Table 1. Comparison of clinical and... | American Society of Hematology

Table 1.

Comparison of clinical and subclinical cobalamin deficiency.

	“Clinical” Deficiency	“Subclinical” Deficiency
Abbreviations: MMA, serum methylmalonic acid; tHcy, plasma total homocysteine.
Cobalamin values are shown in ng/L values, which are used by most clinical laboratories, and pmol/L, which are used in many publications (conversion factor: ng cobalamin × 0.738 = pmol). Methylmalonic acid values are given in nmol/L and μmol/L values, either of which are used by different clinical laboratories and publications. Reference intervals vary widely among laboratories and methods for all tests. The values shown here are based on the following, fairly common cutpoints for abnormality: serum cobalamin < 200 ng/L; serum MMA > 280 nmol/L; plasma tHcy > 15 μmol/L in men, and > 13 in women.
Clinical signs and symptoms	Present (by definition) but: - not every manifestation (e.g., hematologic, neurologic) appears in every patient - the manifestations may be mild.	Absent (by definition) but- some patients may have electrophysiologic neurologic changes.
Cobalamin levels	Low in 97% of cases (< 200 ng/L; < 148 pmol/L) and often very low (< 100 ng/L; < 74 pmol/L).	Usually low, but can be low-normal (250–350 ng/L; 185–258 pmol/L).
Metabolic abnormalities	Present in 99% of cases.  Often severe (MMA >1000 nmol/L or >1.0 μmol/L; tHcy > 50 μmol/L)  All metabolic tests usually abnormal (MMA in 98% and tHcy in 96% of cases).	At least 1 abnormality present, by definition.  Usually mild (MMA 300–800 nmol/L or 0.3–0.8 μmol/L; tHcy 15–25 μmol/L).  Some metabolic tests may be normal.
Causes of the deficiency	Identifiable in almost all cases - malabsorption of free cobalamin in > 90% of cases (abnormal Schilling test) - dietary causes are rare (except infants of mothers with deficiency). - preclinical stage of free cobalamin malabsorption (e.g., pernicious anemia) in a few cases.	Not identifiable in at least half of cases - food-bound cobalamin malabsorption in 30%–40% of cases (normal Schilling test) - dietary causes may occur, but frequency is unknown and probably low
Course	Progressive in almost all cases - usually takes several years to appear, but progresses more rapidly once symptoms appear.	Unknown, but appears to be slow (many years) - some patients remain asymptomatic >10 years after biochemical abnormality appears - progression may be more rapid in those few cases with free cobalamin malabsorption.
Management	Full diagnostic evaluation is mandatory but its nature and extent are debated.  Therapeutic intervention is mandatory - dose and route depend on underlying cause (parenteral or large daily oral doses needed when malabsorption of free cobalamin present).	Diagnostic evaluation is mandatory    Therapeutic intervention is probably advisable - dose unclear, may depend on underlying cause (larger oral doses may be needed in some).
Frequency of entity	Uncommon (even in the elderly, the highest at-risk group).  < 10% of all low cobalamin levels are associated with clinical signs of deficiency.	Found in 10%–20% of the elderly; also present in younger persons but proportion is much lower.  ~70% of low cobalamin levels and ~30% of low-normal levels are thought to represent subclinical deficiency.

	“Clinical” Deficiency	“Subclinical” Deficiency
Abbreviations: MMA, serum methylmalonic acid; tHcy, plasma total homocysteine.
Cobalamin values are shown in ng/L values, which are used by most clinical laboratories, and pmol/L, which are used in many publications (conversion factor: ng cobalamin × 0.738 = pmol). Methylmalonic acid values are given in nmol/L and μmol/L values, either of which are used by different clinical laboratories and publications. Reference intervals vary widely among laboratories and methods for all tests. The values shown here are based on the following, fairly common cutpoints for abnormality: serum cobalamin < 200 ng/L; serum MMA > 280 nmol/L; plasma tHcy > 15 μmol/L in men, and > 13 in women.
Clinical signs and symptoms	Present (by definition) but: - not every manifestation (e.g., hematologic, neurologic) appears in every patient - the manifestations may be mild.	Absent (by definition) but- some patients may have electrophysiologic neurologic changes.
Cobalamin levels	Low in 97% of cases (< 200 ng/L; < 148 pmol/L) and often very low (< 100 ng/L; < 74 pmol/L).	Usually low, but can be low-normal (250–350 ng/L; 185–258 pmol/L).
Metabolic abnormalities	Present in 99% of cases.  Often severe (MMA >1000 nmol/L or >1.0 μmol/L; tHcy > 50 μmol/L)  All metabolic tests usually abnormal (MMA in 98% and tHcy in 96% of cases).	At least 1 abnormality present, by definition.  Usually mild (MMA 300–800 nmol/L or 0.3–0.8 μmol/L; tHcy 15–25 μmol/L).  Some metabolic tests may be normal.
Causes of the deficiency	Identifiable in almost all cases - malabsorption of free cobalamin in > 90% of cases (abnormal Schilling test) - dietary causes are rare (except infants of mothers with deficiency). - preclinical stage of free cobalamin malabsorption (e.g., pernicious anemia) in a few cases.	Not identifiable in at least half of cases - food-bound cobalamin malabsorption in 30%–40% of cases (normal Schilling test) - dietary causes may occur, but frequency is unknown and probably low
Course	Progressive in almost all cases - usually takes several years to appear, but progresses more rapidly once symptoms appear.	Unknown, but appears to be slow (many years) - some patients remain asymptomatic >10 years after biochemical abnormality appears - progression may be more rapid in those few cases with free cobalamin malabsorption.
Management	Full diagnostic evaluation is mandatory but its nature and extent are debated.  Therapeutic intervention is mandatory - dose and route depend on underlying cause (parenteral or large daily oral doses needed when malabsorption of free cobalamin present).	Diagnostic evaluation is mandatory    Therapeutic intervention is probably advisable - dose unclear, may depend on underlying cause (larger oral doses may be needed in some).
Frequency of entity	Uncommon (even in the elderly, the highest at-risk group).  < 10% of all low cobalamin levels are associated with clinical signs of deficiency.	Found in 10%–20% of the elderly; also present in younger persons but proportion is much lower.  ~70% of low cobalamin levels and ~30% of low-normal levels are thought to represent subclinical deficiency.