Q&A on screening persons with Parkinson's for vitamin B12 deficiency
Why should persons with Parkinson’s disease be screened for vitamin B12 deficiency?
Vitamin B12 deficiency is a condition which needs to be recognised and treated promptly, as it may result in permanent, irreversible neurological damages. This has an additional negative impact in persons affected by Parkinson’s disease.
How common is vitamin B12 deficiency in Parkinson’s disease?
Vitamin B12 deficiency is common in Parkinson’s. Parkinson’s is more commonly diagnosed at age over 60. With aging, dietary intake of vitamin B12 decreases and the presence of risk factors for vitamin B12 deficiency significantly increases.
Is anaemia an early symptom of vitamin B12 deficiency?
Unlike what believed by many, neurological symptoms may appear before those of anaemia. In fact, the most common clinical manifestations of vitamin B12 deficiency are neurologic or psychologic symptoms. These are much more common than megaloblastic anaemia.
Are clinical symptoms of vitamin B12 deficiency easy to identify in persons with Parkinson’s disease?
Many of the clinical signs of vitamin B12 deficiency are the same as Parkinson's symptoms, so that makes it more challenging to make a clinical diagnosis of vitamin B12 deficiency in persons with Parkinson’s. Symptoms may include, among others, fatigue, nausea, weakness, numbness, tingling, pins and needles - as in peripheral neuropathy, walking difficulty, orthostatic dizziness, irritability, reduced taste and smell, cognitive impairment, depression, paranoia and dementia.
Why is vitamin B1 therapy in Parkinson's disease an opportunity to detect vitamin B12 deficiency?
As vitamin B12 deficiency symptoms are similar to Parkinson’s, vitamin B12 deficiency may go undiagnosed in persons with Parkinson’s or be recognized too late, when response to treatment is poor. Therefore, before starting B1 therapy, it is important to identify those persons with Parkinson’s who are at higher risk of having vitamin B12 deficiency, so as to treat them promptly. This is an excellent opportunity not to be missed. Vitamin B12 deficiency develops slowly and screening persons with Parkinson’s before they start B1 therapy gives another opportunity of detecting and treating them. Furthermore, if vitamin B1 is started at the same time as treatment of vitamin B12 deficiency, it would be rather difficult to know whether any improvement in symptoms is related to the administration of vitamin B12 or of vitamin B1. This would make it more challenging to find the right dose of vitamin B1 for Parkinson’s.
What is the key message to bring home?
The key message is that it is crucial to recognize and treat vitamin B12 deficiency as early as possible and before starting vitamin B1 therapy.
Are there any vitamin B12 deficiency biomarkers that can aid the diagnosis?
There are four major laboratory indicators of vitamin B12 deficiency: serum total vitamin B12 concentration, homocysteinaemia, methylmalonic acid and holotranscobalamin.
Serum vitamin B12 total concentration is the test most widely used to confirm vitamin B12 deficiency. How reliable is it?
That’s correct. The most widely used biomarker for vitamin B12 deficiency is serum total vitamin B12. Vitamin B12 levels are lower in persons with Parkinson's compared with those without the disease. However, serum vitamin B12 concentrations are not a reliable, sensitive indicator of vitamin B12 deficiency. This means that if we relied only on this test, we would likely miss people with a deficiency in whom serum concentrations of total vitamin B12 are still normal or low/normal. Laboratories most often report as “normal” values which are in the low/normal range, whilst these values may indicate borderline deficiency.
Are there any factors which interfere with vitamin B12 serum test?
In persons who have received parenteral administration of vitamin B12, B12 serum test should be conducted not earlier than at least two weeks after the B12 injection, otherwise serum vitamin B12 levels may be misleadingly elevated. Intake of vitamin A and vitamin C and severe chronic renal disease may increase serum vitamin B12 values while alcohol, smoking and some common medicines (e.g. aspirin) may decrease serum vitamin B12 levels.
If measuring just vitamin B12 total serum concentrations may not be very sensitive, are there other, more reliable laboratory tests which can assist in the diagnosis?
When there is vitamin B12 deficiency, serum levels of homocysteine increase. This is because methylcobalamin, which is one of the two active forms of vitamin B12, participates as a cofactor (helper) in the reaction which converts homocysteine to methionine. When there is a deficiency of methylcobalamin due to vitamin B12 deficiency, the conversion of homocysteine to methionine is adversely affected, homocysteine accumulates and its blood levels increase.
Does an increase in homocysteine levels specifically indicate vitamin B12 deficiency?
No, it does not. An increase in homocysteine may also result from a deficiency of other B vitamins. This is because folates, B6 and betaine participate in homocysteine metabolic pathways, in addition to b12.
