Holo TC (Holotranscobalamin) and Methylmalonic Acid Markers for

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					LabmedLetter Nr. 81 / September 2006


Holo TC (Holotranscobalamin) and Methylmalonic Acid: Markers for Metabolically Available Active Vitamin B12

Background information                                                      The level of methylmalonic acid (MMA) and possibly also of
A deficiency of Vitamin B12, like an elevated serum level, is asso-         homocystein can be determined to confirm this suspected diagnosis.
ciated with various clinical pictures. For this reason the determi-         Both substances are broken down inside the cell by cobalamin. In
nation of Vitamin B12 in blood is part of the standard program              patients with a cellular cobalamin deficiency, there is thus an in-
offered by a medical laboratory. Vitamin B12, or cobalamin, is              creased release of homocystein and methylmalonic acid into the
present in serum but in different protein compounds. About 70-90%           blood, and elevated serum levels of MMA (and homocystein) are
of cobalamin is bound to haptocorrin (HC); this Vitamin V12                 measured. Furthermore, the analysis of MMA can yield evidence of
compound is considered to be metabolically inert since it does not          renal dysfunction in cases where the administration of Vitamin B12
possess any cellular receptors. With the exception of the Vitamin           supplements fails to lower MMA levels.
B12 in the liver, the largest part of Vitamin B12 in the body can           Rechecking a test result by determining the MMA value can also be
therefore not become biologically active. Only the remaining fraction       recommended for the diagnostic exploration of "falsely" elevated
of about 10-30% cobalamin, which in combination with                        Vitamin B levels. If direct measurement of active Vitamin B12 reveals
transcobalamin II (TC) forms the so-called HoloTC complex, is               elevated serum levels which are not attributable to supplementation,
actually effective on the cellular level owing to its specific receptors.   further diagnostic exploration should be carried out to exclude hema-
For this reason, measurement of total Vitamin B12 does not yield            tological disorders (e.g. leukemia, cystic fibrosis) and hepatic disor-
any reliable information as to whether there is really sufficient           ders (e.g. hepatitis, cirrhosis, liver cancer). Despite the extremely
cobalamin available in the body in the form of HoloTC. Even at very         elevated levels of Vitamin B12 found in some cases in patients with
high cobalamin levels due to pathological causes (e.g. the 10-fold          diseases such as CML (up to 10,000 pg/ml), a deficiency of biologi-
elevated cobalamin levels seen in patients with CML leukemia),              cally active B12 may exist; this can be diagnosed by determining the
there may be a deficiency of biologically active Vitamin B12 if the         HoloTC value.
elevated values occur in connection with increased production of
haptocorrin.                                                                Reference range for Holo TC
Another advantage of this test is that the determination of the             > 50 pmol/l: a Vitamin B12 deficiency is unlikely.
HoloTC concentration is largely unaffected by short-term intake of          35-50 pmol/l: gray zone (The determination of methylmalonic acid as
Vitamin B12. With the aid of a microparticle enzyme immunoassay             a metabolic marker for an intracellular deficit of Vitamin B12 is
(MEIA) we can perform a quantitative determination of                       recommended.)
holotranscobalamin; this permits selective diagnostic investigation         < 35 pmol/l: deficiency of active Vitamin B12
of the amount of metabolically available Vitamin B12 in the body.
                                                                            Reference range for methylmalonic acid (MMA):
                                                                            9-32 ng/ml
Clinical significance                                                       Elevated values in patients with an intracellular deficit of Vitamin B12
Vitamin B12 deficiency is common especially among older members
of the population. Holo TC is of particular importance in this context      Material: Serum: 1 ml (for each test)
since it is the only marker attaining pathological values in the early
phase of a deficiency of biologically available Vitamin B12. The most       Method:
importance causes of Vitamin B12 deficiency are: gastrointestinal           Holo TC: MEIA (microparticle enzyme immunoassay)
disorders, chronic atrophic gastritis, alcohol abuse, some                  Methylmalonic acid / MMA: LC-MS/MS
medications (e. g. proton pump inhibitors), etc. Major seqelae of
Vitamin B12 deficiency include neurodegenerative and psychiatric            Contact: Dr. med. Arnold Eberhard Tel: 0231 – 9572 0
disorders (e. g. neuropathies, dementia, cognitive impairment) and
disorder of erythropoiesis (megaloblastic anemia). In patients with a       Literature:
HoloTC level < 50 pmol/l, there is reason to suspect a functional           1.) Nilsson K. et al., Clin Chem Lab Med, 2004, 42(6): 637-643.
                                                                            2.) Herrmann W. et al, Clin Chem Lab Med. 2003, 41(11): 1478-88.
Vitamin B12 deficiency.
                                                                            3.) Nexo E. et al., Clinical Chemistry 2002 (48): 561-562