VIMS Journal: December 2016

Review Article

The Implications of Hypercobalaminemia inClinical Practice And Its Management - A Review

Ms. Tirna Halder, Dr. Rinini Dastidar

Introduction :
Hypercobalaminemia (high serum vitamin B12level) is the clinically underestimated abnormalityof serum B12 level due to defects in tissue uptakeor metabolism of serum B12[1]. But it is somewhatconfusing for the clinicians as they intend to findcobalamin (Cbl) deficiency when referring apatient for vitamin B12 assay[2]. High serumcobalamin level in some cases is paradoxicallyaccompanied with functional and quantitativevitamin B12 deficiency symptoms indicating thefact that, low serum cobalamin level does notnecessarily imply deficiency and abnormallyhigh Cbl level does not rule out deficiency[1].Elevated B12 level might be a causal factor ofa number of serious underlying pathologies andthis should be taken into consideration in thepresent clinical scenario[2]. Till now there are nospecific guidelines for clinical interpretation ofsuch conditions. In this review we aim tosummarize the association of various potentiallyserious diseases with elevated Cbl levels andsuggest strategies for interpretation andmanagement of cases with high Cbl levels.

Prevalence :
There is a dearth of evidence on the prevalenceof high serum B12 (Cobalamin, Cbl) all over theworld though with the growing research its rolehas been revealed in the underlyingpathophysiology of many diseases [1,2]. A totalof 471 patients who attended the OPD and IPDof Ramakrishna Mission Seva Pratishthan from1st Jan 2016 to 31th Oct 2016 were referred toBiochemistry department for B12 testing and23.7% (112/471) patients showedhypercobalaminemia (B12 level >950).

All About Plasma Cobalamin :
Vitamin B12 (Cobalamin) is a member of thewater soluble vitamin B complex group whosemain source for human is animal proteins likemeat, fish, eggs, dairy products. When the foodis ingested, the protein bound Cbl is releasedfrom food and it binds with salivary Haptocorrin(HC). This complex travels through the stomachto the upper small intestine where the gastricintrinsic factor (IF) forms the IF-Cbl complex.This complex is absorbed by the luminalmembrane on the ileal cells after binding withreceptor cubam [Fig 1]. Upon absorption, Cblbinds to either transcobalamin (TC) or HC(previously known as Transcoballamin I,Transcobalamin III or R-binder) when releasedin portal blood. The free Cbl is excreted throughurine whereas the part bound with TC or HCremains in the plasma. The part of Cbl thatremains bound to TCII forms the holo TC oractive B12 through which cellular uptake of Cbloccurs from circulation after binding to cellsurface receptor CD320[2].

Fig. 1: The absorption and transport ofvitamin B12 in human body

The absorption and transport ofvitamin B12 in human body

Normally body stores 3-4mg of Vitamin B12primarily in liver whereas RDA recommends 2.6- 2.8 microgram[3] of daily dietary uptake of Cbl.The reference range of serum cobalamin is 191- 946 pg/ml (as per Roche kit literature followedby our lab). Physiologically Cbl plays a key rolein the normal functioning and maintenance ofbrain and nervous system and also take part inthe formation of blood cells. It is involved as acofactor in the sequential synthesis of DNA.Though required in very small amount it isassociated with the vital functions of the bodyand thus requires to be maintained in sufficientlevels as both deficiency and elevated Cbl levelpoint to various aetiological consequences.

Causes for elevation in serum B12 levels[4]
- Excess cobalamin supplementation or parentaladministration of B12 may lead to elevationof serum B12 level.
- Liberation from internal reservoir can causea rise in Cbl level.
- Excess production or lack of clearance ofTranscobalamin.
- Genetic mutation in TCBII gene leading tolack of affinity of TCB receptor proteinbinding to b12 in hepatocytes causing itsserum elevation.

High serum Cobalamin and associateddiseases :
Though the focus of researchers has always beenon Cbl deficiency compared to high serum Cbllevel but in recent time numerous studies havedemonstrating the role of elevated vitamin B12in the pathogenesis of some chronic diseasesincluding blood, liver, kidney and autoimmunedisorders.

