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For Dr. Ed

Posted by Sharon W on 5/06/03 at 14:08 (117923)

Dr. Ed,

This is in reply to your comment on my post about nutritional neuropathies; the thread fell off the page, so I'm re-posting my response to you.

You made a very important point :D and it bears repeating. You said, '...many nutritional neuropathies are due to malabsorbtion problems. It is important to measure serum levels to see if the nutrients are being absorbed.'

The thing I noticed is that the article I posted before on nutritional neuropathies didn't mention the other two tests that can show evidence of cellular uptake of Vitamin B12 - or lack of it. A peripheral neuropathy (PN) patient named Rose Fuhrman has made this issue a sort of personal crusade. She, too, exhorts anyone with PN to be sure they are tested for SERUM levels of B-12 -- but she adds: 'Many patients are damaged, even disabled while testing well into normal. Rarely, patients are deficient even when blood levels are high, because B-12 does not work in the blood; it works in the tissues. Some people can absorb B-12, but they cannot deliver it from blood to tissues.'

Rose adds, 'If the B-12 result is not clearly deficient, the patient with neurologic symptoms should have follow up tests: methylmalonic acid and homocysteine.' She suggests that those taking oral B-12 should purchase methylcobalamin, a type of B-12 that is well-absorbed by the body.

More detail on this topic can be found in the article: 'Laboratory Diagnosis of Vitamin B-12 and Folate Deficency' by Christopher F. Snow, Archives of Internal Medicine, June 28, 1999 v159 i12 pl289.' Dr. Snow's article is available from the site of the American Medical Association: http://www.ama-assn.org (-- so presumably, any MD could get it for you quite easily).


Re: For Dr. Ed

Ed Davis, DPM on 5/06/03 at 17:40 (117940)

I am not aware of tissue assays being done to look for B12 levels on a cellular level. There is no compelling reason to believe that once B12 or folic acid is in the bloodstream, that cells have difficulty with uptake. On the other hand I have plenty of anectodal evidence of patients with PN of various types getting significant relief with B12 shots (very inexpensive) given by old timers. That practice is scorned but I am suspicious that there is far more than a placebo effect involved.

Absorbtion of B12 requires the presence of intrinsic factor in the stomach as well as adequate levels of stomach acidity (hydrochloric acid). Some hypothesize that low levels of stomach acidity are a bigger problem than expected. Incomplete digestion due to insufficient acidity, delays digestion and thus leads to indigestion, heartburn and GERD (gastroesophageal reflux disease). Those entities are usually treated via drugs like Tagamet, Pepcid which decrease acid production. I have actually tested this hypothesis on myself as I have GERD. If I take Betaine HCl with dinner, I have no symptoms of GERD at night and require no drugs before bedtime. Of course, I am a sample size of one.

I recall some posts on this site in which a patient was treated surgically for TTS and PN, only to discover a deficiency state which led to her cure. That patient was deficient in a B vitamin other than B12 and folic acid.

One possibility is that blood tests only measure serum levels at a specific time so if there are significant fluctuations, that will not be caught.

Re: For Dr. Ed

Sharon W on 5/07/03 at 09:46 (118008)

Dr. Ed,

I can tell you that homosysteine levels indicate absorption of methylcobalamin, the more neurologically active form of B12. Homosysteine and methylmalonic acid (MMA) are both metabolites of vitamin B-12.

However, I've been unable to get Dr. Christopher F. Snow's article (so far), and the abstract is very brief -- it doesn't contain the info in question.

I did find a couple of sites REVIEWING Dr. Snow's article that mention these other tests (and I have included some excerpts):




Prof Nils Tryding, Box 57, 296 21 Åhus
(email removed)

'Recently, the laboratory diagnosis of deficiency states of vitamin B12 and folate appeared simple. The increase of information and knowledge have problemized routine diagnostic concepts'

'Christopher F. Snow addressed the above-mentioned problems i a recent review (1). The author analyzed 59 scientific papers on the topic... Many drugs interfere with cobalamin and folate metabolism, a memento to the observant clinician.'

'The main part of the Snow paper (1) reviewed routine laboratory investigations for suspected vitamin B12 and folate deficiency. For every test, causes of fluctuations and misinterpretations are elucidated. In particular, the Schilling test is subject to many restrictions and limitations. Consequently, the test is about to vanish from clinical routine.'

'The weak points of serum cobalamins are widely recognized by now. In contrast, corresponding restrictions and limitations of folate determinations are not widely acknowledged. The folate level of serum is influenced by temporary dietary restrictions, alcohol intake, and hemolysis in the sample. The serum level of folate reflects dietary habits of the last day or week. The folate level of the erythrocytes is more stable from a biological point of view. The technique of analysis is, however, subject to debate.'

'The metabolites methyl malonate (MMA) and homocysteine have improved routine investigation of suspected deficiency of vitamin B12 and folate.'

'Treatment with vitamin B12, folate and pyridoxine usually lowers MMA and homocysteine in in groups of patients and in individual patients.'



'If intrinsic factor antibody is normal then test for serum gastrin levels as gastrin will be elevated in those patients with PA [pernicious anemia] but without intrinsic factor antibody.'

'Borderline levels of B-12 (100-300 mg/L)

Patients with borderline levels of B-12 (100-300 mg/L) should be tested for methylmalonic acid (MMA).'

'MMA and homocysteine are both elevated in patients with PA.'

'Only 1% of patients with PA have normal MMA levels.'

