Dr. Ron’s Research Review – September 2, 2020

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This week’s research review focuses on elevated vitamin B12.

Hypercobalaminemia is defined by a vitamin B12 level above 950 pg/ml.
Normal is generally 190 - 950 picograms per milliliter (pg/mL).

A Sign of Liver Damage

Elevated vitamin B12 is a sign for liver damage, due to release of the vitamin from damaged liver cells. (Grobin, 1959) (Rachmilewitz et al., 1959)
Elevated B12 levels are not a significant predictor of mortality after ICU admission when liver function is controlled for, and may instead be a proxy for poor liver function. (Callaghan et al., 2014)

Chronic Viral Liver Disease

Falsely elevated serum vitamin B12 levels were associated with the severity and prognosis of chronic viral liver disease. (Sugihara et al., 2017) (Mechie et al., 2015)

Hypervitaminemia B12 in Elderly Patients

Hypervitaminemia B12 is a common laboratory abnormality, frequently unknown. A study confirmed the significance of the link between hypervitaminemia B12 and hematological disorders in elderly patients, with a 5.7 fold higher risk. Importantly, it is to note that a MGUS (monoclonal gammopathy of undetermined significant) was discovered in 17% of the patients. A correlation between the rate of hypervitaminemia B12 and the number of underlying conditions was identified. The patients ≥75 years of age are more susceptible to present hypervitaminemia B12 with an odds ratio of 3.7. (Zulfiqar et al., 2015)
Vitamin B12 or cobalamin deficiency occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%-20% of all cases), insufficient dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. (Andrès et al., 2004)

Functional Deficiency

Hypercobalaminemia is a frequent and underestimated anomaly. Clinically, it can be paradoxically accompanied by signs of deficiency, reflecting a functional deficiency linked to qualitative abnormalities, which are related to defects in tissue uptake and action of vitamin B12.
While low serum cobalamin levels do not necessarily imply deficiency, an abnormally high serum cobalamin level forms a warning sign requiring exclusion of a number of serious underlying pathologies, including solid neoplasms, hematological malignancies and liver and kidney diseases. Functional cobalamin deficiency can thus occur at any serum level. (Andrès et al., 2013)

 

Dr. Ron

 


Articles

 

Vitamin B12 (cobalamin) deficiency in elderly patients.
            (Andrès et al., 2004) Download
Vitamin B12 or cobalamin deficiency occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%-20% of all cases), insufficient dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. We review the epidemiology and causes of cobalamin deficiency in elderly people, with an emphasis on food-cobalamin malabsorption syndrome. We also review diagnostic and management strategies for cobalamin deficiency.

The pathophysiology of elevated vitamin B12 in clinical practice.
            (Andrès et al., 2013)  Download
Hypercobalaminemia (high serum vitamin B12 levels) is a frequent and underestimated anomaly. Clinically, it can be paradoxically accompanied by signs of deficiency, reflecting a functional deficiency linked to qualitative abnormalities, which are related to defects in tissue uptake and action of vitamin B12. The aetiological profile of high serum cobalamin predominantly encompasses severe disease entities for which early diagnosis is critical for prognosis. These entities are essentially comprised of solid neoplasms, haematological malignancies and liver and kidney diseases. This review reflects the potential importance of the vitamin B12 assay as an early diagnostic marker of these diseases. A codified approach is needed to determine the potential indications of a search for high serum cobalamin and the practical clinical strategy to adopt upon discovery of elevated cobalamin levels. While low serum cobalamin levels do not necessarily imply deficiency, an abnormally high serum cobalamin level forms a warning sign requiring exclusion of a number of serious underlying pathologies. Functional cobalamin deficiency can thus occur at any serum level.

High vitamin B12 levels are not associated with increased mortality risk for ICU patients after adjusting for liver function: a cohort study.
            (Callaghan et al., 2014)  Download
BACKGROUND AND AIMS:  Recent research has suggested that high vitamin B12 levels may be associated with increased mortality after ICU admission. However, it is known that impaired liver function may lead to elevated B12 since B12 is metabolized through the liver, and therefore high B12 levels may serve as a proxy for poor liver function. The aim of this study is to assess the impact that liver function and liver disease have on the relationship between high vitamin B12 levels and mortality in the ICU. METHODS:  We performed an observational cohort study using ICU data that were collected from patients admitted to four ICU types (medical, surgical, cardiac care and cardiac surgery recovery) in one large urban hospital from 2001 to 2008. We analyzed the medical records of 1,684 adult patients (age ≥ 18 years) who had vitamin B12 and liver function measurements up to 14 days prior to ICU admission or within 24 hours after admission. RESULTS:  While we found an association between high B12 and mortality when we did not control for any potential confounders, after we adjusted for liver function and liver disease, no significant association existed between B12 and mortality using multivariable logistic regression (30-day mortality: OR=1.18, 95% CI 0.81 to 1.72, p=0.3890; 90-day mortality: OR=1.20, 95% CI 0.84 to 1.71, p=0.3077). CONCLUSIONS:  Elevated B12 levels are not a significant predictor of mortality after ICU admission when liver function is controlled for, and may instead be a proxy for poor liver function.

