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Chapter 39 Megaloblastic Anemias 529

Summary of the Clinical Usefulness of Tests for Cobalamin and Folate Serum Folates Are Misleadingly Elevated in
Deficiencies TABLE Cobalamin (Vitamin B 12) Deficiency and/or Malaria
39.4 Which Are Both Common in Resource-Limited
Within the clinical context of hematologic or neurologic features that Settings * (From Antony, 2015 )
133
a,
suggest the diagnosis of cobalamin deficiency, if the cobalamin levels
are suggestive but not definitive, then the MMA and homocysteine Erythrocyte Serum
tests are an excellent gold standard test to confirm a clinical diagnosis. Serum Folates Folates Cobalamin
Patients with clinical cobalamin deficiency usually have MMA values
over 1000 nM and homocysteine values over 25 µM. The MMA and Pure folate Low Low Normal/
homocysteine test results are much more sensitive than cobalamin deficiency Low*
levels and progressively increase much earlier than the drop in cobala- Pure cobalamin Normal/High* ,b Low* ,b Low
min levels; one or both metabolites was increased in 99.8% of more deficiency
than 400 patients with proven cobalamin deficiency. 22
Based on the lower costs of serum cobalamin and folate compared Folate plus Normal* Low Low
with serum MMA and homocysteine levels, it is recommended (see cobalamin
Table 39.2) to first use the cheaper tests that can assist in the diagnosis deficiency
of cobalamin and folate deficiency. Clinicians should also restrict use Pure malaria Normal*/High* ,c High* ,d,e Normal
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of serum MMA and homocysteine to patients with borderline cobalamin
and folate levels; to patients with existing conditions associated with Malaria plus Normal* Normal*/High*/ Normal
difficulties in the interpretation of test results; to situations in which folate Low
cobalamin and folate levels are low, when a high MMA level is useful in deficiency
confirming cobalamin deficiency (rather than attributing the condition Malaria plus Normal*/High* ,c Normal*/High* ,e Low
to folate deficiency alone); and to patients with clearly low serum
levels but for whom there is an alternative explanation for the findings cobalamin
that caused an unusual serum cobalamin level to be obtained (e.g., deficiency
a diabetic or alcoholic with peripheral neuropathy, an alcoholic with Malaria plus Normal*/High* ,c Low/Normal* ,e,f Low
a high MCV and a low serum cobalamin without anemia). In these folate plus
cases, serum levels of metabolites can assist in the diagnosis of vitamin cobalamin
deficiency. deficiency
Diagnostic algorithms consistently stress the value of clinical data
to improve the pretest probability of serum cobalamin and serum *The asterisk indicates misleading values in the clinical settings shown on the
folate tests. Without detailed clinical information, the combined test left. The information presented in this table has been synthesized from several
22
results for serum cobalamin, folate, and metabolite (homocysteine and sources (see text and references).
a
Both cobalamin deficiency and clinical malaria and other hemolytic states can
MMA) are not sufficiently unambiguous to diagnose and distinguish complicate the diagnosis of folate deficiency using tests for serum- or
cobalamin deficiency from combined cobalamin-plus-folate deficiency. erythrocyte-folate concentration. 134
In combined cobalamin-plus-folate deficiency, both vitamins would b Cobalamin deficiency is accompanied by inability to use folates for one-carbon
be needed to restore baseline values, particularly of homocysteine. 22 metabolism, so folates leak out of erythroid precursors into serum.
c Release of the 30-fold excess folate from infected erythroid precursors,
reticulocytes, and mature erythrocytes during hemolysis raises serum folate
levels. (An as-yet-unknown quantity of folate is released into serum when
folate-rich hepatocytes are destroyed during the exoerythrocytic hepatic phase
to baseline. 127–132 Thus associated nutritional cobalamin deficiency of malaria.)
has the potential to consistently mask the coexistence of mild- to d Hemolysis induces a compensatory reticulocytosis; these reticulocytes are
82,83,127
moderate folate deficiency if the unwary clinician uses the serum richer in folate than mature erythrocytes.
e
Plasmodium falciparum can also synthesize folates in erythrocyte cultures in
folate level as a gold standard for diagnosing folate deficiency in this vitro 135 and raises erythrocyte folates in animal models with high levels of
clinical setting. Second, such patients (with combined nutritional parasitemia. 136
folate and cobalamin deficiency) often reside in malarious regions f Reticulocytopenia in severe Plasmodium falciparum malaria, caused by either
where there may be ongoing hemolysis from malaria per se as well combined cobalamin deficiency plus folate deficiency, which can trigger a
reticulocytopenic (megaloblastic) crisis, or cytokine-induced inhibition of
as intrinsic hemolysis from associated hemoglobinopathies that are hematopoiesis, will negate an expected rise in erythrocyte folates.
common in these regions (e.g., thalassemia, sickle cell disease, glucose- Reused with permission from Antony AC. Megaloblastic anemias. In: Goldman
6-phosphate dehydrogenase deficiency). In a patient with malaria L, Schafer A, eds. Cecil Medicine, 25th Edition. Philadelphia, 2015, Elsevier-
during hemolysis of Plasmodium falciparum infected erythroid precur- Saunders: Volume 1, Chapter 164, pp. 1104–1114.
sors, reticulocytes, and mature erythrocytes, there will be substantial
release of the 30-fold more folate-rich intraerythrocyte contents into
serum, thereby artificially raising the baseline serum folate level.
Moreover, red cells normally contain substantial amounts of various Other Tests
forms of folate, i.e., 5-methyltetrahydrofolate (monoglutamates) and
69
folate-polyglutamates of different glutamate chain lengths ; whereas The clinical use of low holo-transcobalamin II (holo-TCII) levels, to
clearance of such released folate monoglutamates would be hindered provide information on the extent of saturation of serum TCII as an
137
with associated cobalamin deficiency, 127–132 we also know that the early marker of cobalamin homeostasis or to diagnose cobalamin
released folate polyglutamates are also inefficiently transported back deficiency in lieu of serum cobalamin values, is still unclear. This test
34
into cells relative to monoglutamates, thereby also resulting in has not yet been sufficiently clinically validated 116,138 to define sensi-
poor clearance. In this clinical context, the current assays for serum tivity, specificity, and other clinical confounders that can alter the
folate (which are primarily designed to measure physiologic serum results.
5-methyltetrahydrofolate monoglutamate) may not consistently
discriminate among these forms of folates. The net result is that
a high serum folate could be reported in all such individuals with PATHOGENESIS OF COBALAMIN DEFICIENCY
malaria, even when the patient’s tissue folates are significantly depleted.
This predictable masking of tissue folate depletion argues against Nutritional Cobalamin Deficiency
the use of serum tests for folate deficiency in this clinical setting,
where assessing the intake of folate-rich foods in the diet is a better Vegetarian diets can be classified as lactovegetarian, ovovegetarian,
method to assess folate status. (See Masking of Nutritional Folate lacto-ovovegetarian, or vegan, respectively, if they include dairy
Deficiency by Associated Cobalamin Deficiency and/or Malaria and products, eggs, dairy products and eggs, or no animal products at
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Table 39.4.) all. However, all these vegetarian diets contain insufficient amounts