Pernicious Anaemia/B12 Deficiency Support Group - Page

05/22/2025

A possible explanation as to why symptoms may return before your injection is due or why some people require more frequent B12 injections than others.

Medical Hypotheses

Research Article
‘Hypercobalaminuria’ – Is urinary cobalamin loss a potential determinantof parenteral cobalamin (B12) efficacy in Pernicious Anaemia?
Andrew McCaddon a,* Ebba Nexo b, Ralph Green c , Kourosh R Ahmadi d , Luciana Hannibal e, Alfie Thain d , Joshua W Miller f

ABSTRACT

It is unknown why many patients with pernicious anaemia are satisfactorily treated with injections of hydroxocobalamin or cyanocobalamin every 1–3 months whereas others require far more frequent replacement regimens, sometimes even weekly. A substantial but inconstant fraction of an injected dose of cobalamin is excreted in the urine within 72 hours of injection, with subsequent loss of variable smaller amounts. We hypothesize the
existence of ‘hypercobalaminuria’, whereby increased urinary cobalamin losses constitute a currently unrecognized factor influencing treatment refractoriness in some individuals. The hypothesis is testable by comparing cobalamin urinary losses in patients needing frequent as opposed to 1–3-monthly injections of cobalamin to remain symptom free. It implies that ‘less-responsive’ patients are likely to have significant hypercobalaminuria.

Introduction

Vitamin B12 (cobalamin) is an essential nutrient required for haematopoiesis and normal neurological function [1,2]. It is only available from biosynthesis by a few soil, aquatic and rumen microorganisms[3,4]. Their symbiosis with animals enriches foods such as meat, fish, milk, eggs, and dairy products [5].

Deficiency of the vitamin is a significant global health issue affecting all ages. It arises from either dietary insufficiency or malabsorption. Dietary insufficiency commonly occurs in those following an unsupplemented vegetarian or vegan diet [6]. A common cause of malabsorption is pernicious anemia (PA) characterized by autoimmune gastritis (AIG) with destruction of parietal cells and loss of intrinsic factor (IF), which is required for absorption of cobalamin in the terminal ileum [7].

In the UK, maintenance treatment of PA is usually via intramuscular
injection of hydroxocobalamin, every 2–3 months, given by a health
care professional. In North America (USA and Canada) the preferred
form is cyanocobalamin, administered monthly [8].

Regardless of the form and frequency conventionally used, many
patients become symptomatic prior to their next scheduled injection appointment [9]. A survey of ‘Pernicious Anaemia Society’ (PAS) members found that many patients feel they do not receive their injection sufficiently frequently for adequate and continuous symptom relief [10].

The PAS and James Lind Alliance (PAS/JLA) recently identified ten
research priorities for PA through a Priority Setting Partnership [11].
Two of these relate to treatment efficacy, 1) why do people with PA need cobalamin injections at different frequencies? and 2) why do some people with PA continue to experience recurrence of symptoms, even after treatment with cobalamin?

The hypothesis

As with any nutrient, deficiency essentially arises from three main
sources in genetically normal individuals: inadequate dietary intake,
inadequate absorption, increased utilisation and/or losses. However, regarding cobalamin, the latter possibility has been overlooked. Other than a few publications in the 1950′s and 60′s [12–14] and the 2000 s2010 s [15–17] there is a remarkable paucity of literature concerning urinary cobalamin losses.

Conclusion

The possibility that increased urinary cobalamin loss can contribute
to deficiency and its associated symptoms has been hitherto neglected. Such a mechanism affords a potential explanation for poor ‘treatment responses’ in a subset of patients with PA. The hypothesis is testable by measuring total urinary excretion of cobalamin for several days following its parenteral administration to well characterised deficient individuals and determining the relationship of the rate of loss to plasma levels of cobalamin and duration of symptom relief.

It would also be possible to gain insight into the likely underlying
mechanism for any increased excretion, by determining whether the loss in such individuals primarily comprises only free or also transcobalamin bound cobalamin, the former being more likely.

