scholarly journals Clinical spectrum and diagnosis of cobalamin deficiency [see comments]

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 871-881 ◽  
Author(s):  
SP Stabler ◽  
RH Allen ◽  
DG Savage ◽  
J Lindenbaum
Keyword(s):  
Cell Volume ◽  
Peripheral Blood ◽  
Methylmalonic Acid ◽  
Peripheral Blood Smear ◽  
Normal Subjects ◽  
Lactic Dehydrogenase ◽  
Serum Levels ◽  
Cobalamin Deficiency ◽  
Mean Cell Volume ◽  
Total Homocysteine

To better estimate how frequently patients with low serum cobalamin (Cbl) levels in current clinical practice are truly deficient in Cbl and to determine the incidence of atypical or nonclassic presentations of Cbl deficiency, we prospectively studied 300 unselected consecutive patients with serum Cbl concentrations less than 200 pg/mL seen at two medical centers over a 2-year period. Baseline hematologic, neuropsychiatric, and biochemical measurements were obtained, followed by a course of parenteral Cbl therapy and reassessment. A response to Cbl therapy was defined as one or more of the following: (1) an increase in hematocrit of 0.05 or more; (2) a decrease in mean cell volume of 5 fL or more; (3) a clearing of hypersegmented neutrophilis and macroovalocytes from the peripheral blood smear; and (4) an unequivocal and prompt improvement of neuropsychiatric abnormalities. Of the 300 patients with serum Cbl levels less than 200 pg/mL, 86 had one or more responses to Cbl therapy and 59 had no response. In 155, insufficient data was available. In the Cbl-responsive patients, normal values were found for the following tests: hematocrit, 44%; mean cell volume less than or equal to 100 fL, 36%; white blood cell count, 84%; platelet count, 79%; serum lactic dehydrogenase, 43%; and serum bilirubin, 83%. Peripheral blood smears were nondiagnostic in 6% when reviewed by the investigators, but 33% as reported by routine laboratories. Serum Cbl levels in the 100 to 199 pg/mL range were present in 38%. Neuropsychiatric abnormalities were noted in 28%, often in the absence of anemia, macrocytosis, or both. Serum levels of methylmalonic acid and/or total homocysteine were elevated greater than 3 SDs above the mean for normal subjects in 94% of the Cbl-responsive patients. We conclude that Cbl deficiency should be considered and investigated in patients with unexplained hematologic or neuropsychiatric abnormalities of the kind seen in Cbl deficiency, even if anemia, an elevated mean cell volume, a marked depression of the serum Cbl, or other classic hematologic or biochemical abnormalities are lacking. Levels of serum methylmalonic acid and total homocysteine are useful as ancillary diagnostic tests in the diagnostis of Cbl deficiency.

scholarly journals Clinical spectrum and diagnosis of cobalamin deficiency [see comments]

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 871-881 ◽  
Author(s):  
SP Stabler ◽  
RH Allen ◽  
DG Savage ◽  
J Lindenbaum
Keyword(s):  
Cell Volume ◽  
Peripheral Blood ◽  
Methylmalonic Acid ◽  
Peripheral Blood Smear ◽  
Normal Subjects ◽  
Lactic Dehydrogenase ◽  
Serum Levels ◽  
Cobalamin Deficiency ◽  
Mean Cell Volume ◽  
Total Homocysteine

Abstract To better estimate how frequently patients with low serum cobalamin (Cbl) levels in current clinical practice are truly deficient in Cbl and to determine the incidence of atypical or nonclassic presentations of Cbl deficiency, we prospectively studied 300 unselected consecutive patients with serum Cbl concentrations less than 200 pg/mL seen at two medical centers over a 2-year period. Baseline hematologic, neuropsychiatric, and biochemical measurements were obtained, followed by a course of parenteral Cbl therapy and reassessment. A response to Cbl therapy was defined as one or more of the following: (1) an increase in hematocrit of 0.05 or more; (2) a decrease in mean cell volume of 5 fL or more; (3) a clearing of hypersegmented neutrophilis and macroovalocytes from the peripheral blood smear; and (4) an unequivocal and prompt improvement of neuropsychiatric abnormalities. Of the 300 patients with serum Cbl levels less than 200 pg/mL, 86 had one or more responses to Cbl therapy and 59 had no response. In 155, insufficient data was available. In the Cbl-responsive patients, normal values were found for the following tests: hematocrit, 44%; mean cell volume less than or equal to 100 fL, 36%; white blood cell count, 84%; platelet count, 79%; serum lactic dehydrogenase, 43%; and serum bilirubin, 83%. Peripheral blood smears were nondiagnostic in 6% when reviewed by the investigators, but 33% as reported by routine laboratories. Serum Cbl levels in the 100 to 199 pg/mL range were present in 38%. Neuropsychiatric abnormalities were noted in 28%, often in the absence of anemia, macrocytosis, or both. Serum levels of methylmalonic acid and/or total homocysteine were elevated greater than 3 SDs above the mean for normal subjects in 94% of the Cbl-responsive patients. We conclude that Cbl deficiency should be considered and investigated in patients with unexplained hematologic or neuropsychiatric abnormalities of the kind seen in Cbl deficiency, even if anemia, an elevated mean cell volume, a marked depression of the serum Cbl, or other classic hematologic or biochemical abnormalities are lacking. Levels of serum methylmalonic acid and total homocysteine are useful as ancillary diagnostic tests in the diagnostis of Cbl deficiency.

