What Causes Neuropathy—and How To Treat It

This is an important topic and something that’s fairly commonly experienced. There’s not a lot of great information out there in the conventional medical world on how to troubleshoot neuropathy if you’re experiencing it.

In this episode, we cover:

2:28 Potential Causes of Neuropathy
5:44 Testing for B12 Deficiency
10:10 Four stages of B12 Deficiency
14:40 Five Potential Causes of B12 Deficiency
17:36 Treating B12 Deficiency 

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Chris Kresser:  Hey, everyone. It’s Chris here. Steve is away. Unfortunately, he had a death in the family and Jordan is not available. So you’re stuck just listening to me go on and on for this episode. We’ll keep it relatively short, since listening to a monologue is never as interesting as a conversation.

But this is an important topic and I figured I would just go ahead and do it, because it’s something that’s fairly commonly experienced, and there’s not a lot of great information out there in the conventional medical world on how to troubleshoot this if you’re experiencing it. Let’s go ahead and listen to the question, and then we’ll get started.

Matt:  Hi, Chris. My question is, what sort of dietary changes, lifestyle changes, and possible supplementation would you recommend for neuropathy? As neuropathy can be associated with diabetes, B12 deficiency, toxin exposure, among other things, what tweaks would you make to your approach of those conditions, if neuropathy is also an issue? Similarly, if one just has idiopathic neuropathy, what recommendations would you suggest? Thanks.

Chris Kresser:  Again, great question. As is often the case, diagnosis is really key. In functional medicine, we always want to address the underlying cause of a problem. That’s what’s going to lead to the most effective and longest-lasting change and solution.

That’s the difference with the conventional model, which is often oriented more around symptoms suppression and disease management, irrespective of the underlying cause. For example, if you have high blood pressure, you take a medication to lower it. If you have high cholesterol, you take a medication to lower it. There’s oftentimes very little investigation into what the underlying causes of those symptoms or conditions may be.

Potential Causes of Neuropathy

With neuropathy, there are a number of potential causes, too many to cover in detail here. We’re going to focus on the ones that I think are the most common and most likely for listeners to be experiencing. Just to give you an idea of the many different things that can lead to neuropathy: we’ve got B12 deficiency; diabetes; toxic exposure, heavy metals; mold toxicity or something called chronic inflammatory response syndrome (CIRS), which I’m going to be talking more about in the future; liver-kidney disease; infections like Lyme disease; obstructive sleep apnea can worsen neuropathy. Then you have some drugs that have neuropathy as a side effect. Cardiac drugs for arrhythmias, certain antibiotics and antivirals that are used to treat HIV, some blood pressure medications, psychiatric drugs that are used to treat bipolar disorders, and anti-seizure medications.

To use a really simple example, if you’re taking one of these drugs and you have neuropathy, the simplest solution would be to talk to your doctor about finding another alternative treatment that’s not going to cause that kind of side effect. But for most people who are listening to this, I imagine that the cause of their neuropathy is something else.

B12 deficiency is, in my experience, by far the most common, and definitely the most common in my patient population. Statistically speaking, in the US, probably diabetes is the most common cause of neuropathy, because diabetes is just epidemic at this point. Then things like toxic exposure, mold toxicity, liver-kidney disease, and infections are probably less common causes.

Again, the most effective treatment here will depend on the cause. If blood sugar is the issue, diabetic neuropathy, then there is some evidence that a ketogenic diet may be helpful. There’s one account in the scientific literature of a complete reversal of diabetic neuropathy after two months of a ketogenic diet. The caveat is that the study was done in mice, not humans, so we can’t say for sure that that’s going to apply to humans. But we have enough research behind the effects of ketogenic diets in many other conditions with humans that I think it’s at least plausible.

And of course, all of the other things that we’ve talked about on the show and on my website and in my book about managing blood sugar, making sure you’re eating enough protein, making sure you’re getting enough exercise, particularly high-intensity exercise and strength training, can be helpful for improving metabolic health.  You want to make sure you’re getting enough sleep. We have tons of research now that shows how poor sleep contributes to diabetes and obesity. You want to make sure you’re managing your stress, reducing your intake of all of the highly-processed and refined foods that contribute to obesity and diabetes, and really focusing on real nutrient-dense, whole foods. We have all those basics. On top of that, doing a ketogenic approach for a period of time might be helpful, as the study I mentioned suggests.

Testing for B12 Deficiency

The next cause is B12 deficiency. We’re going to spend a little bit more time on this, because it’s much more poorly understood in general, even in the sort of functional, alternative medicine community I think.

I’ve written a couple of articles on B12 deficiency that you should definitely check out, if you haven’t already. If you just Google “Chris Kresser B12,” they’ll pop right up at the top. I go into some detail about the prevalence of B12 deficiency in various populations: omnivores, vegans, vegetarians. We talked about some really important information, not very well-known information about testing and diagnosis of B12 deficiency, which I’m going to kind of review here. Then we talked a little bit about treatment.

One of the most important things to understand about B12 deficiency is that the serum B12 is not a very reliable marker for diagnosing B12 deficiency. When you measure B12 in the serum, you’re measuring all of the different cobalamins. Cobalamins are all the different B12 compounds. That ranges from the most inactive forms of cobalamin, like cyanocobalamin, to the more active forms of cobalamin, like methylcobalamin and adenosylcobalamin, which are referred to as active B12. That’s the type of B12 that can actually be delivered, get in the cells, and do what it’s supposed to do. Then there are intermediate forms of cobalamins, like hydroxocobalamin, which are not super active, but more active than something like cyanocobalamin.

When you measure serum B12, you’re measuring all of those different B12s. So it would be possible to have a normal or even high level of serum B12, and have most of that be inactive, and still be suffering from B12 deficiency, because you don’t really have enough of the active B12 that gets in the cells.

I’ve definitely seen that in my practice when I run B12 tests. Every patient that comes to my practice gets a blood test that includes B12. In many cases, we’ll also go on to do more advanced testing for B12 deficiency, which I’m about to tell you about. And I see many patients who have normal B12 levels in the serum, but have evidence of B12 deficiency using the more sensitive markers. So this is something that’s really important to understand.

What are those sensitive markers? Well, the most practical and most available at this time is methylmalonic acid, or MMA for short. You can test methylmalonic acid in the urine or the serum. Methylmalonic acid is an organic acid. It’s a by-product of normal cellular metabolism. It’s converted into succinic acid via a B12-dependent enzyme. That enzyme only can use active B12. So if methylmalonic acid (MMA) is elevated, it suggests there’s not enough active B12 to make that conversion. Therefore, it’s a sensitive indicator for active B12 deficiency.

Urine methylmalonic acid is thought to be more sensitive than serum methylmalonic acid as a marker, because MMA is more concentrated in the urine than it is in the serum. But there are a couple of caveats. Urine methylmalonic acid is not accurate in the case of kidney disease. So if you have kidney issues, it’s not a good marker for B12 deficiency. And serum methylmalonic acid is not accurate in cases of intestinal bacterial overgrowth, which we know is very common. In my patient population, intestinal bacterial overgrowth is far, far more common than kidney disease. In fact, in all the years that I’ve been doing this, I think I’ve only had a few patients with full-blown kidney disease. So I run urine methylmalonic acid as a result, because it’s much more reliable in my patient population.

There is another marker that’s even more sensitive for detecting B12 deficiency. That’s called holotranscobalamin (holoTC). HoloTC is composed of B12 attached to transcobalamin. This represents the biologically active part of B12 that can be delivered into the cells.

Four Stages of B12 Deficiency

There are actually four stages of B12 deficiency. I want to go over them with you, because it really highlights the importance of using this more sensitive testing and the limitations of using serum B12, and then also markers like hemoglobin and red blood cells—the markers of anemia—to detect B12 deficiency.

Stage I and II of B12 deficiency is when the plasma and cell stores of B12 become depleted, and transcobalamin is reduced. That’s all that happens in stage I and II. Typically, there are no other noticeable signs or symptoms. That is what holotranscobalamin (holoTC) will pick up. So there’s no other way that we know of right now to detect B12 deficiency in stage I and II, other than holotranscobalamin.

Stage III characterizes functional B12 imbalance, which involves elevated homocysteine and blood methylmalonic acid. That’s where you can detect B12 deficiency using methylmalonic acid as a marker, in that stage III. That may manifest in some symptoms, but it’s often not obvious to either the patient or the doctor, that those symptoms are B12-related.

I mentioned homocysteine. This is another marker that can be used to detect B12 deficiency at an earlier stage than serum B12. Homocysteine requires B12 and folate to be converted back into methionine. So if you see elevated homocysteine, you can suspect either B12 or folate deficiency. It’s important to understand that homocysteine is not specific to B12. The elevated homocysteine could be more related to folate deficiency than B12, so you can’t use it as an exclusive marker for B12 deficiency. But used in combination with methylmalonic acid, it can be really helpful for detecting B12 deficiency at that earlier stage.

Stage IV of B12 deficiency is when the clinical signs and symptoms of it become evident. That’s when you start to see things like neuropathy, anemia, severe fatigue, and other symptoms that develop with B12 deficiency.

If you think about this, in the conventional model, most people won’t even end up at the doctor until stage III or IV, because that’s when the symptoms start to become evident. By then, B12 deficiency has already progressed to the later stages. If it’s stage III, the doctor runs a serum B12 test, it’s in the normal range, they’ll say, “Oh, this isn’t a problem. Nothing to worry about.” But if you run homocysteine or methylmalonic acid in that stage, you’ll actually be able to detect it before it progresses into that stage IV, where in some cases, the effects of B12 deficiency, neurological damage, can be irreversible. So it’s really, really important to intervene at an early point here.