Full article

05/21/2025

PERSPECTIVE

Treatment of vitamin B12 deficiency–Methylcobalamine?
Cyancobalamine? Hydroxocobalamin?—clearing the
confusion
K Thakkar1,3 and G Billa1

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl).
There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and
promoted. This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl
is primarily involved along with folate in hematopiesis and development of the brain during childhood. Whereas deficiency of
AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin. Thereby, it is
important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl or hydroxocobalamin or Cbl.

European Journal of Clinical Nutrition (2015) 69, 1–2; doi:10.1038/ejcn.2014.165; published online 13 August 2014

fil:///C:/Users/korni/OneDrive/Kim%202021%20Tax%20Documents/Adenosylcobalamin%20needed/thakkar2014.pdf

05/11/2025

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency
Luciana Hannibal 1, Vegard Lysne 2, Anne-Lise Bjørke-Monsen 3, Sidney Behringer 1, Sarah C Grünert 1, Ute Spiekerkoetter 1, Donald W Jacobsen 4, Henk J Blom 1

Abstract
Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of 250 pmol/L), low (150–249 pmol/L), and acute deficiency (650 pmol/L), such as cancer (Arendt et al., 2016) and autoimmune lymphoproliferative syndrome (ALPS) (Bowen et al., 2012).

Homocysteine
Homocysteine is a metabolite of one-carbon metabolism that is remethylated by MeCbl-dependent MS or betaine-homocysteine methyltransferase as part of the methionine cycle (Finkelstein and Martin, 1984) and degraded by cystathionine β-synthase (CBS) in the transsulfuration pathway (Figure 2). Conversion of Hcy to Met by MS depends on the availability of both vitamin B12 and folate (as N5-CH3-THF), and therefore, nutritional deficiencies in either one of these micronutrients lead to the accumulation of Hcy in serum and urine. Likewise, inborn errors of metabolism that impair the upstream processing and trafficking of B12 or folate lead to elevation of this metabolite, a condition collectively known as hyperhomocystinemia. The normal range of total plasma Hcy (tHcy) in human plasma is 5–15 μmol/L (Ueland et al., 1993) and values >13 μmol/L may be considered elevated in adults (Jacques et al., 1999). Homocysteine levels are always higher in serum compared to plasma due to the release of Hcy bound to cellular components (Jacobsen et al., 1994). Hence, plasma and not serum should be used to determine the levels of tHcy. Although gender and age reference intervals have been established in some studies (Jacobsen et al., 1994; Rasmussen et al., 1996; van Beynum et al., 2005), they are usually ignored in the reporting of tHcy levels. Because of the dual biochemical origin of elevated Hcy, this biomarker is of limited value to assess vitamin B12 status as a stand-alone measurement. This is also true for the newborn screening of inborn errors of vitamin B12 metabolism found in the cblD, cblF, and cblJ (Huemer et al., 2015) disorders.

Methylmalonic acid
MMA increases upon inactivation of AdoCbl-dependent MCM in the mitochondrion. Nutritional and functional deficiencies of vitamin B12 result in the inactivation of MCM leading to buildup of its substrate methylmalonyl-CoA, which enters circulation as free MMA. The reaction catalyzed by MCM (Figure 2) is not affected by other vitamins of one-carbon metabolism, and therefore, MMA is considered a more specific marker of vitamin B12 deficiency (Clarke et al., 2003). Serum values of MMA, ranging from >260 to 350 nmol/L indicate elevation of this metabolite (Clarke et al., 2003). Nonetheless, there are few pathologies such as renal insufficiency that lead to an increase in MMA (Iqbal et al., 2013). For example, one study showed that 15–30% of individuals with high vitamin B12 concentrations in serum also had elevated MMA concentrations, which may reflect renal dysfunction instead of authentic vitamin B12 deficiency (Clarke et al., 2003). Thus, the utility of this marker should be considered carefully in older patients and patients with suspected or established renal disease. Assessment of a second marker of vitamin B12 status, such as holo-transcobalamin (holo-TC) (Iqbal et al., 2013) should be considered. Another study showed that the clearance of both Hcy and MMA may be compromised in patients with reduced kidney function (Lewerin et al., 2007).