Progressive Imbalance and Visual Impairment in a Patient With Diabetes

2021 ◽  
pp. 248-250
Author(s):  
Neeraj Kumar
Keyword(s):  
Lower Limb ◽  
Peripheral Blood ◽  
Blood Smear ◽  
Serum Gastrin ◽  
Methylmalonic Acid ◽  
Intrinsic Factor ◽  
Peripheral Blood Smear ◽  
Vitamin B ◽  
Neurologic Manifestations ◽  
History Of

A 72-year-old man with hypothyroidism and type 2 diabetes sought care for a 3-year history of slowly progressive, ascending lower limb paresthesias and imbalance. Three months earlier, he noted subacute onset of finger numbness and substantial worsening of imbalance with infrequent falls. He also had a 1-year history of progressive visual decline that persisted despite cataract surgery. Additional symptoms included intermittent light-headedness and confusion. Laboratory evaluations showed a decreased hemoglobin value and an increased mean corpuscular volume. Macrocytic red blood cells were noted on a peripheral blood smear. Serum vitamin B12 level was less than 70 ng/L. Levels of plasma homocysteine and serum methylmalonic acid were markedly increased to 375 µmol/L and 143 nmol/L, respectively. Serum copper level was normal. Serum parietal cell antibodies were increased to 46 U, and intrinsic factor antibodies were absent. Serum gastrin was markedly increased. The clinical presentation in this patient suggested a myeloneuropathy. His vitamin B12 level was undetectable and accompanied by a macrocytic anemia and increased methylmalonic acid and homocysteine levels. Even though intrinsic factor antibodies were negative, the clinical picture was supportive of subacute combined degeneration in the setting of pernicious anemia. The patient was started on vitamin B12 replacement. At 6-month follow-up he had striking improvement in gait and vision. The light-headedness and confusion were no longer present. His examination was remarkable only for mild impairment, with tandem gait and a slightly positive Romberg sign. The lower limb reflexes were reduced. Impaired position perception at the toes persisted, but vibration perception in the lower limbs improved. Laboratory investigations showed normalization of the hemoglobin, vitamin B12, methylmalonic acid, and homocysteine levels. The serum gastrin level had improved but was still increased at 742 pg/mL. The best-characterized neurologic manifestations of vitamin B12 deficiency include myelopathy and myeloneuropathy. Autonomic neuropathy, optic neuropathy, and neuropsychiatric manifestations have also been reported. Neurologic manifestations may occur without evidence of the characteristic hematologic derangement, megaloblastic anemia. Macrocytosis or hypersegmented neutrophils on peripheral blood smear may be clues.

scholarly journals Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3404-3413 ◽  
Author(s):  
SP Stabler ◽  
J Lindenbaum ◽  
DG Savage ◽  
RH Allen
Keyword(s):  
Blood Donors ◽  
Pyridoxal Phosphate ◽  
Elevated Serum ◽  
Normal Subjects ◽  
Serum Levels ◽  
Folate Deficiency ◽  
Normal Range ◽  
Cystathionine Beta Synthase ◽  
Total Homocysteine ◽  
Chromatographic Mass