So, why should we measure homocysteine?
A normal level of plasma homocysteine rules out vitamin B12 and folate deficiency in an asymptomatic patient.
Are there any factors which may interfere with homocysteine measurement?
Homocysteine levels may increase also as a result of chronic kidney disease, hypothyroidism and smoking.
So, serum vitamin B12 total concentrations alone are not a fully reliable measure of vitamin B12 deficiency - as they may be in the low/normal range even when there is B12 deficiency. Also, homocysteine values may help rule out vitamin B12 deficiency if they are normal and may alert the physician about the presence of a deficiency of vitamin B12 and some other B vitamins if they are increased. Is there any test which more specifically relates to b12 deficiency?
Methylmalonic acid is a biomarker of vitamin B12 deficiency, which is specifically linked to vitamin B12.
Why is methylmalonic acid a more accurate measure of vitamin B12 deficiency?
Methylmalonic acid reflects intracellular vitamin B12 status much more accurately than the other indicators we have seen so far. When there is vitamin B12 deficiency, the level of methylmalonic acid increases and this occurs also when: a) vitamin B12 deficiency is mild; and b) vitamin B12 levels are in the normal reference range. In this case, vitamin B12 deficiency may still be subclinical - so no clinical signs may be manifested yet.
Now, what is the relationship between vitamin B12 and methylmalonic acid?
We have seen that one of the two active forms of B12 is methylcobalamin and that when there is vitamin B12 deficiency homocysteine levels increase. The other active form of vitamin B12 is adenosylcobalamin. If there is a deficiency of vitamin B12 and therefore of adenosylcobalamin, the levels of methylmalonic acid increase.
Are there other conditions in which methylmalonic acid levels may increase?
Methylmalonic acid levels may rise also in the presence of renal insufficiency, hypothyroidism and in the elderly.
What is the “active” vitamin b12?
After absorption, vitamin B12 circulates bound to transcobalamin - holotranscobalamin - and haptocorrin. Transcobalamin carries a small part of the total vitamin B12, 6 to 20%, but this is the one which is transported inside the cells and it has therefore been called the "active" vitamin B12.
What about measuring holotranscobalamin?
Holotranscobalamin is a more sensitive and earlier indicator of vitamin B12 deficiency than total vitamin B12, but the test is not yet widely available.
Are there conditions other than vitamin B12 deficiency which may affect holotranscobalamin levels?
Levels may increase also in the presence of reduced kidney function and liver disorders.
What is so peculiar about vitamin B12 deficiency in Parkinson’s disease?
In Parkinson's disease, vitamin B12 deficiency is associated with peripheral neuropathy, increased walking imbalance issues, cognitive impairment and more rapid progression of the disease.
Hyperhomocysteinemia is also an independent risk factor for osteoporosis and fractures in Parkinson's. It is common in Parkinson's because of the levodopa use. There is an association between higher doses of levodopa, higher levels of homocysteine and lower bone mineral density in persons with Parkinson's, who have a higher prevalence of osteoporosis than controls.
We have seen that the deficiency in vitamin B12 and folic acid may lead to an increase in homocysteine in the blood. Hyperhomocysteinaemia is a risk factor for a number of cardiovascular system disorders and is associated, as we've just seen, to osteoporosis and fractures in people with Parkinson's.
You have mentioned peripheral neuropathy. Why is it important in Parkinson’s disease?
Peripheral neuropathy, especially small fibre neuropathy, is much more common in people with Parkinson's than it was previously thought. Reported rates in Parkinson's may be as high as 55% in some studies, one in two people, compared with 9% in the general population.
Also, neuropathy in Parkinson's is often associated with vitamin B12 deficiency. Persons with Parkinson's who have neuropathy have markedly lower vitamin B12 levels.
Should all persons with Parkinson’s then be tested for vitamin B12 deficiency?
It would be advisable to test all persons with Parkinson’s for b12 deficiency, but that may be an expensive strategy. A cost-effective analysis should be carried out to look into the cost issue. We have identified and selected just a number of risk factors that we have used to develop a proposed screening tool to identify those persons with Parkinson’s who are at higher risk of vitamin B12 deficiency. The presence of any of these factors would be an indication to carry out laboratory testing for vitamin B12 deficiency.
What are these factors?
The first factor is age. Vitamin B12 deficiency and subclinical vitamin B12 deficiency are common in the elderly. The prevalence of vitamin B12 deficiency in those over 60 ranges from 10 to 15% and keeps increasing with age. In the UK, the incidence of vitamin B12 deficiency was in one study found to be 24% of adults aged over 65, much higher than in the general population. Now, since most people with Parkinson's are elderly over 60, they have by definition the age risk factor.