Total serum holo-transcobalamin
Dietary B12 is transported in the digestive system via the use of three protein transporters that bind the micronutrient in a sequential fashion, following the order haptocorrin (HC), intrinsic factor (IF), and transcobalamin (TC) (Fedosov et al., 2007; Fedosov, 2012). After absorption in the intestine, vitamin B12 bound to TC (holo-TC) reaches circulation and it is distributed to every cell in the body. Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (TCblR; CD320) (Quadros et al., 2009). Because the only fraction of dietary vitamin B12 that is bioavailable for systemic distribution is in the form of holo-TC (Valente et al., 2011), the level of holo-TC in serum has been successfully utilized as a marker of bioactive vitamin B12 (Nexo et al., 2000, 2002; Valente et al., 2011; Yetley et al., 2011). Holo-TC represents 6–20% of the total vitamin B12 present in serum (Nexo et al., 2000, 2002; Valente et al., 2011; Yetley et al., 2011). This marker is more accurate in assessing the biologically active fraction of vitamin B12 in circulation than serum B12 itself, and its level correlates well with the concentration of vitamin B12 in erythrocytes (Valente et al., 2011). The diagnostic value of holo-TC has proven superior to Hcy and MMA for the assessment of vitamin B12 status in the elderly (Valente et al., 2011). The normal range of holo-TC in healthy subjects is 20–125 pmol/L (Valente et al., 2011). Additional research is needed to elucidate the mechanisms that control holo-TC homeostasis in the normal population and in pathologies that alter vitamin B12 transport and utilization. For example, abnormally low levels of holo-TC have been documented in patients receiving chemotherapy, macrocytosis and in individuals carrying the TC polymporphism 67A>G, without vitamin B12 deficiency (Vu et al., 1993; Wickramasinghe and Ratnayaka, 1996; Riedel et al., 2005, 2011). Insufficient sensitivity (44%) of holo-TC as a marker of vitamin B12 status was noted in a cohort of 218 institutionalized elderly patients (Palacios et al., 2013). At present time, it is unknown whether and how holo-TC levels vary in patients harboring inborn errors affecting intracellular vitamin B12 metabolism (cblA-cblJ). Thus, the diagnostic value of holo-TC as a first line test awaits further investigation.

Algorithms for the diagnosis of vitamin B12 deficiency
According to the World Health Organization (WHO), vitamin B12 status in adults is defined by the serum levels of the micronutrient with the following cut-offs and definitions: >221 pmol/L is vitamin “B12 adequacy”; between 148 and 221 pmol/L is “low B12,” and lower than 148 pmol/L is “B12 deficiency” (de Benoist, 2008; Allen, 2009). However, stand-alone markers of B12 status, such as serum B12, have proven insufficient for the unequivocal diagnosis of vitamin B12 deficiency (Fedosov, 2013; Palacios et al., 2013; Remacha et al., 2014; Fedosov et al., 2015). Further, the WHO criterion does not account for age effects. Algorithms that combine a minimum of two biomarkers have been employed worldwide, each exhibiting advantages and disadvantages (Palacios et al., 2013; Remacha et al., 2014).

A study performed on a Swedish population proposed that when physicians request testing for suspected vitamin B12 or folate deficiency, the first-line test of choice should be tHcy, and only when tHcy > 9 μM, should additional markers be tested to discriminate between vitamin B12 and folate deficiencies (Schedvin et al., 2005). This approach proved effective in reducing diagnostic costs by 30% (Schedvin et al., 2005).

