Cobalamin pseudodeficiency due to a transcobalamin I deficiency.

ABSTRACT

Cobalamin (vitamin [B.sub.12]) deficiency warrants appropriate evaluation because cobalamin is necessary in certain biochemical functions. R-binder deficiency, which causes low cobalamin levels, is a rare and benign pseudodeficiency. If not further evaluated by determining levels of methylmalonic acid and homocysteine, however, such a patient would be given unneeded treatment. We report a case in which a patient has an R-binder deficiency, specifically transcobalamin I deficiency, with a low vitamin [B.sub.12] level but no true vitamin [B.sub.12] deficiency.

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DETERMINATION OF TRUE VITAMIN [B.sub.12] (cobalamin) deficiency is important because cobalamin is required for biosynthesis of DNA, RNA, and protein. (1) As cobalamin-intrinsic factor complex is absorbed from the ileum into the plasma, 25% of cobalamin binds to transcobalamin (TC) II, which carries all of the initially absorbed cobalamin and is rapidly cleared from the blood. Because TCII is necessary for cobalamin transportation to tissues, congenital deficiency of TCII causes severe hematologic sequelae, typically leading to premature death.

Conversely, approximately 75% of plasma cobalamin binds to TCI, (2) a nonspecific R-binder protein similar to gastric R-binder protein ("R" denotes rapid electrophoretic mobility, distinguishable from intrinsic factor). Analogues of cobalamin, when bound to TCI, represent one third of the serum vitamin [B.sub.12] level. (3) This complex is slowly cleared within 9 to 12 days. (4) An R-binder deficiency, which is autosomal recessive or X-linked, (5) is rare and benign. R-binder deficiency should be considered in the differential diagnosis of a low cobalamin level, however, before an asymptomatic, nonanemic patient is labeled cobalamin-deficient and given unnecessary treatment. We report the case of a patient with an extremely low vitamin [B.sub.12] level because of an apparent TCI deficiency, without true vitamin [B.sub.12] deficiency.

CASE REPORT

A 48-year-old researcher with a history of headaches and cervical spine osteoarthritis presented before a trip to Antarctica for a history and physical examination that was required by her employer. She had no history of gastrointestinal disease or surgeries, and she was not a vegetarian. She took baclofen as needed for muscle spasms of the jaw. She reported consuming 1 to 2 alcoholic beverages per day but she denied using tobacco or illicit drugs. There was no family history of vitamin [B.sub.12] deficiency or gastrointestinal disease, except for peptic ulcer disease in her father. Review of systems revealed no abnormalities. Findings on physical examination were normal, with the exception of limited range of motion of the neck when attempting complete flexion and extreme rotation to the right.

The complete blood count revealed a white blood cell count of 4.2 x [10.sup.3]/[micro]L with a normal differential count. The hemoglobin and hematocrit levels were 12.8 g/dL and 38.5%, respectively, with a mean corpuscular volume (MCV) of 99.1 fL, mean corpuscular hemoglobin (MCH) level of 32.9 pg, and mean corpuscular hemoglobin concentration (MCHC) of 33.2 g/dL. The red blood cell count was 3.89 x [10.sup.6]/[micro]L, red blood cell distribution width index (RDW) 12.8%, and platelet count 176 x [10.sup.3]/[micro]L Results of other required laboratory studies were normal.

Because of the mildly elevated MCV and MGH and the anticipated extended stay in Antarctica, folate and vitamin [B.sub.12] levels were measured. The folate level was normal at 9.4 ng/mL. However, the vitamin [B.sub.12] level was <26 pg/mL (normal, 200-1,000 pg/mL). To rule out laboratory error, a second specimen was tested, and the result was identical. The vitamin [B.sub.12] level of the second specimen, sent to another laboratory, was 139 pg/mL. Schilling test demonstrated 17.7% excretion in a 24-hour period (normal, 9% to 100%). Methylmalonic acid and homocysteine levels were 0.19 [micro]mol/L (normal, <0.4 [micro]mol/L) and 6 [micro]mol/L (normal, <13 [micro]mol/L), respectively. Unsaturated vitamin [B.sub.12]-binding capacity was normal at 1,122 ng/mL, intrinsic-factor-blocking antibody was negative, and parietal cell antibodies were normal at < 1:20.