So why not test holoTC, since it can detect stage I and stage II B12 deficiency? I would love to be able to test that. Unfortunately, it’s not a readily available marker right now. When I wrote the article that I mentioned earlier, Quest Diagnostics had listed it on their website. It’s listed as a test that’s available. But at least here in the Bay Area, it’s not yet available at any Quest lab location. I have yet to hear anyone that’s been able to reliably order it. Hopefully, that will change in the near future. For now, we can use methylmalonic acid and homocysteine to at least detect B12 deficiency that’s progressed to stage III. Fortunately, if you intervene at that point, it’s usually, in my experience, the symptoms of B12 deficiency, including neuropathy, are reversible at that point.

Potential Causes of B12 Deficiency

Let’s talk a little bit about what the potential causes of B12 deficiency are, because it is, as I mentioned, at least in my patient population, the most common cause of neuropathy.

One would be pernicious anemia. This is often missed, I find. I’ve diagnosed several patients with pernicious anemia that didn’t know that they had it. This is an autoimmune disease that involves destruction of the parietal cells in the stomach. The parietal cells are where intrinsic factor is produced. Intrinsic factor binds to B12. The complex of intrinsic factor in B12 is absorbed in the small intestine. If you can’t produce intrinsic factor because your parietal cells are being attacked by your immune system, then essentially, you can’t absorb B12 orally. So people could be eating meat and all kinds of B12-rich foods like liver and shellfish, and they can still be B12 deficient. That’s important to understand, because it’s definitely true that B12 deficiency is way more common in vegans and vegetarians. According to recent tests that have used these more sensitive markers like methylmalonic acid, about 83% of vegans are deficient in B12 and 68% of vegetarians are deficient in B12, versus 5% of omnivores. But an omnivore who has pernicious anemia, for example, could still have B12 deficiency.

Small intestinal bacterial overgrowth (SIBO) and low stomach acid can both impair the absorption of B vitamins, including B12. So I see B12 deficiency in people with SIBO.

Glutathione deficiency can lower B12 levels because one of glutathione’s roles is to protect B12 in the circulation. If it can’t protect it, then B12 gets damaged, and it can’t activate the cells as it should. So you could be glutathione-deficient if you have any kind of autoimmune disease, if you’re suffering from oxidative stress, if you’re not sleeping enough, if you’re not getting enough exercise or getting too much. Basically, anything that causes oxidative stress can deplete glutathione levels.

Then impaired methylation can cause B12 deficiency or interfere with B12 metabolism. We talked a lot about methylation on a recent episode, so I’ll just refer you to that.

Of course, inadequate dietary intake can cause B12 deficiency, which is why vegans and vegetarians have such high levels of B12 deficiency. There are really no adequate sources of B12 in the vegan and vegetarian diet. So if they’re not supplementing with B12 and preferably active forms of B12, then they could definitely have this problem.

Addressing B12 Deficiency

In terms of addressing this, if it is B12 deficiency and it is dietary intake, of course, adding animal foods that contain B12 to your diet is a good idea, if you’re open to that. I list what the highest sources of B12 are in the articles that I mentioned, so check that out. Shellfish, organ meats, and meats, red meat in general, are among the higher sources of B12. If you’re going to supplement with B12, it’s best to take an active form. So methylcobalamin and/or adenosylcobalamin, which is sometimes referred to as dibencozide, are the best forms of B12. If you’re dealing with pernicious anemia, SIBO, or low stomach acid, you’re going to have problems digesting capsules or tablets of B12. The best thing to do would be to use a sublingual form, so that the B12 gets absorbed that way and bypasses the digestive route. I think I carry a form of B12 in my store that I recommend, which is Jarrow Formulas sublingual lozenge of methylcobalamin.

There are studies that show that higher dose sublingual administration of B12 is as effective as injections in some cases. But what I’ve seen is that while most patients do well with B12 lozenges, sublingual form, some actually do better with injections, and they’re not comparable. So if you’re really dealing with pretty serious neuropathy, you’ve got B12 deficiency and have had it for a while, you’ve tried the sublingual lozenges and they’re not working for you, you may want to talk to your doctor about injections. You can get the active forms of vitamin B12 in injection. The typical injection that a doctor will prescribe will be the inactive form, cyanocobalamin. But you can get methylcobalamin injections. Those will generally be more effective.

There are some other supportive nutrients for B12 deficiency. Those include folate; trimethylglycine; vitamin B6, or the active form, which is pyridoxal-5-phosphate (P5P); and vitamin B2, or the active form, which is riboflavin 5’-phosphate (R5P).

If you’re dealing with a lot of oxidative stress and glutathione deficiency, then the antioxidants like vitamin A, E, and C, CoQ10, glutathione itself, selenium, which is important for immune regulation and glutathione production, N-acetylcysteine (NAC), and alpha lipoic acid (ALA) can all be really helpful in putting the brakes on oxidative stress.

I think we’ll stop there. I know that was a ton of information. I didn’t have Steve to interrupt me and help you to absorb everything. Hopefully, that helps those of you who are dealing with neuropathy, especially if it’s related to B12 deficiency.

We’ll talk to you next week. Steve will be back. Keep sending us your questions. We continue to get some really great questions and SI want this show to be all about you and what you want to know, so keep the questions coming in. We’ll talk to you next week.