Homocysteine can be methylated to form methionine by the cobalamin- (Cbl) and folate-dependent enzyme, methionine synthase; serum levels of total homocysteine are elevated in greater than 95% of patients with either Cbl or folate deficiency. Homocysteine can also condense with serine to form cystathionine in a pyridoxal phosphate-dependent reaction catalyzed by cystathionine beta-synthase. Cystathionine is subsequently cleaved to cysteine and alpha-ketobutyrate by the pyridoxal phosphate-dependent enzyme gamma-cystathionase. To assess levels of cystathionine in Cbl and folate deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured cystathionine in the serum of normal subjects and patients with clinically confirmed deficiencies of these vitamins. The normal range for serum cystathionine was 65 to 301 nmol/L (median = 126 nmol/L) for 50 normal blood donors. In 30 patients with clinically confirmed Cbl deficiency, values for cystathionine ranged from 208 nmol/L to 2,920 nmol/L (median = 816 nmol/L) and 26 (87%) had levels above the normal range. In 20 patients with clinically confirmed folate deficiency, cystathionine concentrations ranged from 138 nmol/L to 4,150 nmol/L (median = 1,560 nmol/L) and 19 (95%) had values above the normal range. Five homozygotes for cystathionine beta-synthase deficiency had high values for serum-total homocysteine and low or low-normal values for serum cystathionine that ranged from 30 nmol/L to 114 nmol/L even though they were on treatment with pyridoxine and had partially responded. One patient with a defect in the synthesis of 5-CH3- tetrahydrofolate and five patients with defects in the synthesis of CH3- Cbl had high values for serum-total homocysteine and high values for cystathionine that ranged from 311 nmol/L to 1,500 nmol/L even though they were on treatment with folic acid and Cbl, respectively, and had partially responded. We conclude that levels of cystathionine are evaluated in the serum of most patients with Cbl and folate deficiency and that they are useful in the differential diagnosis of an elevated serum-total homocysteine level.

scholarly journals High frequency of vitamin B12 deficiency in a Brazilian population

2010 ◽  
Vol 13 (8) ◽  
pp. 1191-1197 ◽  
Author(s):  
JM Xavier ◽  
FF Costa ◽  
JM Annichino-Bizzacchi ◽  
STO Saad
Keyword(s):  
High Frequency ◽  
Methylmalonic Acid ◽  
Vitamin B12 Deficiency ◽  
Cobalamin Deficiency ◽  
Vitamin B ◽  
Mean Cell Volume ◽  
Adult Participants ◽  
B12 Deficiency ◽  
Older Subjects ◽  
Brazilian Populations

AbstractObjectiveThere are few studies regarding vitamin B12 deficiency in developing countries. In Brazil, a late diagnosis of vitamin B12 deficiency progressing to severe neurological damage is common. Thus, the aim of the present study was to verify the frequency of vitamin B12 deficiency in two Brazilian populations (elderly and adult participants) and to compare different methods of vitamin B12 deficiency detection.DesignFive hundred participants were recruited from health centres from south-east Brazil and were separated into two groups: 60 years old or more and 30–59 years old. Vitamin B12 and folate concentrations were measured using electrochemiluminescence immunoassay (ECI) and RIA. Methylmalonic acid (MMA) was measured by LC coupled to tandem MS. Full blood counts were acquired using standard methods.ResultsAll participants had normal blood count results and mean cell volume less than 99 fl; none of them presented folate deficiency according to the results, which were all greater than 3 ng/ml. Cobalamin levels less than 200 pmol/l were identified by one of the two or by both methods in 7·2 % of the participants aged 60 years or more and 6·4 % of the participants aged 30–59 years. MMA levels were higher in older subjects (P = 0·007) compared with younger subjects. A greater correlation of MMA v. RIA was observed than of MMA v. ECI (P = 0·0017 v. P = 0·014). MMA quantification estimated that cobalamin deficiency was present in more than 11 % of the subjects for both studied groups.ConclusionsThe study shows that vitamin B12 deficiency is frequent in Brazilian adults and suggests that RIA is more sensitive than ECl for measuring cobalamin levels.

Methylmalonic acid concentrations in serum of normal subjects: biological variability and effect of oral L-isoleucine loads before and after intramuscular administration of cobalamin

1990 ◽  
Vol 36 (7) ◽  
pp. 1295-1299 ◽  
Author(s):  
K Rasmussen ◽  
J Møller ◽  
K Ostergaard ◽  
M O Kristensen ◽  
J Jensen
Keyword(s):  
Methylmalonic Acid ◽  
Normal Subjects ◽  
Reference Interval ◽  
Cobalamin Deficiency ◽  
Intramuscular Administration ◽  
Significant Relation ◽  
Clinical Value ◽  
Individual Variations ◽  
Significant Difference ◽  
Before And After

