Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Supportive Care in Cancer
Published in: Supportive Care in Cancer 8/2016

01-08-2016 | Original Article

Functional vitamin B12 deficiency in advanced malignancy: implications for the management of neuropathy and neuropathic pain

Author: Lawrence R. Solomon

Published in: Supportive Care in Cancer | Issue 8/2016

Login to get access

Abstract

Background and aim

Treatment of neuropathic pain and chemotherapy-induced peripheral neuropathy (CIPN) in patients with malignancy is often unsuccessful. Functional vitamin B12 deficiency, defined by elevated levels of the B12-dependent metabolites, methylmalonic acid (MMA), and/or homocysteine, despite normal B12 values, may cause neuropathy and is associated with disorders linked to increased oxidative stress. Since both cancer and neurotoxic antineoplastic agents increase oxidative stress, a role for functional B12 deficiency in CIPN was considered.

Methods

A retrospective record review of 241 cancer subjects evaluated by the adult palliative care service for B12 deficiency in a university-based cancer center between October 2008 and September 2012 with measurement of B12, MMA, and/or homocysteine levels was performed.

Results

B12 values were elevated (>900 pg/ml) in 30 % and low (≤300 pg/ml) in 17 % of subjects tested. Elevated MMA (>250 nmol/l) and homocysteine (>12.1 μmol/l) levels occurred in 38 and 23 % of subjects respectively and at least one metabolite was increased in 54 % of evaluable subjects. Even when B12 values were ≥1500 pg/ml (n = 36), increased MMA and homocysteine values occurred in 31 and 23 % of subjects, respectively. B12 therapy decreased MMA values in all four subjects studied and improved neurologic findings in the three subjects tested.