Herrmann and Obeid proposed a two-step algorithm for the diagnosis of vitamin B12 in adults that utilizes holo-TC and MMA as biomarkers (Herrmann and Obeid, 2013). Analysis of 1359 samples submitted to the laboratory for total vitamin B12 assessment showed that patients exhibiting holo-TC values between 23 and 75 pmol/L and normal renal function should also be tested for MMA (Herrmann and Obeid, 2013). This guideline was widely recommended in Germany (Herrmann and Obeid, 2008) for the diagnosis of vitamin B12 deficiency in risk groups including infants, unexplained anemia, unexplained neuropsychiatric symptoms, gastrointestinal conditions including stomatitis, anorexia and diarrhea, the elderly, vegetarians and individuals with gastrointestinal diseases such as ilium resection, chronic atrophic gastritis, Crohn's disease and Helicobacter pylori infection and individuals under treatment with proton-pump inhibitors (Herrmann and Obeid, 2008; Hartmann et al., 2009; Koch, 2009; Heinzl, 2014). A cutoff of holo-TC of 50 pmol/L was set to discriminate between individuals unlikely to have vitamin B12 deficiency (holo-TC > 50 pmol/L) vs. those potentially deficient in the micronutrient (holo-TC < 50 pmol/L) (Herrmann and Obeid, 2008). Patients with potential vitamin B12 deficiency were first stratified by holo-TC levels as very low (holo-TC < 35 pmol/L) and low (holo-TC 36–50 pmol/L), and a second-line testing of MMA follows thereafter. Results from MMA lead to a three-block classification of patients, where (a) MMA < 271 nmol/L with holo-TC < 35 pmol/L represents a negative vitamin B12 balance (insufficiency), (b) MMA < 271 nmol/L with holo-TC 36–50 pmol/L suggests the patient is unlikely to be vitamin B12 deficient, and (c) a range of possible vitamin B12deficient patients is characterized by MMA > 271 nmol/L with holo-TC being very low or low (Herrmann and Obeid, 2008).

Berg and Shaw presented a cascade-testing algorithm that stratified patients first by total serum vitamin B12 levels and second by MMA levels, using cutoffs of 118 pmol/L and 0.80 μmol/L, respectively (Berg and Shaw, 2013). The authors encouraged the sequential measurement of these two biomarkers prior to the implementation of vitamin B12 therapy in patients.

Guidelines from the British Committee for Standards in Hematology suggested the use of total serum vitamin B12 as the first-line test, with MMA as the second-line test (Devalia et al., 2014). For the reasons presented in the sections above, this approach would exclude a significant fraction of patients for which serum vitamin B12 does not reflect cellular, genetic, and pharmacological disturbances that lead to functional vitamin B12 deficiency. It was also recommended that individuals classified as having “subclinical deficiency” be provided with empirical therapy with oral CNCbl 50 μg daily for 4 weeks, and have their serum B12 levels re-checked after 3 months (Devalia et al., 2014). Immediate medical attention was recommended for patients with symptoms of neuropathy.

Functional B12 deficiency: serum markers vs. cellular status of vitamin B12
A number of studies point to the lack of correlation between serum and cellular levels of vitamin B12 (Carmel, 2000; Solomon, 2005; Devalia et al., 2014; Lysne et al., 2016), and this is particularly important in the case of inborn errors of cobalamin metabolism whereby serum levels of the micronutrient are within the normal range(Watkins and Rosenblatt, 2013). In this regard, serum vitamin B12 and holo-TC should be avoided as sole markers of B12 deficiency in neonatal screening. Time-consuming metabolic studies to uncover genetic complementation or lack of function continue to be utilized in a very limited number of metabolic centers worldwide (Figure 3). In newborn screenings where biochemical markers are indicative of vitamin B12 deficiency, the diagnosis of inborn errors of vitamin B12 metabolism is performed via functional studies on cultured fibroblasts isolated from skin biopsies (Watkins and Rosenblatt, 2013) or via molecular genetic analysis of putative genes. Functional studies include [14C]-propionate or [14C]-N5−methyl-tetrahydrofolate incorporation into cellular macromolecules, to assess the activities of MCM and MS, respectively, and biosynthesis of MeCbl and AdoCbl upon metabolic labeling with holo-TC made from apo-TC and commercially available [57Co]-vitamin B12 (Watkins and Rosenblatt, 2013). Decreased uptake of [57Co]-vitamin B12 is indicative of impaired receptor-mediated endocytosis of holo-TC by the transcobalamin receptor. Accumulation of [57Co]-vitamin B12 in the lysosome suggests a dysfunctional cblF or cblJ protein unable to mediate exit of B12 from the organelle (Figure 1). Isolated or combined disruption of MeCbl and AdoCbl levels indicates failures in intracellular processing (cblC, cblX), trafficking (cblD), and/or coenzyme biosynthesis and utilization (cblA, cblB, cblG, cblE, mut). When results from [14C]-propionate or [14C]-N5-methyl-tetrahydrofolate incorporation suggest abnormal vitamin B12 metabolism, somatic cell complementation analysis usually follows (Watkins and Rosenblatt, 2013). Cells from patients are fused with cells from other patients with confirmed mutations using polyethylenglycol and the [14C]-propionate or [14C]-N5-methyl-tetrahydrofolate incorporation studies are repeated to interrogate complementation of function. If the incorporation is corrected with respect to control cell lines, then the two cell lines belong to different complementation groups. In contrast, lower than normal [14C]-propionate or [14C]-N5-methyl-tetrahydrofolate incorporation after fusion of cell lines with polyethylenglycol confirms that the two patients possess the same genetic defect (Watkins and Rosenblatt, 2013). Nowadays, the vast majority of genes whose mutation lead to functional vitamin B12 deficiency have been identified, and therefore, sequencing of these genes or next generation sequencing permits unequivocal diagnosis (Pupavac et al., 2016).

Combined B12 and iron deficiency
Iron deficiency is a condition that could lead to masking of megaloblastic anemia caused by vitamin B12 and folate deficiencies (Remacha et al., 2013). The combined deficiency of iron and vitamin B12 deficiency is more prominent in individuals aged 60 and older. In general, albeit not always, iron deficiency leads to microcytosis whereas vitamin B12 and folate deficiencies result in macrocytosis (Green, 2012). An algorithm to distinguish between these two large classes of anemia based on a decreased in RBC count, hematocrit and hemoglobin levels has been described (Green, 2012). In addition, an algorithm that introduces age and tHcy levels has been developed to discriminate iron deficiency anemia vs. iron and vitamin B12 combined anemia (Remacha et al., 2013).

The article is longer but well worth reading. This should be a link to the full article.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4921487/

05/11/2025

Bringing this to the top of the page.
https://www.facebook.com/PAB12DSupportGroupPage/videos/835026806640041

04/30/2025

How many women have received an abnormal result for a pap smear. B12 deficiency and or folate deficiency can be a cause of an abnormal pap smear. If this happens to you, please have B12 and folate tested. If you are already on B12 treatment, you may need more frequent B12 injections but also have folated tested.

03/11/2025

How has your experience been with getting a diagnosis and or treatment since the new NICE guidelines came into affect in March of this year.
The following study is asking for patient experience as per the new guidelines. Has it been worse. Has your doctor refused to test intrinsic factor antibodies as per the NICE guidelines. Have you been told that your child could not possibly be deficient in B12 because the guidelines apply only to 16 years old and above. If you are a UK resident and want to share your experience in a study, please fill out form at link below. Pat Kornic

https://forms.office.com/pages/responsepage.aspx?id=48B4T1DS3027HBXTFFaXzPbds7cabuNBjRZ7wDSgNfJUN1BVWlJCV0NOSzRYREdLUE1GREk2SkVVRC4u&route=shorturl

01/04/2025

Cobalamin C Deficiency
Note: testing for Cobalamin C Deficiency is now part of the newborn screening process in the United States. I do not know about other countries. However, as this just came into effect in the year 2000, this means there is a large population that would not have been screened and could result in late onset development of Cobalamin C Deficiency in adults. This deficiency can only be diagnosed by genetic testing. (PK)

Cobalamin C (Cbl-C) defect is the most common inborn cobalamin metabolism error; it causes impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The gene responsible for the Cbl-C defect has been recently identified, and more than 40 mutations have been reported. MMACHC gene is located on chromosome 1p and catalyzes the reductive decyanation of CNCbl. Cbl-C patients present with a heterogeneous clinical picture and, based on their age at onset, can be categorized into two distinct clinical forms. Early-onset patients, presenting symptoms within the first year, show a multisystem disease with severe neurological, ocular, haematological, renal, gastrointestinal, cardiac, and pulmonary manifestations. Late-onset patients present a milder clinical phenotype with acute or slowly progressive neurological symptoms and behavioral disturbances. To improve clinical course and metabolic abnormalities, treatment of Cbl-C defect usually consists of a combined approach that utilizes vitamin B12 to increase intracellular cobalamin and to maximize deficient enzyme activities, betaine to provide a substrate for the conversion of homocysteine into methionine through betaine-homocysteine methyltransferase, and folic acid to enhance remethylation pathway.

B12 and folate levels will always appear normal or even high in Cobalamin C Deficiency. However, homocysteine and MMA will be above range.

Hydroxocobalamin, folic acid and betaine is the recommended treatment. In one research article, the research doctors set a target level of B12 at over 1,000,000 pg/ml,

Pearls & Oy-sters: Late-Onset Cobalamin C Deficiency Presenting With Subacute Combined Degeneration

Abstract
Cobalamin C (CblC) deficiency is a rare inborn error in cobalamin (vitamin B12) metabolism which results in impaired intracellular processing of dietary vitamin B12. This leads to a wide range of clinical manifestations including cognitive impairment, psychiatric symptoms, myelopathy, thrombotic events, glomerulonephritis, and pulmonary arterial hypertension. CblC deficiency typically presents in the pediatric population but can also present in adulthood. Diagnosis in adults can be challenging due to the rarity of this condition and its myriad clinical presentations. CblC deficiency is treatable, so early diagnosis is important in preventing permanent neurologic damage. Although CblC deficiency results from a defect in vitamin B12 metabolism, B12 levels remain normal. Diagnosis depends on testing metabolites altered by vitamin B12 dysfunction such as methylmalonic acid (MMA) and homocysteine. We presented a case of a 20-year-old woman who presented with chronic progressive lower extremity weakness and sensory changes. She was eventually diagnosed with subacute combined degeneration because of CblC deficiency and effectively treated. This case highlights the importance of considering inborn errors of metabolism in adult patients and including testing of metabolites such as MMA and homocysteine when suspecting vitamin B12 dysfunction.

Pearls
Cobalamin C (CblC) deficiency is a rare cause of myelopathy in adults.
CblC deficiency can present with a range of neurologic, psychiatric, and systemic symptoms.
CblC deficiency is treatable, and early diagnosis can help prevent permanent neurologic damage.

Oy-sters
Testing solely for vitamin B12 without methylmalonic acid (MMA) and homocysteine will miss inborn errors in metabolism such as CblC deficiency.

Treatment is adjusted to target vitamin B12 levels above1,000,000 pg/mL, normalization of methionine, and reduction in MMA and total homocysteine.1 There are limited guidelines for long-term surveillance, but it is common to monitor vitamin B12, MMA, total homocysteine, renal function, and hematologic parameters.5 All patients with CblC deficiency should be seen by an ophthalmologist at the time of diagnosis regardless of symptoms.5 Patients should be counseled to avoid protein restriction and nitrous oxide exposure, such as with dental anesthesia.5 Outcomes are variable, ranging from complete recovery to death, and depend in part on the genetic profile and duration of untreated disease. Patients with late onset disease tend to do better and can have significant improvement if treated early.

Cobalamin C (CblC) deficiency is a rare inborn error in cobalamin (vitamin B12) metabolism which results in impaired intracellular processing of dietary vitamin B12. This leads to a wide range of clinical manifestations including cognitive impairment, psychiatric symptoms, myelopathy, thrombotic eve...