Anaemia: cobalamin deficiency was best diagnosed on blood film or metabolite levels.

Clinical bottom line (level 4)

  1. Cobalamin deficiency was common in patients with low serum cobalamin.
  2. The following clinical investigations helped diagnose cobalamin deficiency responsive to parenteral therapy in patients with low serum cobalamin:
    • blood smear (LR+25)
    • normal white cell count (LR+13)
    • raised MMA or Hcy (LR+9.1)
    • serum cobalamin<100 pmol/l (LR+6.1)
    • LDH>300 U/l (LR+5.8)
    • macrocytosis (LR+5.4)
  3. Cobalamin deficiency was slightly less likely in patients with:
    • abnormal white cell count (LR-0.15)
    • normal Schilling test (LR-0.21)
    • both MMA and Hcy normal (LR-0.25)
Stabler et al: Blood 1990; 76 (5): 871-881 Expires December 2003

The study

Setting: two university hospital, USA

300 patients (aged ?, ?% male) serum cobalamin <200 pmol/l

Independent ?blinded reference standard, applied in some patients from a consecutive appropriate spectrum.
Reference standard:
  • response to cobalamin therapy within four months- multiple injections of 1000 µ g of parenteral cobalamin:
    • increases in haemocrit of 0.05 or more
    • decrease in MCV of 5 fl or more
    • disappearance of hypersegmented polymorphonuclear leukocytes on peripheral blood smear
    • improvement of neuropsychiatric abnormalities that were unequivocal and prompt
Diagnostic test: blood test and neuropsychiatric symptoms
  • 145 patients underwent the reference standard test.

The evidence

pre-test probability of cobalamin deficiency: 59%, (95% CI: 51% to 67%)

diagnostic test cobalamin deficiency no deficiency LR+
(95% CI)		 post-test probability LR-
(95% CI)		 post-test probability
anaemia 48 25 1.3
(0.93 to 1.9) 		66% 0.77
(0.56 to 1.1) 		53%
macrocytosis (MCV >100 fl) 55 7 5.4
(2.6 to 11) 		89% 0.41
(0.30 to 0.55) 		37%
normal white blood cells 74 4 13
(4.9 to 33) 		95% 0.15
(0.09 to 0.25) 		18%
normal platelet count 68 55 0.85
(0.75 to 0.96) 		55% 3.1
(1.1 to 8.7) 		82%
neuropsychiatric findings 24 27 0.61
(0.39 to 0.95) 		47% 1.3
(1.0 to 1.7) 		66%
raised folate 19 4 3.3
(1.2 to 9.1) 		83% 0.84
(0.73 to 0.95) 		55%
serum cobalamin <100 pmol/l 53 6 6.1
(2.8 to 13) 		90% 0.43
(0.32 to 0.57) 		38%
anti-intrinsic factor antibodies 42 11 2.6
(1.5 to 4.7) 		79% 0.63
(0.49 to 0.80) 		48%
raised methylmalonic acid and homocysteine 66 5 9.1
(3.4 to 21) 		93% 0.25
(0.17 to 0.38) 		27%
raised methylmalonic acid alone 8 8 0.69
(0.27 to 1.7) 		50% 1.1
(0.93 to 1.2) 		60%
raised homocysteine alone 7 5 0.96
(0.32 to 2.9) 		58% 1.0
(0.91 to 1.1) 		59%
serum gastrin >200 ng/l 54 18 2.1
(1.4 to 3.1) 		75% 0.54
(0.39 to 0.74) 		44%
total 86 59


diagnostic test deficiency no deficiency LR+
(95% CI)		 post-test probability LR-
(95% CI)		 post-test probability
abnormal blood smear 42 1 25
(3.6 to 180) 		98% 0.34
(0.24 to 0.49) 		36%
total 63 38


diagnostic test deficiency no deficiency LR+
(95% CI)		 post-test probability LR-
(95% CI)		 post-test probability
LDH>300 U/l 26 2 5.8
(1.5 to 23) 		93% 0.67
(0.55 to 0.82) 		60%
total 70 31


diagnostic test deficiency no deficiency LR+
(95% CI)		 post-test probability LR-
(95% CI)		 post-test probability
11 1 5.3
(0.71 to 39) 		92% 0.86
(0.76 to 0.97) 		64%
total 65 31


diagnostic test deficiency no deficiency LR+
(95% CI)		 post-test probability LR-
(95% CI)		 post-test probability
32 14 2.5
(1.6 to 3.8) 		70% 0.21
(0.09 to 0.48) 		16%
total 37 40

Comments

  1. Neither the presence of anaemia or neuropsychiatric symptoms was helpful in diagnosing cobalamin deficiency.
  2. Commonest neuropsychiatric symptoms were paraesthesia (88%), impaired vibration sense (50%), with ataxia (38%). These did not assist with diagnosing those who would benefit from parenteral therapy.
  3. Several patients with cobalamin deficiency had neuropsychiatric symptoms without anaemia or macrocytosis.

Citation

  1. Stabler SP, Allen RH, Savage DG, et al: Clinical spectrum and diagnosis of cobalamin deficiency. Blood 1990; 76 (5): 871-881
Search Terms: reference in review article
Contributor: Chris Ball and Clare Wotton, June 2000
Reviewer: Donald Stanley

Clinical Question.
Patient serum cobalamin ,200 pmol/l
Intervention or Exposure blood tests and neuropsychiatric symptoms
Outcome diagnosis of cobalamin deficiency