Conclusions

Functional vitamin B12 deficiency is common in subjects with advanced malignancy. Further studies are needed to determine if this disorder is a risk factor for CIPN and if B12 therapy has a role in the management and/or prevention of neuropathy and neuropathic pain in this population.
Literature
1.
Velasco R, Bruna J (2010) Chemotherapy-induced peripheral neuropathy: an unresolved issue. Neurologica 25:116–121
2.
Beijers A, Mols F, Dercksen D, Driessen C, Vreugdenhil G (2014) Chemotherapy-induced peripheral neuropathy and impact on quality of life after treatment with chemotherapy. J Commun Support Oncol 12:401–406CrossRef
3.
Finnerup NB, Sindrup SH, Iensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581CrossRefPubMed
4.
Attal N, Bouhassira D (2015) Pharmacotherapy for neuropathic pain: which drugs, which treatment algorithms. Pain 156:S104–S114CrossRefPubMed
5.
Solomon LR (2007) Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev 21:113–130CrossRefPubMed
6.
Nardin RA, Amick ANH, Raynor EM (2007) Vitamin B12 and methylmalonic acid levels in patients presenting with polyneuropathy. Muscle Nerve 36:532–535CrossRefPubMed
7.
Saperstein DS, Wolfe GI, Gronseth GS, et al. (2003) Challenges in the identification of cobalamin deficiency and polyneuropathy. Arch Neurol 60:1296–1301CrossRefPubMed
8.
Schrempf W, Eulitz M, Neumeister V, et al. (2011) Utility of measuring vitamin B12 and its active fraction, holotranscobalamin, in neurologic B12 deficiency syndromes. J Neurol 258:393–401CrossRefPubMed
9.
Solomon LR (2011) Diabetes mellitus as a cause of clinically significant functional cobalamin deficiency. Diabetes Care 3:1077–1080CrossRef
10.
Sun A, Ni Y, Li X, et al. (2014) Urinary methylmalonic acid as an indicator of early vitamin B12 deficiency and its role in polyneuropathy in type 2 diabetes. J Diabet Res 2014:92616
11.
Solomon LR (2005) Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid and homocysteine testing. Blood 105:978–985CrossRefPubMed
12.
13.
Solomon LR (2015) Functional cobalamin (vitamin B12) deficiency: role of advanced age and disorders associated with increased oxidative stress. Eur J Clin Nutr 69:687–692CrossRefPubMed
14.
Birch CS, Brasch NE, McCaddon A, et al. (2009) A novel role for vitamin B12: cobalamins are intracellular antioxidants in vitro. Free Radic Biol Med 47:184–188CrossRefPubMed
15.
Solomon LR. Low cobalamin (vitamin B12) levels as predictors of cobalamin deficiency: importance of comorbidities associated with increased oxidative stress. Am J Med 2015; in press.
16.
Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutation Res 711:193–201CrossRefPubMed
17.
Chen Y, Jungsuwadee P, Vore M, Butterfield DA, St Clair DK (2007) Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Molec Interventions 7:147–267CrossRef
18.
DiCesare ML, Zanardelli M, Failli P, et al. (2012) Oxaliplatin-induced neuropathy: oxidative stress as a pathological mechanism. Protective effect of silibin. J Pain 13:276–284CrossRef
19.
Meshkini A, Yazdanparast R (2012) Involvement of oxidatives stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells. Exper Toxicol Pathol 64:357–365CrossRef
20.
Riley PA (1994) Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 65:27–33CrossRefPubMed
21.
Reynolds A, Laurie C, Mosley RL, Gendelman HE (2007) Oxidative stress and the pathogenesis of neurodegenerative disorders. Intl Rev Neurobiol 82:297–325CrossRef
22.
Carozzi VA, Canta A, Chiorazzi A (2015) Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms? Neurosci Lett 596:90–107CrossRefPubMed
23.
Vu T, Amin J, Ramos M, Flener V, Vanyo L, Tisman G (1993) New assay for the rapid determination of plasma holotranscobalamin II levels: preliminary evaluation in cancer patients. Am J Hematol 42:202–211CrossRefPubMed
24.
Tisman G, Vu T, Luszko AG, Brenner M, Ramos M, Flener V, Cordts V, Bateman R, Malkin S, Bowder T (1993) Measurement of red blood cell vitamin B12: a study of the correlation between intracellular B12 content and concentrations of plasma holotranscobalamin II. Am J Hematol 43:226–229CrossRefPubMed
25.
Smith AD, Refsum H (2011) Do we need to reconsider the desirable blood level of vitamin B12? J Int Med 271:179–182CrossRef
26.
Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G (2008) The use of blood concentrations of vitamins and theirs respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull 29(suppl):567–573
27.
Pfeiffer CM, Caudill SP, Gunter EW, et al. (2005) Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2003. Am J Clin Nutr 82:442–450PubMed
28.
Carmel R, Eisenberg L (1977) Serum vitamin B12 and transcobalamin abnormalities in patients with cancer. Cancer 40:1348–1353CrossRefPubMed
29.
Koletzko B, Bachmann C, Wendel U (1990) Antibiotic therapy for improvement of metabolic control in methylmalonic aciduria. J Pediatr 117:99–101CrossRefPubMed