- Haematological malignancies and disorders:
High serum cobalamin has been frequentlyobserved in malignant blood disorders such aspolycythaemia vera[5], acute leukemias[6], andMPDs (Myeloproliferative disorders) includingchronic myelo - monocytic leukaemia, primaryhypereosinophillic syndrome, promyelocyticleukaemia[4-6]. In 1950s, researchers first reportedan association of elevated Cbl and ChronicMyeloid Leukemia (CML)[1]. Later studieshypothesised that release of Haptocorrin fromproliferating leukocytes cause the elevation ofserum Cbl in patients suspected of CML. EitherHC or TCB levels are found to be altered inmost of the blood disorders ultimately leadingto the elevation of serum Cbl[7,8]. The precisemechanism of this upsurge of TCB is yet to beelucidated but the involvement of macrophageactivity cannot be ignored[9] in this regard.

- Solid Neoplasms
Caramel et.al first documented the correlationof excess B12 with solid neoplasms[10,11] theelevation is most frequently reported in patientswith liver tumours, breast cancer[10], renal cancer[12], colon cancer, stomach and pancreatictumours[13,10,14]. 30-40% high serum Cbl wasobserved in patients with hepatocellularcarcinoma[15,4,16]. It has been reported by Chicheet,al. that 73% of unknown solid neoplasm wereassociated with Cbl elevation, of which 80%were still at non-metastatic stage[1].
The primary mechanism behind this elevationof Cbl in liver tumour is the decreased hepaticclearance of HC-Cbl complex as a result of excessdegradation of hepatocytes. This occurs due toquantitative reduction of HC receptors on tumourhepatocytes and poor hepatic vascularisation. Inother solid neoplasms, hyperleukocytosis causesincrease in HCs and the tumour cells secreteTCB[4] thus elevating the total B12 level.

- Liver diseases
Impaired liver function might lead to the elevationof Cbl levels in acute and chronic liver diseasesregardless of their aetiologies[17,18,19]. Severalstudies suggest an association between liverdiseases and elevated Clb level[20,21]. Cbl levelis suggested as a prognostic marker inhepatocellular carcinoma (HCC)[21]. IncreasedHaptocorin production by the damagedhepatocytes and / or decreased cellular in livermight contribute to the underlying pathogenesisof hypercobalaminemia in liver diseases.

- Renal diseases
In normal condition, TC with a molecular weightof 38 KDa is filtered by kidney but HC (mw.>70KDa) is highly glycosylated and is not filteredby kidney[22]. But when kidney function isperturbed both TC and HC are not filtered andthus the total Cbl is increased in serum. Anothermechanism suggests that in renal diseases,transport of Cbl in cells is impaired which leadsto cellular deficiency[23]. Several studies suggest a close relationship between elevated haptocorinand transcobalamin with decreased renalclearance and prevent transport of Cbl in cellscausing cellular deficiency of B12.

- Autoimmune Disorders
Patients with many autoimmune diseases likerheumatoid arthritis, SLE, adult onset Still'sdisease[24] have reported high serum Cbl levels.Secretion of HC by polymorphonucleargranulocytes and TC by macrophages secreteelevates the total serum B12 levels[25,26,24]. It hasbeen validated by many studies that increasedproduction of HC and TC causes increase inB12 levels in autoimmune disorders[25]. Presenceof autoantibodies against transcobalamin mightbe a reason for unexplained hypercobaliminemia[27]. Production of anti TCBII antigenantibodycomplex hinders the clearance oftranscobalamin[28].
Though high Cbl appears to be an 'unspecificcancer marker' as it has been associated withvarious types of cancers and different lifethreatening diseases over the years, but furtherstudies are required to reach a firm conclusionon the fact.

Management of high serum Cobalamin:
The correct interpretation of the futureconsequences of high serum Cbl level is notencouraged till now inspite of its associationwith an array of multiple diseases. Cbl levels>1000 pg/ml should be taken into considerationfor proper management[29]. The followingbiochemical examinations including Alkalinephosphatase (ALP), C-reactive protein (CRP),Complete Blood count (CBC) could be suggestedwhen confronted with high B12.