The vitamin [B.sub.12] level after the Schilling test was 277 pg/mL. Before her trip to Antarctica, the patient was empirically treated with a single intramuscular dose of 1,000 [micro]g of vitamin [B.sub.12]. At follow-up 6 months later, the vitamin [B.sub.12] level was 135 pg/mL. Hemoglobin level was 13.7 g/dL, hematocrit value was 40.1% MCV was 94.8 fL, MCH was 32.4 pg, and MCHC was 34.2 g/dL. The patient reported some paresthesias, but no neuropathy could be documented.

Because of a suspected transport-carrier deficiency, a consultant recommended that the patient receive weekly intramuscular injections of 1,000 [micro]g of vitamin [B.sub.12] for 6 weeks. Her vitamin [B.sub.12] levels were then checked weekly in attempt to establish a decay curve. One week after her last injection, her vitamin [B.sub.12] level was 924 pg/mL, followed by subsequent weekly vitamin [B.sub.12] levels of 347 pg/mL, 271 pg/mL, 259 pg/mL, and 214 pg/mL. During this time, she was taking a daily multivitamin containing 600 [micro]g of vitamin [B.sub.12]; however, the multivitamin did not sustain her vitamin [B.sub.12] level. In the following weeks, her vitamin [B.sub.12] level decreased further; measurements over the subsequent weeks were 235 pg/mL, 250 pg/mL, 202 pg/mL, 149 pg/mL, 185 pg/mL, and 155 pg/mL. The hemoglobin, hematocrit, MCV, and MCH levels remained stable, the paresthesias resolved, and findings on physical examination were stable. In addition, methylmalonic acid level and homocysteine level remained normal.

DISCUSSION

Cobalamin is necessary for 2 important biochemical functions. First, methylcobalamin is a cofactor in the transformation of homocysteine to methionine. Insufficient methylcobalamin leads to decreased methionine and increased homocysteine levels. Decreased methionine, which serves as a methyl donor in the folate metabolic pathway, interferes with folate metabolism. Folate is intergrally involved in purine synthesis, which is necessary for the synthesis of nucleic acids. The subsequent defects of DNA synthesis cause megaloblastic changes in the formation of red blood cells. Second, adenosylcobalamin is required for the conversion of methylmalonyl coenzyme A (methylmalonic acid) to succinyl coenzyme A. Insufficient adenosylcobalamin causes increased methylmalonic acid levels and, consequently, incorporation of nonphysiologic fatty acids into neuronal lipids. (6) Because of these functions, cobalamin deficiency may cause hematologic and neurologic manifestations. Hematologic problems include megaloblastic anemia with associated symptoms such as weakness, light-headedness, and palpitations. Neurologic manifestations, which may occur even before anemia develops, (6) are caused by demyelination and axonal degeneration. Numbness and paresthesias of the extremities may be the earliest symptoms. In addition, diminished vibratory sensation, memory deficit, ataxia, personality changes, and psychosis may develop. Also, gastrointestinal problems, which are due to the effect of cobalamin deficiency on rapidly-proliferating gastrointestinal epithelium, include a sore, beefy, red tongue and anorexia.

Further evaluation of patients with low vitamin [B.sub.12] levels should be considered, particularly when the patient is asymptomatic and there is no evidence of megaloblastic anemia. Swain (7) reported that vitamin [B.sub.12] levels of 150 to 350 pg/mL require confirmation of deficiency, while levels <150 pg/mL probably do not need to be confirmed. True cobalamin deficiency is confirmed if methylmalonic acid level and homocysteine level are elevated. The minimum daily requirement of cobalamin is 2.5 [micro]g, and it has a high storage potential. (6) Therefore, it may take 3 to 6 years for cobalamin deficiency to develop after absorption has ceased. (7) In the elderly, cobalamin levels decrease 18 to 28 pg/mL per year because of a gradual decrease in gastric acidity with age. (7)

Our patient was asymptomatic with no pertinent physical findings, but the MCV and MCH values were mildly increased with a normal hemoglobin level. The vitamin [B.sub.12] levels were extremely low, and subsequent testing revealed normal methylmalonic acid level, homocysteine level, and Schilling test results. After intramuscular loading with vitamin [B.sub.12] the serum vitamin [B.sub.12] level showed a transient increase because of enhanced ability of TCII to carry vitamin [B.sub.12] for a longer time, (8) followed by a rapid decline in vitamin [B.sub.12] level. Typically, only 10% of TCII's binding sites are occupied, and TCII, therefore, represents most of the unsaturated cobalamin-binding capacity in plasma. (9.10) In this case, the vitamin [B.sub.12] had initially saturated the TCII binding sites, and then binding decreased because of a TCI deficiency. Normal methylmalonic acid and homocysteine levels and absence of neurologic, hematologic, and gastrointestinal effects confirmed the TCI deficiency in this case. Cautious observation and monitoring of methylmalonic acid and homocysteine levels, instead of vitamin [B.sub.12] levels, may be considered for a patient with a documented TCI deficiency.

CONCLUSION

Low and borderline levels of vitamin [B.sub.12] should be confirmed with additional testing, specifically determination of me thylmalonic acid and homocysteine levels, if the patient is asymptomatic and has no anemia. The excessive and expensive evaluation for this patient is not necessary for each patient. If this patient's extremely low vitamin [B.sub.12] level had not been confirmed, however, she would have been empirically, unnecessarily treated with vitamin [B.sub.12]. Because of normal methylmalonic acid and homocysteine levels and lack of manifestations of vitamin [B.sub.12] deficiency, the patient diagnosed with benign TCI deficiency, and, therefore, no treatment was required.

References

(1.) Antony AC: Megaloblastic anemias. Hematology: Basic Principles and Practice. Hoffman R, Benz EJ, Shattil SJ, et al (eds). Philadelphia, Churchill-Livingstone, 3rd Ed, 2000, pp 446-485

(2.) Nexo E: Characterization of the cobalamins attached to transcobalamin I and transcobalamin II in human plasma. Scand J Haematol 1977; 18:358-360

(3.) Herzlich BC, Herbert V: Cobalamin-specific R binder in pernicious anemia gastric juice: production by digestive enzyme action on saliva R binder. Am J Gastroenterol 1985; 80:841-852

(4.) Burger RL, Schneider RJ, Mehlman CS, et al: Human plasma R-type vitamin [B.sub.12]-binding proteins. II. The role of transcobalamin I, transcobalamin III, and the normal granulocyte vitamin [B.sub.12]-binding protein in the plasma transport of vitamin [B.sub.12]. J Biol Chem 1975; 250:7707-7713

(5.) Yang SY, Coleman PS, Dupont B: The biochemical and genetic basis for the microheterogeneity of human R-type vitamin [B.sub.12] binding proteins. Blood 1982; 59:747-755

(6.) Babior BM, Bunn HF: Megaloblastic anemias. Harrison's Principles of Internal Medicine. Fauci AS, Braunwald E, Isselbacher KJ, et al (eds). New York, McGraw-Hill, 14th Ed, 1998, pp 653-659

(7.) Swain R: An update of vitamin [B.sub.12] metabolism and deficiency states. J Fam Pract 1995; 411:595-600

(8.) Carmel R: R-binder deficiency. a clinically benign cause of cobalamin pseudodeficiency. JAMA 1983; 250:1886-1890

(9.) Lee GR, Herbert V: Nutritional factors in the production and function of erythrocytes. Wintrobe's Clinical Hematology. Lee GR, Foerster J, Lukens J, et al (eds). Baltimore, Williams & Wilkins Co, 10th Ed, 1999, pp 228-266

(10.) Babior BM: Metabolic aspects of folic acid and cobalamin. Williams Hematology. Beutler E, Lichtman MA, Coller BS, et al (eds). New York, McGraw-Hill, 6th Ed, 2001, pp 305-318

RELATED ARTICLE: KEY POINTS

* Vitamin [B.sub.12] (cobalamin) is required for DNA, RNA, and protein biosynthesis; therefore, patients should be carefully monitored for cobalamin deficiency.

* Patients who are otherwise asymptomatic and without anemia, but who exhibit low or borderline levels of cobalamin, should have additional tests, specifically determination of methylmalonic acid and homocysteine levels, to confirm true vitamin [B.sub.12] deficiency.

* R-binder deficiency is rare and benign but should be considered in the differential diagnosis for asymptomatic, nonanemic patients.

From the Department of Family Medicine, College of Community Health Sciences, University of Alabama, Tuscaloosa.

Reprint requests to Jerry T. McKnight, MD, 700 University Blvd E, Tuscaloosa, AL 35401.