Serum Vitamin B(12) Content as an Index of Hepatic Damage.
            (Grobin, 1959)  Download
The increase in total serum vitamin B12 within 48 hours after ad- ministration of CC4 had a quantitative relationship to the decrease in vitamin B12 in the whole liver; this suggests strongly that the rise in serum vitamin B12 is due to release of stored vitamin B12 following hepatocellular disintegration. Rachmilewitz et al. suggest the use of vitamin B12 determination as an index of the degree of hepatic damage which is more sensitive than commonly used liver function tests, including serum transaminase estimations.

Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study.
            (Mechie et al., 2015)  Download
BACKGROUND:  Chronic hepatitis C (CHC) is a global health challenge. New therapeutic agents with excellent sustained virological response (SVR) rates are available mainly in developed countries, while the majority of CHC patients live in countries with low health budget. Predictors of therapeutic response are therefore necessary. Vitamin B12 appears to be involved in hepatitis C virus replication. METHODS:  We therefore studied retrospectively the relationship between baseline serum vitamin B12 levels and clinical features in 116 CHC genotype 1 infected patients. Logistic regression models with univariate and multivariate analysis were used in the statistical analysis. RESULTS:  Baseline serum vitamin B12 levels were found to be positively associated with serum transaminase activities (AST, p = 0.002, ALT, p = 0.04), baseline viral load (p < 0.0001), stage of fibrosis (p = 0.0001) and favorable interferon-λ3/4 (IFNL3/IFNL4) rs12979860 genotypes (p = 0.04), and inversely with SVR (p < 0.001) as well as with rapid virological response (p = 0.001). Patients with baseline serum vitamin B12 levels below a cut-off value of 570 ng/L achieved a SVR rate of 59% with an odds ratio (OR) of 13.4 [confidence interval (CI) 4.3-41.9, p < 0.0001] compared to patients above the cut-off value. By combining serum vitamin B12 levels and IFNL3/IFNL4 rs12979860 genotypes, patients with baseline serum vitamin B12 levels below the cut-off value of 570 ng/L and IFNL3/IFNL4 rs12979860 CC genotype achieved a SVR rate of even 80% with an OR of 54 (CI 9.9-293, p < 0.0001) compared to patients above the cut-off value and non-CC-genotypes. CONCLUSION:  Our data suggest baseline serum vitamin B12 levels as useful noninvasive marker for characterizing CHC patients. They might further help to identify responders to a standard treatment.

Serum cyanocobalamin (vitamin B12) as an index of hepatic damage in chronic congestive heart failure.
            (Rachmilewitz et al., 1959)  Download
It has been shown that liver-cell damage caused by various agents (viral,1-4 chemical,5 infiltrating tumor 6) is associated with markedly increased levels of cyanocobalamin (vitamin B12) in the blood, which are due to the release of the vitamin from damaged liver cells. Serum cyanocobalamin (vitamin 12) activity was estimated in 28 patients suffering from severe chronic congestive heart failure. Elevated serum cyanocobalamin levels were found in 23 of them, while the commonly used hepatocellular function tests were usually normal. The serum cyanocobalamin levels decreased considerably in cases where compensation was attained. The serum cyanocobalamin concentration in chronic congestive heart failure may serve as an index of the degree of hepatic damage.

