The megaloblastosis dictably, two or more polymorphisms in the same individual (a
responds well to folate therapy. 15 combined heterozygote) can be associated with an increased risk for
249
certain congenital diseases in offspring such as Down syndrome or
Regional Enteritis and Other Small other birth defects. However, because disease association is not
equivalent to disease causation, much more study is required to
Intestinal Disorders strengthen such relationships. A listing of the spectrum of these
250
polymorphisms can be found in specialized texts. Excellent reviews
The distal small intestine is involved in 80% of individuals with of inborn errors of folate metabolism are available. 165
Crohn disease, so extensive ileal involvement or ileal bypass can result
in malabsorption of cobalamin. Moreover, a poor diet or extensive
237
mucosal disease can increase requirements for folate whereas sul- MEGALOBLASTIC ANEMIA NOT CAUSED BY FOLATE OR
fasalazine can inhibit the absorption of folates via interference with COBALAMIN DEFICIENCY
PCFT function. 238
Several chemotherapeutic agents (e.g., antimetabolites, alkylating
agents) kill malignant cells primarily by interfering with DNA syn-
Cerebral Folate Deficiency thesis; megaloblastosis is therefore an expected side effect. (See box
on Miscellaneous Megaloblastic Anemias Not Caused by Cobalamin
Cerebral folate deficiency is a broad syndrome whereby several dis- or Folate Deficiency.)
eases can be accompanied by neurologic findings and low CSF folates
but with normal serum folate levels. 239,240 The GPI-anchored folate
receptor-α on the basolateral surface of choroid plexus cells is critical
to the transport of folate from the blood across the CSF into the Miscellaneous Megaloblastic Anemias Not Caused by Cobalamin or
brain. Predictably, therefore, mutation of folate receptor-α, or the Folate Deficiency
generation of antibodies to folate binding proteins found in cow’s I. Congenital disorders of deoxyribonucleic acid (DNA) synthesis
milk that cross react with choroid plexus folate receptor-α, can (rare)
perturb folate transport into the brain and lead to cerebral folate A. Orotic aciduria
deficiency. Indeed, among a group of 14 children with extremely low B. Lesch-Nyhan syndrome
(≤5 nmol/l) levels of 5-methyl-THF in the CSF, mutations in folate C. Congenital dyserythropoietic anemia
receptor-α, which led to a failure in expression of functional folate II. Acquired disorders of DNA synthesis
receptors, were identified in 10 of them (71%). 46,47 These patients A. Deficiency—thiamine-responsive megaloblastic anemia
presented at <3 years with symptoms of developmental delay, move- (thiamine transporter 1 mutation)
ment disturbances, ataxia, myoclonic seizures, infantile spasms, and B. Erythroleukemia, refractory sideroblastic anemias
leukodystrophy that was reversed by folinic acid. 46,241 The finding of C. Drugs—all antineoplastic drugs that inhibit DNA synthesis
(including antinucleosides used against human
two older patients (aged 13 and 15 years) with severe polyneuropathy immunodeficiency virus [HIV] and other viruses), alcohol
raises the possibility of other patients who may also have such defects
that can present in young adulthood with unexplained neurologic
disorders.
Acquired infantile-onset cerebral folate deficiency, which is associ-
ated with autoantibodies to folate receptor-α, 242,243 usually develops CLINICAL PRESENTATIONS AND EVALUATION FOR
4 to 6 months after birth and is characterized by agitation, insomnia, FOLATE AND COBALAMIN DEFICIENCY
delayed development with deceleration of head growth, psychomotor
retardation, cerebellar ataxia, pyramidal tract signs in the legs, dyski- Clinical presentations and evaluations for folate and cobalamin
nesias (such as choreoathetosis and ballismus), a severe polyneuropa- deficiency are shown in Table 39.6.
thy, and in some cases, seizures. Untreated, central visual disturbances
can become manifest and lead to optic atrophy and blindness by the
third year. The folate receptor autoantibody titer decreases with The Interview
restriction of bovine milk intake but promptly increases upon rechal-
lenge. Cerebral folate deficiency responds to high doses of folinic acid The patient’s general demeanor and answers to questions may reveal
and a cow’s milk–free diet. 244 a blunted affect with evidence of depression, irritability, forgetfulness,
Among 93 patients with autism spectrum disorders, 75% had and sleep deprivation (common in pure folate deficiency). Alterna-
autoantibodies to folate receptor in the serum; treatment with high tively, cobalamin deficiency may present with paranoid ideation,
245
dose leucovorin led to improvement in one-third of those treated. dementia, cognitive dysfunction, delusions, or lack of energy mani-
Of added significance, an adult-onset presentation of cerebral folate fested by slowed responses. Hallucinations or even obtundation may
deficiency with progressive memory loss and myoclonus caused by preclude obtaining an adequate history. The family may indicate the
perturbation of folate receptor function by autoantibodies has also progressive evolution of a marked personality change and may be able
246
been described. Finally, although antifolate receptor antibodies are to help trace the evolution of symptoms and deviations from the
76
247
also associated with neural tube defects, infertility, and orofacial time when the patient was last well. Intermittent therapy with