30.
Miyagi Y, Higashiyama M, Gochi A, et al. (2011) Plasma free amino acid profiling of 5 types of cancer patients and its application to early detection. PLoS one 6:e24143CrossRefPubMedPubMedCentral
31.
Schloss JM, Colosimo M, Airey C, Vitetta L (2015) Chemotherapy-induced peripheral neuropathy (CIPN) and vitamin B12 deficiency. Support Care Cancer 23:1843–1850CrossRefPubMed
32.
Alt RS, Morrissey RP, Gang MA, et al. (2011) Severe myeloneuropathy from acute high-dose nitrous oxide (N2O) abuse. J Emerg Med 41:378–380CrossRefPubMed
33.
Gauchan D, Joshi N, Gill AS, et al. (2012) Does an elevated serum vitamin B12 level mask actual vitamin B12 deficiency in myeloproliferative disorders. Clin Lymphoma Myeloma Leuk 12:269–273CrossRefPubMed
34.
Vlasveld LT, Bos GM, Ermens AA, Bakker JA, Lindemans J (2006) Hyperhomocysteinemia and functional cobalamin deficiency due to granculocytosis-induced alterations in cobalamin-binding protein. Haematologica 91:394–396PubMed
35.
Li KM, Rivory LD, Clarke SJ (2007) Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with venorelbine: implications for further optimization of pemetrexed schedules. Brit J Cancer 97:1071–1076CrossRefPubMedPubMedCentral
36.
Guren MG, Schneede J, Tveit KM, et al. (1994) Biochemical signs of impaired cobalamin status during and after radiation therapy for rectal cancer. Intl J Radiat Biol 65:27–33CrossRef
37.
Bystrom P, Bjorkegren K, Larsson A, Johansson L, Berglund A (2009) Serum vitamin B12 and folate status among patients with chemotherapy treatment for advanced cancer. Upsala J Med Sci 114:160–164CrossRefPubMedPubMedCentral
38.
Xu G, Lv ZW, Feng Y, Tang WZ, Xu GX (2013) A single-center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia. Pain Med 14:884–894CrossRefPubMed
39.
Kuwabara S, Nakazawa R, Azuma N, et al. (1999) Intravenous methylcobalamin treatment of uremic and diabetic neuropathy in chronic hemodialysis patients. Int Med 38:472–475CrossRef
40.
Talaei A, Mnsour S, Majidi H, et al. (2009) Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int J Food Sci Nutr 60:71–76CrossRefPubMed
41.
Hosseinzadeh H, Moallem SA, Moshiri M, et al. (2012) Anti-nocioceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice. Arzneimittelforschung 62:324–329PubMed
42.
Erfenparast E, Escort M, Maroufi S, et al. (2014) Systemic and local injections of vitamin B12 suppressed orofacial nociception induced by formalin in rats. Drug Res 64:85–90
43.
Gan L, Qian M, Shi K, et al. (2014) Restorative effect and mechanism of mecocobalamin on sciatic nerve crush in mice. Neural Regen Res 9:1979–1984PubMedPubMedCentral
44.
Sun H, Yang T, Li Q, et al. (2012) Dexamethasone and vitamin B12 synergistically promote peripheral nerve regeneration in rats by upregulating the expression of brain-derived neurotrophic factor. Arch Med Sci 8:924–930CrossRefPubMedPubMedCentral
45.
Jian-bo L, Cheng-ya W, Jai-wei C, et al. (2010) The preventive efficacy of methylcobalamin on rat peripheral neuropathy influenced by diabetes via neural IGF-1 levels. Nutr Neurosci 13:79–86CrossRefPubMed
46.
Yamashiki M, Nishimura A, Yosaka Y (1992) Effects of methylcobalamin (vitamin B12) on in vitro cytokine production of peripheral blood mononuclear cells. J Clin Lab Immunol 37:173–182PubMed
47.
Ghazanfari S, Imenshahidi M, Etemad L, Hosseinzadeh H (2013) Effect of cyanocobalamin (vitamin B12) in the induction and expression of morphine tolerance and dependence in mice. Drug Res 64:113–117CrossRef
48.
Solomon LR (2006) Oral pharmacologic doses of cobalamin may not be as effective as parenteral cobalamin therapy in reversing hyperhomocysteinemia and methylmalonic academia in apparently normal subjects. Clin Lab Haematol 28:275–278CrossRefPubMed
Metadata
Title
Functional vitamin B12 deficiency in advanced malignancy: implications for the management of neuropathy and neuropathic pain
Author
Lawrence R. Solomon
Publication date
01-08-2016
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 8/2016
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-016-3175-5

Other articles of this Issue 8/2016

Supportive Care in Cancer 8/2016 Go to the issue

Original Article

Palliative care specialists’ beliefs about spiritual care

Original Article

Access to oral care before hematopoietic stem cell transplantation: understand to improve

Review Article

Comparison of the FACT-C, EORTC QLQ-CR38, and QLQ-CR29 quality of life questionnaires for patients with colorectal cancer: a literature review

Original Article

Impact of a behavioral weight loss intervention on comorbidities in overweight and obese breast cancer survivors

Review Article

The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review

Original Article

Preferences for the organization of long-term follow-up in adolescent and young adult cancer survivors
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits