Common causes, other than cobalamin deficiency, for abnormal cobalamin, methylmalonic acid, and homocysteine levels.
| Cobalamin . | Methylmalonic Acid . | Homocysteine . |
|---|---|---|
| Abbreviations: MMA, methylmalonic acid; MTHFR, methylenetetrahydrofolate reductase. | ||
| The causes are listed in roughly descending frequency. The list is not exhaustive but includes the most common and important causes. | ||
| † The test abnormality particular to the entity can be severe sometimes; cobalamin level can be < 100 ng/L in some entities, whereas MMA can be > 1000 nmol/L in others, and homocysteine can be > 50 μmol/L in still others. | ||
| ‡ Volume contraction has often been given as the explanation for some elevated MMA results that are otherwise hard to explain (e.g., in occasional patients with folate deficiency). Although volume contraction is a very plausible mechanism, evidence to support the explanation has rarely been provided. | ||
| § Homocysteine levels improve very often after folate supplementation even when evidence for folate deficiency is not found. The very common improvement may have many explanations (e.g., pharmacologic effect of folate in mild genetic conditions; subclinical folate deficiency). | ||
| * Some of these may be surrogates for other influences. | ||
| ¶ For all 3 tests, abnormal results may be obtained because of the use of a possibly improper reference range by the laboratory or because of assay error. The reference interval controversy about cobalamin is discussed in some detail in the text, but issues exist for the other assays also. (This category is listed last in each column because the frequency of the problem is difficult to compare with other causes.) | ||
| Idiopathic | Renal insufficiency | Incorrect sample or processing |
| Pregnancy† | Volume contraction‡ | Renal insufficiency/ ↑ creatinine |
| Mild transcobalamin I deficiency | Infancy | Folate responsiveness§ |
| Miscellaneous disease associations (e.g., HIV infection, myeloma) | ? Mild MMA-related enzyme defects | Age, sex, life style factors* |
| ? Bacterial contamination of the gut | Enzyme polymorphisms (e.g., MTHFR) | |
| Folate deficiency | Severe enzyme defects (e.g., mutase deficiency)† | Alcohol abuse (hard liquor)† |
| Miscellaneous drugs (e.g., anticonvulsants, oral contraceptives) | [Laboratory error¶] | Folate deficiency† |
| Vitamin B6 deficiency | ||
| Hypothyroidism | ||
| Severe transcobalamin I deficiency† | Various drugs (e.g., isoniazid) | |
| [Laboratory error¶] | Various disease associations (e.g., renal transplant, leukemia) | |
| Inborn errors of homocysteine metabolism† | ||
| [Laboratory error¶] | ||
| Cobalamin . | Methylmalonic Acid . | Homocysteine . |
|---|---|---|
| Abbreviations: MMA, methylmalonic acid; MTHFR, methylenetetrahydrofolate reductase. | ||
| The causes are listed in roughly descending frequency. The list is not exhaustive but includes the most common and important causes. | ||
| † The test abnormality particular to the entity can be severe sometimes; cobalamin level can be < 100 ng/L in some entities, whereas MMA can be > 1000 nmol/L in others, and homocysteine can be > 50 μmol/L in still others. | ||
| ‡ Volume contraction has often been given as the explanation for some elevated MMA results that are otherwise hard to explain (e.g., in occasional patients with folate deficiency). Although volume contraction is a very plausible mechanism, evidence to support the explanation has rarely been provided. | ||
| § Homocysteine levels improve very often after folate supplementation even when evidence for folate deficiency is not found. The very common improvement may have many explanations (e.g., pharmacologic effect of folate in mild genetic conditions; subclinical folate deficiency). | ||
| * Some of these may be surrogates for other influences. | ||
| ¶ For all 3 tests, abnormal results may be obtained because of the use of a possibly improper reference range by the laboratory or because of assay error. The reference interval controversy about cobalamin is discussed in some detail in the text, but issues exist for the other assays also. (This category is listed last in each column because the frequency of the problem is difficult to compare with other causes.) | ||
| Idiopathic | Renal insufficiency | Incorrect sample or processing |
| Pregnancy† | Volume contraction‡ | Renal insufficiency/ ↑ creatinine |
| Mild transcobalamin I deficiency | Infancy | Folate responsiveness§ |
| Miscellaneous disease associations (e.g., HIV infection, myeloma) | ? Mild MMA-related enzyme defects | Age, sex, life style factors* |
| ? Bacterial contamination of the gut | Enzyme polymorphisms (e.g., MTHFR) | |
| Folate deficiency | Severe enzyme defects (e.g., mutase deficiency)† | Alcohol abuse (hard liquor)† |
| Miscellaneous drugs (e.g., anticonvulsants, oral contraceptives) | [Laboratory error¶] | Folate deficiency† |
| Vitamin B6 deficiency | ||
| Hypothyroidism | ||
| Severe transcobalamin I deficiency† | Various drugs (e.g., isoniazid) | |
| [Laboratory error¶] | Various disease associations (e.g., renal transplant, leukemia) | |
| Inborn errors of homocysteine metabolism† | ||
| [Laboratory error¶] | ||