Abstract The clinical value of measuring concentrations of methylmalonic acid in serum (S-MMA) as an aid in the diagnosis of cobalamin deficiency has recently aroused interest. In 58 healthy subjects, ages 40-68 years, we found a 0.95 reference interval of 0.05-0.37 mumol/L (mean 0.21, SD 0.094). In 33 of the subjects, who were studied further, day-to-day variation (SD) was 0.031 mumol/L. Intake of food had no effect. Weekly and three-monthly intra-individual variations were both 0.038 mumol/L. In all seven subjects with S-MMA greater than 0.30 mumol/L, the concentrations declined significantly after intramuscular administration of cobalamin. No significant difference was found between mean serum cobalamin concentrations in these seven and in the remaining subjects. We have also established the normal response of S-MMA to standardized oral loading of L-isoleucine: 100 mmol caused a significant average S-MMA increase of 0.072 mumol/L before cobalamin administration vs 0.013 mumol/L after cobalamin, without significant relation to initial S-MMA values. Our results provide a necessary background for interpretation of S-MMA measurements in clinical studies.

Studies on methylmalonic acid in humans. I. Concentrations in serum and urinary excretion in normal subjects after feeding and during fasting, and after loading with protein, fat, sugar, isoleucine, and valine.

1989 ◽  
Vol 35 (12) ◽  
pp. 2271-2276 ◽  
Author(s):  
K Rasmussen
Keyword(s):  
Urinary Excretion ◽  
Methylmalonic Acid ◽  
Vitamin B12 Deficiency ◽  
Normal Subjects ◽  
Cobalamin Deficiency ◽  
Absolute Amount ◽  
Ambulatory Patients ◽  
B12 Deficiency ◽  
First Time

Abstract Determination of methylmalonic acid (MMA) in serum or urine for evaluation of tissue cobalamin (vitamin B12) deficiency is becoming an important diagnostic procedure. Here I present the first investigation of dietary influence on concentrations of MMA in serum and urine. Everyday meals caused an increase in urinary excretion, whereas the concentration in serum was not increased significantly. It is difficult to prime the accumulation of MMA in normal subjects by stressing the metabolic pathway; after loading subjects with 100 mmol of isoleucine or valine, the absolute amount of MMA excreted increased by only about 3 mumol. Its concentration in serum tended to decrease and its urinary excretion declined after lack of protein intake for more than 15 h. Although a linear relationship was demonstrated, for the first time, between concentrations in serum and urinary excretion, my results indicate that patients with early evidence of cobalamin deficiency and normal subjects may best be differentiated by measurements in serum, especially in the case of nonfasting (i.e., ambulatory) patients.

Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3302-3308 ◽  
Author(s):  
Ralph Carmel ◽  
Stepan Melnyk ◽  
S. Jill James
Keyword(s):  
Pernicious Anemia ◽  
Metabolic Pathways ◽  
Healthy Subjects ◽  
Serum Levels ◽  
Metabolic Changes ◽  
Cobalamin Deficiency ◽  
Methionine Metabolism ◽  
Biochemical Basis ◽  
Neurologic Dysfunction ◽  
Total Homocysteine

AbstractThe unknown biochemical basis for neurologic dysfunction in cobalamin deficiency and the frequent divergence between neurologic and hematologic manifestations led us to study homocysteine metabolism in 22 patients with pernicious anemia. Serum levels of total homocysteine (tHcy), methionine, S-adenosylmethionine (AdoMet), cysteine, cysteinylglycine (cys-gly), and glutathione (GSH) were measured. Only levels of tHcy and cysteine were increased and only GSH was decreased in cobalamin deficiency as a whole, compared with 17 control subjects. AdoMet correlated only with methionine levels (P = .015) and cysteine only with cys-gly (P = .007) in healthy subjects, but in cobalamin-deficient patients AdoMet correlated instead with cysteine, cys-gly, and folate levels only (P = .008,P = .03, and P = .03, respectively). Significant differences appeared in clinically subgrouped cobalamin-deficient patients. The 11 patients with neurologic defects had higher mean levels of folate (27.9 versus 15.4 nM), AdoMet (117.2 versus 78.6 nM), cysteine (462 versus 325 μM), and cys-gly (85.0 versus 54.7 μM) than the 11 neurologically unaffected patients. Cobalamin therapy restored all metabolic changes to normal. The results indicate that changes in several metabolic pathways differ in patients with and without neurologic dysfunction. Cysteine levels were the most significant predictors of neurologic dysfunction, but it is unclear if they are direct or indirect indicators of neurotoxicity. The higher AdoMet levels in neurologically affected patients may result from inhibition of glycine N-methyltransferase by those patients' higher folate levels. The origin of the folate differences is unclear and possibly varied. Low AdoMet and GSH levels were independent predictors of anemia.

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