Falsely Elevated Serum Vitamin B|12| Levels Were Associated with the Severity and Prognosis of Chronic Viral Liver Disease.
            (Sugihara et al., 2017)  Download
BACKGROUND:  Vitamin B|12| is stored primarily in the liver, and highly elevated serum vitamin B|12| levels occur in acute hepatitis and severe alcoholic liver disease. We evaluated the relationship between vitamin B|12| levels and liver disease severity and long term prognosis in patients with chronic viral hepatitis and cirrhosis. METHODS:  We enrolled 90 patients (57 men, 33 women) with chronic viral hepatitis and cirrhosis who admitted to our hospital as a prospective cohort study. Overall, 37 patients had chronic hepatitis and 53 had cirrhosis (Child-Pugh A 33, B 13, and C 7); 57 patients had primary liver cancer. Serum vitamin B|12| concentration and holotranscobalamin (holoTC) II (active form of vitamin B|12|) were determined and followed prospectively for at least 5 years. RESULTS:  Mean total serum vitamin B|12| concentration was significantly higher in Child-Pugh C (1308 ± 599 pg/mL) compared to those with chronic hepatitis (655 ± 551 pg/mL), Child-Pugh A (784 ± 559 pg/mL), and Child-Pugh B (660 ± 464 pg/mL) (P = 0.036) Presence of primary liver cancer also influenced serum vitamin B|12| levels [657 (167-2956) vs. 432 (189-2956); P = 0.015]. Patients were divided into quartiles by vitamin B|12| level. Patients without primary liver cancer in quartile 4 (≥ 880 pg/mL) demonstrated significantly poorer prognosis than those in quartiles 1-3 (< 880 pg/mL) (P = 0.023). The percentage of holohaptocorrin (holoHC) [(total vitamin B|12| - holoTC II) × 100] was significantly higher in Child-Pugh B and C 86 (80-87)% than chronic hepatitis and Child-Pugh A 77 (31-89)% (P = 0.006) Multivariate analysis indicated serum vitamin B|12| levels (HR = 1.001, P = 0.029) as a prognostic factor. CONCLUSION:  Falsely elevated serum vitamin B|12| levels mainly composed of increased holoHC were associated with severity (Child-Pugh C and primary liver cancer) and prognosis in chronic viral liver disease.

 

Hypervitaminemia B12 in elderly patients: Frequency and nature of the associated or linked conditions. Preliminary results of a study in 190 patients.
            (Zulfiqar et al., 2015)  Download
Hypervitaminemia B12 is a common laboratory abnormality, frequently unknown. Hypervitaminemia B12 has been associated or linked with a range of conditions, the majority of which are serious, with a systematic inquiry being decisive for prognosis. But in practice, physicians often do not know what to do. his letter reports preliminary results of such a study in a well- documented population of elderly patients. The objective of the present study is to determine the frequency of hypervitaminemia B12 and the nature of the associated or linked conditions. Our study confirms the significance of the link between hypervitaminemia B12 and hematological disorders in elderly patients, with a 5.7 fold higher risk. Importantly, it is to note that a MGUS is dis- covered in 17% of the patients. In our study, there is an apparent correlation between the rate of hypervitaminemia B12 and the number of underlying conditions identified. The patients ≥75 years of age are more susceptible to present hypervitaminemia B12 with an odds ratio of 3.7

Hypervitaminia B12: A Useful Additional Biomarker for the Diagnosis and Monitoring of Liver Diseases
            (Zulfiqar et al., 2016)  Download
B12 hypervitaminemia is a biological abnormality, yet one that is significantly underestimated. According to the literature, high levels of vitamin B12 is associated or linked with a range of conditions, the majority of which are serious. These conditions include solid neoplasia (whether metastatic or otherwise) and, either acute or chronic, malignant haematological disorders. But there are others causes like liver disorders, which are described in the literature, but poorly known.

 


References

Andrès, E, et al. (2004), ‘Vitamin B12 (cobalamin) deficiency in elderly patients.’, CMAJ, 171 (3), 251-59. PubMed: 15289425
Andrès, E, et al. (2013), ‘The pathophysiology of elevated vitamin B12 in clinical practice.’, QJM, 106 (6), 505-15. PubMed: 23447660
Callaghan, FM, et al. (2014), ‘High vitamin B12 levels are not associated with increased mortality risk for ICU patients after adjusting for liver function: a cohort study.’, ESPEN J, 9 (2), e76-83. PubMed: 24665415
Grobin, W (1959), ‘Serum Vitamin B(12) Content as an Index of Hepatic Damage.’, Can Med Assoc J, 81 (11), 935-36. PubMed: 20326055
Mechie, NC, et al. (2015), ‘Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study.’, BMC Res Notes, 8 260. PubMed: 26109044
Rachmilewitz, M, et al. (1959), ‘Serum cyanocobalamin (vitamin B12) as an index of hepatic damage in chronic congestive heart failure.’, Arch Intern Med, 104 406-10. PubMed: 14435678
Sugihara, T, et al. (2017), ‘Falsely Elevated Serum Vitamin B12 Levels Were Associated with the Severity and Prognosis of Chronic Viral Liver Disease.’, Yonago Acta Med, 60 (1), 31-39. PubMed: 28331419
Zulfiqar, AA, et al. (2015), ‘Hypervitaminemia B12 in elderly patients: Frequency and nature of the associated or linked conditions. Preliminary results of a study in 190 patients.’, Eur J Intern Med, 26 (10), e63-4. PubMed: 26410155
Zulfiqar, AA, et al. (2016), ‘Hypervitaminia B12: A Useful Additional Biomarker for the Diagnosis and Monitoring of Liver Diseases’, J Blood Disord Transfus, 7 (362), 2. PubMed: