Page 623 - Hematology_ Basic Principles and Practice ( PDFDrive )

532 Part V Red Blood Cells

continued low pH of the luminal contents reaching the ileum may Disorders of Plasma Cobalamin Transport
also perturb interaction of the IF-cobalamin complex with
IF-cobalamin receptors (which requires a pH above 5.4). Polymorphism or absence of TCI can be associated with low
cobalamin levels, but the MMA and homocysteine levels are normal.
By contrast, either deficiency or defective TCII can present with
Usurpation of Luminal Cobalamin megaloblastic anemia in infancy; this can be associated with normal
cobalamin levels (because TCI, which binds over 75% of serum
The near-sterile condition of the small bowel is maintained by a cobalamin is normal). However, there will be metabolic evidence
combination of the mechanical cleansing action of peristalsis and the of cobalamin deficiency that can be reversed by daily or biweekly
chemical action of gastric acid. Disorders conducive to relative stasis, injections of 1 mg of cobalamin, which ensures passive cobalamin
impaired motility, and hypogammaglobulinemia are predisposing delivery into cells. Mutations in the gene for the TCII receptor
factors that favor colonization by bacteria. Many of these bacteria can (CD320) have also been identified. 174
take up free cobalamin, but not IF-bound cobalamin. However, if
colonization extends proximally to the locus at which IF and cobala- Disorders of Intracellular Cobalamin Use
min interact, significant cobalamin may be usurped before it can bind
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to IF. This cobalamin malabsorption can be corrected to some
extent by a 7- to 10-day course of antibiotic therapy. Congenital Metabolic Defects of Cobalamin
Approximately 3% of individuals infested with the fish tapeworm Metabolism: Cobalamin Mutants A to J
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Diphyllobothrium latum, which avidly usurps cobalamin for growth
can develop frank cobalamin deficiency. Humans become infected Given the multitude of chaperones or transporters involved in escort-
when they eat partially cooked or raw fish containing plerocercoids, ing cobalamin intracellularly to their destination to function as
which develop into adult worms in the jejunum in about 6 weeks, coenzymes for methionine synthase and methylmalonyl-CoA mutase,
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growing to a length of 10 m, with up to 4000 proglottids ; when it is not difficult to envision that there would invariably be inborn
these worms lay eggs, the life cycle is repeated. After ova have been errors of cobalamin metabolism where one of these escorts or trans-
identified in the stools, expulsion of the worms by praziquantel (10 porters is missing. The combination of megaloblastic anemia with
to 20 mg/kg as a single dose taken orally) and cobalamin replenish- increased levels of homocysteine or MMA, or both, in serum and
ment is curative. urine despite normal cobalamin and folate levels should suggest an
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inborn error of cobalamin metabolism. The inherited defects of
Disorders of Ileal Intrinsic Factor–Cobalamin cobalamin use (see Fig. 39.3) are heterogeneous and are empirically
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Receptors or Mucosa defined as cobalamin mutations A to J (cblA to cblJ).
These infants must be differentiated from those with nutritional
cobalamin deficiency who could have similar clinical features. Patients
Absence of Intrinsic Factor–Cobalamin Receptors suspected of having an inborn error of metabolism should be evalu-
ated by specialized laboratories, such as the McGill University labora-
The distal ileum has the greatest density of IF-cobalamin receptors. tory of Prof David Rosenblatt—a premier diagnostic center. 176
Disease or removal of only 1 to 2 feet of terminal ileum by resection
or bypass reduces ileal IF-cobalamin receptor numbers for interaction
with IF-cobalamin, resulting in cobalamin malabsorption. 15,22 Functional Cobalamin Deficiency After Nitrous
Oxide Exposure
Defective Intrinsic Factor–Cobalamin Receptors or Nitrous oxide (N 2 O) inactivates coenzyme forms of cobalamin by
Post-Intrinsic Factor–Cobalamin Receptor Defects oxidizing the fully reduced cob(I)alamin to cob(III)alamin; this
results in a state of functional intracellular cobalamin deficiency. This
Imerslund-Gräsbeck syndrome is a term used collectively for a heteroge- syndrome was first identified in patients with tetanus given nitrous
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neous group of congenital (autosomal recessive) disorders in children oxide for up to 6 days. Subsequently, persons exposed to nitrous
arising from biallelic mutations (in 80% of cases) involving either the oxide for open heart surgery and through chronic (surreptitious,
cubilin (CUBN) or amnionless (AMN) genes that constitute the func- accidental, or occupational) exposure have been recognized as being
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tional IF-cobalamin receptor (i.e., cubam). This results in selective at high risk for developing megaloblastosis and cobalamin-deficient
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cobalamin malabsorption. Children present between 3 and 10 years of neuromyelopathy. The slang word for recreational use of nitrous
age with megaloblastic anemia and neurologic presentations with low oxide is nanging; capsules that are used for making whipped cream
serum cobalamin levels associated with mild, persistent, benign pro- are a cheap and easy source of nitrous oxide in the community.
teinuria (in 90% of cases). Because cubam also participates in the renal Megaloblastosis develops within 24 hours and lasts less than 1 week
tubular absorption of albumin, this is the basis for proteinuria found after a single exposure. The neurologic syndrome is usually seen with
in Imerslund-Gräsbeck syndrome. Diagnosis requires analysis of chronic intermittent exposure. Severe neurologic deficits have been
mutational status of gastric IF, CUBN, and AMN genes. 164,171 reported after prolonged intraoperative exposure to nitrous oxide in
patients with unsuspected cobalamin deficiency. 22
Drug-Induced Defects
Subclinical Cobalamin Deficiency
Long-term use of H 2 antagonists and/or proton pump inhibitors may
interfere with the handover of food-cobalamin to IF, especially in The entity of subclinical cobalamin deficiency is defined when there
those with preexisting borderline cobalamin stores. Long-term treat- is biochemical evidence for cobalamin deficiency, reflected by a low
ment with metformin can interfere with IF-cobalamin binding to cobalamin value (and increased MMA and homocysteine) but
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ileal cubam receptors and progressively increases the risk for without overt clinical manifestations. Although dependent on the
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cobalamin deficiency over time. Therefore, screening for cobalamin population studied, the frequency of (silent) subclinical cobalamin
deficiency and additional confirmation of metabolic evidence of deficiency in the United States is suspected to be 10 times higher
cobalamin deficiency (elevated MMA) can be reason to trigger than classic (overt) cobalamin deficiency that is found in 1% to 2%
replacement therapy with cobalamin. Other drugs (e.g., cholestyr- of the population. Nevertheless, the issue of subclinical cobalamin
amine, colchicine, neomycin) probably also impair transepithelial deficiency has been a vexing problem and a semantic dilemma. Many
transport of cobalamin. 15 elderly persons may have various symptoms consistent with aging