A higher age threshold (75 years) has been chosen in our tool as an independent risk factor as the prevalence of vitamin B12 deficiency increases with age and is much greater in people aged 75 years or older than those less than 75.
Could we be missing those persons with Parkinson’s who have B12 deficiency and are older than 60 but less than 75 years old?
Elderly with Parkinson’s with a lower age than 75 (i.e. 60-74 years old) who are at risk of vitamin B12 deficiency would likely not be missed because many conditions associated with vitamin B12 deficiency are common at that age and occur more frequently in persons with Parkinson’s than in the control population.
Why is vitamin B12 deficiency more common in Parkinson’s disease and in the elderly?
As I said, the main reason for the increased prevalence of vitamin B12 deficiency in the elderly is that, with ageing, there is an increased prevalence of risk factors for vitamin B12 deficiency. On the one hand, we have an inadequate intake from the diet; on the other hand, we have a reduced absorption of vitamin B12. This is especially due to the high prevalence of atrophic gastritis and the frequent administration of medicines in the elderly. Another condition which tends to affect the elderly more than younger people is pernicious anaemia. The prevalence in the elderly over 60 has been estimated by some authors to be 2%, much higher than in the general population, where it has been reported to be 0.1%.
This is why we propose the cut-off age of 75 years as an independent risk factor in persons with Parkinson’s.
So, age is one risk factor. Is diet also a risk factor?
Being strictly vegan is another risk factor for vitamin B12 deficiency. Over 50% of vegans, one in two, in the European Prospective Investigation into Cancer and Nutrition - the EPIC Oxford study, were found to be vitamin B12 deficient. Adequate amounts of vitamin B12 are in fact found almost exclusively in animal-based foods. Vegans exclude from their diet all animal foods, including eggs and dairy products. They consume a diet exclusively based on plant products, which lack vitamin B12. As seen for other groups, they also have an increased risk of vitamin B12 deficiency with ageing.
Does chronic alcoholism increase the risk of vitamin B12 deficiency?
High and chronic intake of alcohol is another risk factor for vitamin B12 deficiency, due to reduced dietary intake and reduced B12 absorption.
Are there any medicines which may interfere with vitamin B12 absorption and increase the risk of vitamin B12 deficiency?
Medicines are an important risk factor for vitamin B12 deficiency in persons with Parkinson's. Carbidopa/levodopa is a medicine which is widely used to control motor signs in Parkinson's. When carbidopa/levodopa is given at high doses and for a long time, levodopa can reduce vitamin B12 levels and increase homocysteine levels, in this way causing neuropathy. This is one reason why some neurologists as a preventive measure prescribe high-dose vitamin B12 in persons with Parkinsons who are given levodopa. Levodopa gel infusion can also cause vitamin B12 deficiency.
Metformin is one of the most widely prescribed drugs in the world. A large body of evidence suggests that patients with type 2 diabetes mellitus treated with metformin are at risk of developing vitamin B12 deficiency over time. This is due to the reduced absorption of vitamin B12 caused by metformin. The risk has been related in some studies to both the dose and the duration of the therapy.
Is there any other medicine which is commonly prescribed in people with Parkinson’s which may increase the risk of B12 deficiency?
Proton Pump Inhibitors (PPI) are medicines which are very commonly prescribed, also in general medical practice. These medicines are used to reduce stomach acidity in conditions such as gastroesophageal reflux, peptic ulcer, Helicobacter pylori infection, gastrinoma, and so on. Some of these conditions are very common also in Parkinson's disease. Vitamin B12 absorption process initially requires the presence of an acid environment to enable the release of the vitamin from food proteins to which it is bound. So, in situations where the gastric environment is no longer acid - like what we find for example in atrophic gastritis and in subjects treated with the proton pump inhibitors, in these situations, dietary vitamin B12 is no longer freed from food. Also, the use of PPIs has been associated with vitamin B12 deficiency.
Are there gastrointestinal conditions which interfere with vitamin B12 absorption?
There is a series of gastrointestinal conditions with vitamin B12 malabsorption. Let's have a look at just some of these conditions.
Atrophic gastritis is common in people over 60 years old. It results from a chronic infection of Helicobacter pylori or is a result of autoimmunity. It leads to reduced production of gastric acid and pepsin. The reduced acidity of the gastric environment leads to vitamin B12 not being freed anymore from food.