Fig. 2: Suggested first line of clinical examinations when confronted with cases of high serumcobalamin

Suggested first line of clinical examinations when confronted with cases of high serumcobalamin

Fig. 3: Suggested management guidelines for clinicians in cases with high serum cobalamin

Suggested management guidelines for clinicians in cases with high serum cobalamin

When encountered with High serum Cbl levelbut shows clinical symptoms of B12 deficiency,then Serum Homocystein and Methylmalonicacid are tested for confirmation of B12 deficiency.This is because with the physiological decreaseof intracelluar B12 level there is an increase ofserum homocystein and methylmalonic acidlevels. These are the confirmatory tests forintracellular B12 deficiency but can be falselypresented with High Cbl levels.

Active B12 : A better diagnostic marker thantotal B12 for detection of B12 deficiency ortoxicity

Serum B12 remains bound to two proteins-Transcobalamin and Haptocorin. Only 1% ofTCBII is saturated with vitamin B12. This is theonly part available for cellular uptake and carriesout the intracellular functions of Cbl. Thus thisTCB bound Cbl is called active B12 or HoloTC(metabolically active fraction of B12). This facthas fostered the cncept of measuring HoloTCto estimate B12 deficiency[30]. Emergingevidences suggest HoloTC as a more reliablemarker for identifying impaired B12 status thantotal serum B12. Also population based clinicalstudies have validated the efficiency of HoloTCover total serum Cbl in identifying B12deficiency.

Conclusion :
The pivotal role of high serum B12 level inpathogenic background of many severe and lifethreatening diseases has been demonstrated innumerous literatures, but more focus should begiven on B12 research to face many unansweredquestions and challenges. Till today, HoloTc /active B12 testing has not acquired wide clinicalacceptance due to its high cost and limitedavailability but it has proved to be an excellentmarker over total vitamin B12 for diagnosis ofvitamin B12 status. Importance should be givenfor thorough evaluation of high serum Cbl levelas a marker for many diseases rather thanfocusing on its deficiency in clinical settingswhich has already been established.

References
  1. E. Andres, K. Serraj, J.Zhu, A.J.M. Vermorken. Thepathophysiology of elevated vitamin B12 in clinicalpractice; Q J Med 2013; 106:505-515.

  2. Arendt J.F.B and Nexxo E. Unexpected high plasmacobalamin; Clin Chem Lab Med 2012.

  3. Institute of Medicine. Food and Nutrition Board. DietaryReference Intakes: Thiamin, Riboflavin, Niacin, VitaminB6, Folate, Vitamin B12, Pantothenic Acid, Biotin, andCholine. Washington, DC: National Academy Press,1998.

  4. Ermens AA, Vlasveld LT, Lindemans J. Significanceof elevated cobalamin (vitamin B12) levels in blood.Clin Biochem 2003; 36:585-90.

  5. Zittoun J, Zittoun R, Marquet J, Sultan C. The threetranscobalamins in myeloproliferative disorders andacute leukaemia. Br J Haematol 1975;31:287 - 98.

  6. Zittoun J, Farcet JP, Marquet J, Sultan C, Zittoun R.Cobalamin (vitamin B12) and B12 binding proteinsin hypereosinophilic syndromes and secondaryeosinophilia. Blood 1984;63:779 - 83.

  7. Arnalich F, Zamorano AF, Martinez-Hernandez P, PenaJM, Barbado FJ, Vazquez JJ. Additional predictivevalue of serum unsaturated vitamin B12 proteins inmultiple myeloma. J Med 1990;21:277 - 86.

  8. Gimsing P, Nexo E. Cobalamin-binding capacity ofhaptocorrin and transcobalamin: age-correlated reference intervals and values from patients. Clin Chem1989;35:1447 - 51.

  9. Moller HJ, Moestrup SK, Weis N, Wejse C, Nielsen H,Pedersen SS, et al. Macrophage serum markers inpneumococcal bacteremia: prediction of survival bysoluble CD163. Crit Care Med 2006;34:2561-6.

  10. Carmel R, Eisenberg L. Serum vitamin B12 andtranscobalamin abnormalities in patients with cancer.Cancer 1977;40:1348-53.

  11. Carmel R. Extreme elevation of serum transcobalaminI in patients with metastatic cancer. N Engl J Med1975;292:282-4.

  12. Lildballe DL, Nguyen KQ, Poulsen SS, Nielsen HO,Nexo E. Haptocorrin as marker of disease progressionin fibrolamellar hepatocellular carcinoma. Eur J SurgOncol 2011;37:72 - 9.

  13. Jensen HS, Gimsing P, Pedersen F, Hippe E.Transcobalamin II as an indicator of activity in metastaticrenal adenocarcinoma. Cancer 1983;52:1700-4.

  14. Wakatsuki Y, Inada M, Kudo H, Oshio G, Masuda T,Miyake T, et al. Immunological characterization andclinical implication of cobalamin binding protein inhuman gastric cancer. Cancer Res 1989;49:3122 - 8.

  15. Arendt JFB, Nexo E. Cobalamin related parametersand disease patterns in patients with increased serumcobalamin levels. PLoS ONE 2012; 9:e45979.

  16. Gimsing P, Hippe E. Increased concentration oftranscobalamin I in a patient with metastatic carcinomaof the breast. Scand J Haematol 1978; 21:243-9.

  17. Baker H, Leevy CB, DeAngelis B, Frank O, Baker ER.Cobalamin and holotranscobalamin changes in plasmaand liver tissue in alcoholics with liver disease. J AmColl Nutr 1998; 17:235-8.

  18. Hagelskjaer L, Rasmussen K. Methylmalonic acidconcentration in serum not affected in hepatic disease.Clin Chem 1992; 38:493-5.

  19. Lambert D, Benhayoun S, Adjalla C, Ge´lot MM,Renkes P, Ge´rard P, et al. Alcoholic cirrhosis andcobalamin metabolism. Digestion 1997; 58:64-71.

  20. Boisson F, Fremont S, Migeon C, Nodari F, DroeschS, Gerard P, et al. Human haptocorrin in hepatocellular carcinoma. Cancer Detect Prev 1999;23:89 - 96.

  21. Fremont S, Champigneulle B, Gerard P, Felden F,Lambert D, Gueant JL, et al. Blood transcobalaminlevels in malignant hepatoma. Tumour Biol 1991;12:353-9.

  22. Nielsen MJ, Rasmussen MR, Andersen CB, Nexo E,Moestrup SK. Vitamin B12 transport from food to thebody's cells - a sophisticated, multistep pathway. NatRev Gastroenterol Hepatol 2012;9:345-54.

  23. Obeid R, Kuhlmann MK, Kohler H, Herrmann W.Response of homocysteine, cystathionine, andmethylmalonic acid to vitamin treatment in dialysispatients. Clin Chem 2005;51:196-201.

  24. Kalyoncu U, Buyukasik Y, Akdogan A, Karadag O,Bilgen SA, Kiraz S, et al. Increased serum vitaminB12 levels are associated with adult-onset Still's diseasewith reactive macrophage activation syndrome. JointBone Spine 2010;77:131-4.

  25. Christensen PA, Brynskov J, Gimsing P, Petersen J.Vitamin B12 binding proteins (transcobalamin andhaptocorrin) in serum and synovial fluid of patientswith rheumatoid arthritis and traumatic synovitis.Scand J Rheumatol 1983;12:268-72.

  26. Arnalich F, Zamorano AF, Benito-Urbina S, Gijon-Banos J, De Miguel E, Pena JM, et al. Increasedapotranscobalamin II levels in rheumatoid arthritis.Br J Rheumatol 1990;29:171-3.

  27. Jeffery J, Millar H, MacKenzie P, Fahie-Wilson M,Hamilton M, Ayling RM. An IgG complexed form ofvitamin B-12 is a common cause of elevated serumconcentrations. Clin Biochem 2010;43:82-8.

  28. Carmel R, Tatsis B, Baril L. Circulating antibody totranscobalamin II causing retention of vitamin B12 inthe blood. Blood 1977; 49:987-1000.

  29. Laboratory reference intervals for the Central andNorthern regions of Denmark. Available from: https://www.itsundhed.dk/laboratorie_liste/Prog/d_udskriftsvenlig_udgave. aspx?id = 179.

  30. Nexo E. and Hoffman-Lucke E. Holotranscobalamin,a marker of vitamin B-12 status: analytical aspectsand clinical utility; Am J Clin Nutr: 1S-7S.

Search

Current Issue

Archives