It may also lead to the lack of the natural barrier to bacteria, which can then cause a condition called “Small intestinal bacterial overgrowth” or SIBO. SIBO is very common in Parkinson's disease. Up to one in two people with Parkinson's are likely to be affected by it, according to some reports. SIBO may be a consequence also of proton pump inhibitors which lead to excessive growth of bacteria in the intestine.
Gastroesophageal reflux disease is very common also in people with Parkinson's, 1 in 4, in some reports. It is associated with higher High Unified Parkinson's Disease Rating Scale (UPDRS) scores and is also a condition in which proton pump inhibitors are often used. And we have seen that those are risk factors for B12 deficiency as well.
You also mentioned Helicopter pylori infection.
There is a high prevalence of Helicobacter pylori infection in Parkinson's disease. The infection leads to a marked reduction in vitamin B12 levels. It is associated with worse UPDRS scores and its eradication has been reported to lead to clinical improvement and to increase in vitamin B12 levels.
Are there other conditions which may be associated with vitamin B12 deficiency?
Yes, there are a number of other conditions, like those caused by surgery, for example total gastrectomy - the removal of the stomach, which take away the acid environment which enables the freeing of vitamin B12 from protein food and which acts as a barrier to bacteria, therefore increasing the chances of developing SIBO.
Also, the removal of large portions of small intestine - ileum - where absorption of vitamin B12 takes place, may lead to vitamin B12 deficiency. This includes Chron’s disease with ileal resection.
Malabsorption syndromes – e.g. in untreated celiac disease - may also lead to vitamin B12 deficiency. And let’s remember also pernicious anaemia.
So, those are risks for vitamin B12 deficiency which are common in persons with Parkinson’s. Are there other risk factors?
Yes, there are. The list I have referred to is not comprehensive but is likely to identify a large number of persons with Parkinson’s who are at higher risk of vitamin B12 deficiency and who are therefore good candidates for laboratory testing. These include those persons with Parkinson’s who are more at risk of having clinical or subclinical vitamin B12 deficiency. I should stress the fact that we are referring to a specific group of people, those with Parkinson’s, who are already more likely to be at risk of vitamin B 12 deficiency. So, they are by definition a group at risk. The screening tool does not apply to specific groups (e.g. pregnant, breastfeeding women).
Could you summarise the reasons which would justify screening persons with Parkinson’s for testing for vitamin B12 deficiency?
I’ll reiterate some considerations, made also in the literature reviewed:
a) Vitamin B12 deficiency is more common in the elderly and most persons with Parkinson’s are diagnosed with Parkinson’s when they are elderly;
b) Conditions which cause vitamin B12 deficiency are frequently present in the elderly and Parkinson’s;
c) Most symptoms in vitamin B12 deficiency overlap with those of Parkinson’s;
d) Vitamin B12 deficiency treatment is considered safe and efficacious.
Has the screening tool been tested? How accurate is it?
This instrument has not been reviewed nor tested yet. Its sensitivity and specificity have yet to be established. It is therefore proposed only for academic discussion at this stage.
The tool is likely to favour sensitivity (i.e. increasing the ability to identify persons with Parkinson’s with risk for vitamin B12 deficiency – true positives) at the expenses of specificity (i.e. reducing the ability to identify persons with Parkinson’s without risk for vitamin B12 deficiency – true negatives), thus including for screening also some of those who in fact are less likely to be at higher risk of vitamin B12 deficiency.
This choice is justified by the high prevalence of vitamin B12 deficiency in Parkinson’s and the risks of irreversible neurologic damage in those who are not promptly diagnosed and treated. Also, much consideration has been given to the fact that vitamin B12 deficiency symptoms in Parkinson’s add substantial burden on persons with Parkinson’s (e.g., falls, fractures leading to disability).
Could you describe the screening tool that b1parkinsons.org has proposed for persons with Parkinson’s?
The proposed screening tool is based on the most common, well established risk factors for vitamin B12 deficiency, that I have described so far. It is presented in a simple format of six straightforward questions, aiming to identify those people with Parkinson’s who are more at risk for vitamin B12 deficiency and for whom laboratory testing for vitamin B12 deficiency would be advisable. Its ease of use and the fact that it takes only few minutes to go over it makes it suitable for use by general practitioners / family physicians. It is recognized that a limitation is represented by the fact that the information is obtained only through history, which is not always 100% complete, but we are talking about a population, that with Parkinson’s, which is by definition at higher risk of vitamin B12 deficiency.
If “YES” is answered to any of those six questions, then a laboratory screening for vitamin B12 deficiency should be considered. The more the “YES” answers, the more likely the risk of vitamin B12 deficiency.
How would the screening tool be used?
The physician first asks the following six screening questions.
First question: "How old are you?”. This is a routine question which in this case identifies those who are 75 years old or older. We have seen that the risk for vitamin B12 deficiency increases with age and is much higher at the age of 75 or older.
Second question: "Do you have numbness, tingling, stabbing sharp pain, pins and needles, burning feeling at hands or feet?" This suggests the possibility of the presence of peripheral neuropathy at the extremities, which is common in people with Parkinson’s.
Third question: "Are you vegan and not taking any B12 supplements?" We have seen why this is a risk factor for B12 deficiency as well.
Fourth question: “Do you have a chronic, high alcohol intake?"
Fifth question: "Are you taking levodopa, metformin or proton pump inhibitors?" There are also other medicines which may cause vitamin B12 deficiency, but we have limited our list to these three as they are more likely to be commonly used in conditions in Parkinson’s. The higher and the longer their use, the higher the risk for b12 deficiency.
Sixth question: "Do you have any of the following conditions (or have you been found / diagnosed to have any of the following conditions), such as atrophic gastritis, SIBO, gastroesophageal reflux disease, Helicopter pylori infection, gastrectomy, malabsorption, inflammatory bowel disease, pernicious anaemia or anaemia or macrocytosis?
If the answer to any of these questions is "yes", then laboratory tests are needed to confirm the suspicion of vitamin B12 deficiency.
Which laboratory tests would then be recommended in a person with Parkinson’s in whom the screening tool has found the presence of one or more risk factors for vitamin B12 deficiency?
We can currently think of three possible scenarios, based on accessibility to the laboratory tests. Access here refers to both distance (geographical access) and economic access (ability to afford the cost of the test). The scenarios are:
1. the laboratory can test only vitamin B12 levels;
2. the laboratory can test also homocysteine but not methylmalonic acid; and
3. the laboratory can test both homocysteine and methylmalonic acid.
Can we see these scenarios a little more in detail?
The first scenario is the one where the laboratory can test only vitamin B12 levels. It is very common to see physicians requesting this laboratory test when suspecting B12 deficiency. Vitamin B12 is measured and, while waiting for laboratory results, if the patient has symptoms suggestive of peripheral neuropathy, the physician may consider starting a combination of vitamins B, such as B12, B9, B6, B2, depending on the severity of the symptoms and national guidelines.
If the values reported by the laboratory are in the range between 111 and 294 pmol/L, this suggests the possibility that a borderline vitamin B12 deficiency is present and would require if possible further evaluation through other tests, for example methylmalonic acid.
If the values are less than 111 pmol/L, this suggests vitamin B12 deficiency.
If the values are equal to or greater than 295 pmol/L, vitamin B12 deficiency is unlikely.
The second scenario refers to the situation where the laboratory can test vitamin B12 levels and also homocysteine. We measure homocysteinaemia.
If the homocysteine levels are less than 15 micromol/L, we may conclude that vitamin B12 deficiency is unlikely.
If the levels are 15 micromol/L or higher, vitamin B12 deficiency is possible.
Lastly, if the laboratory can test both homocysteinemia and methylmalonic acid, we measure:
a) Homocysteinaemia.
If the levels of homocysteinaemia are equal to, or greater than, 15 micromol/L, then vitamin B12 deficiency is possible, but we don't know yet whether the increase in the levels of homocysteine is due to vitamin B12 or other B vitamins. So, we need to measure methylmalonic acid for confirmation, as methylmalonic acid is very specific for vitamin B12.
b) Methymalonic acid.
If the methylmalonic acid levels are not elevated, we conclude that the reason for the increase of homocysteine levels is not vitamin B12 deficiency. But the increase in homocysteine levels may be due to a deficiency of other B vitamins, like B9 or B-6.
If the methylmalonic acid levels are elevated, over 0.27 micromoles per liter, we then conclude that the patient has vitamin B12 deficiency.
Interpretation of the laboratory findings may be more complex than what I have just described and the patient may need to be referred to a specialist for further investigations.
The aim of the screening tool is to identify for laboratory testing those persons with Parkinson’s who are more at risk of having clinical or subclinical vitamin B12 deficiency. Unlike other screening approaches which may apply to all people, this tool applies specifically to adults with Parkinson’s Disease and does not include specific groups (e.g. pregnant, breastfeeding women).
This Q&A post on screening for b12 deficiency is based on the b1parkinsons.org document “SCREENING FOR TESTING FOR VITAMIN B12 DEFICIENCY IN PARKINSON’S DISEASE B1 THERAPY”, which is part of the b1parkinsons.org technical basis series on the rationale for the High-dose Thiamine (HDT) protocol in Parkinson’s disease. References are provided in that document, which is available in the website “Member area”, reserved for registered users.