'If B-12 levels are borderline and MMA and folate levels are normal the patient is unlikely to have PA and can be followed and subsequently retested if symptoms persist.'

'If MMA is elevated proceed with testing for intrinsic factor antibody and gastrin.'

'It is important to remember that folate may correct the hematological abnormality in B-12 deficient patients but that neurological damage will progress until the B-12 deficiency is corrected'

Re: For Dr. Ed

Sharon W on 5/07/03 at 10:38 (118012)

Dr. Ed,

Here's some more info on Vitamin B-12 deficiency and its metabolites, from Postgraduate Medicine (and some excerpts follow):




Two cobalamin-dependent enzymatic reactions occur in humans. The first reaction converts methylmalonyl-coenzyme A (CoA) to succinyl-CoA using cobalamin as a cofactor. Vitamin B12 deficiency leads to an increase in serum methylmalonyl-CoA and its metabolic product, methylmalonic acid (MMA). The second reaction uses cobalamin as a cofactor in the synthesis of methionine from homocysteine. Deficiency in B12 leads to an accumulation of homocysteine. Thus, both MMA and homocysteine levels increase in vitamin B12 deficiency. Homocysteine levels also increase in folic acid deficiency (12), vitamin B6 deficiency, renal failure, and hypothyroidism as well as in aging persons and persons with a genetic defect involving cystathionine beta-synthase (13,14). Thus, an elevated MMA level is viewed as a more specific marker for vitamin B12 deficiency except in chronic renal failure, in which MMA increases independently of B12 levels.'

'Conditions that affect absorption

...Pernicious anemia, once believed to be the most common cause of vitamin B12 deficiency (15), may account for only a small percentage of cases (4). Deficiency most often results from food-cobalamin malabsorption due to gastric dysfunction that may be exacerbated by the use of acid-lowering agents (eg, proton pump inhibitors, histamine2 receptor antagonists) (16,17).Certain other drugs (eg, cholestyramine [LoCHOLEST, Prevalite, Questran], p-aminosalicylate, metformin hydrochloride [Glucophage], colchicine) cause malabsorption through effects on the ileal mucosa or membrane receptors or by other means (10).'

'Vitamin B12 deficiency may take decades to develop, and affected patients may be asymptomatic or may present with a wide spectrum of hematologic and neuropsychiatric manifestations. Herbert (1) outlined four stages in the development of vitamin B12 deficiency. Stages 1 and 2 represent conditions in which the biochemical depletion of vitamin B12 occurs prior to any obvious clinical damage; serum B12 levels may still be normal. Stages 3 and 4 represent conditions of true deficiency with obvious metabolic components, clinical components, or both; serum B12 levels are low, and serum MMA and homocysteine levels are high. Any hematologic and neurologic features tend to occur in the late stages (1).'

'Hematologic and neuropsychiatric manifestations can occur simultaneously, in sequence, or independently... a rapid-onset, postoperative myeloneuropathy due to nitrous oxide anesthesia that inactivates marginal B12 stores has been described (18). Shooting pains in the extremities (Lhermitte's sign) indicate spinal cord involvement, root involvement, or both, but are not specific for vitamin B12 deficiency. The presence of ataxia, altered tendon reflexes, Romberg's sign, and extensor plantar reflexes suggests subacute combined degeneration (ie, involvement of posterior or lateral columns of the spinal cord, or both). Neurologic features may improve rapidly with therapy, and damaged axons may regenerate (10,19). The window of opportunity to initiate treatment to reverse or minimize complications is narrow.'

Re: For Dr. Ed

Ed Davis, DPM on 5/07/03 at 11:34 (118022)

That is particularly interesting because homocysteine has been implicated as a major factor in the development of atherosclerosis. Homcysteine levels can be controlled via ingestion of B12, folic acid and trimethylglycine (a supplement termed 'homocysteine factor' has exactly those three and is produced by Pure Encapsulations: http://www.purencapsulations.com )

Re: For Dr. Ed

Sharon W on 5/07/03 at 17:16 (118045)

Thanks, Dr. Ed!

Maybe I'll order some of those 'homocysteine factor' supplements for myself... But I do worry about one thing -- is there a risk of taking TOO MUCH of these nutrients? I've been taking a multivitamin AND a B-100% complex with additional B-12. Would I have to stop taking either of them?


Re: For Dr. Ed

Sharon W on 5/08/03 at 07:16 (118077)

Dr. Ed,

My PCP also mentioned the homosysteine link with heart disease -- I'm glad mine was normal! (Of course, I do want it to STAY that way...)

This quote by itself would be a good reason for taking that 'homosysteine factor' supplement:



Lancet6 (vol. 346, pg. 1395-98, 1995)

'These findings suggest that tHcy (homocysteine) is a strong and independent risk factor for stroke.'

'Moderately elevated Hcy concentrations, reflecting less severe genetic defects and deficiency of nutritional factors required for Hcy metabolism (folic acid, vitamin B12, vitamin B6) are common in the general population. There are consistent data from more than 20 cross-sectional and case-control studies linking moderate hyperhomocysteinaemia with vascular disease, including peripheral vascular disease, ischaemic heart disease and stroke.'

Re: For Dr. Ed

elliott on 5/08/03 at 09:12 (118084)


Not to take away your never-ending thunder with all this PN discussion, nor do I claim to know the particulars of your case, but for balance I'd like to say that after a less-than-perfect TTS surgical outcome, doctors for lack of something better to say often are too quick to tell their patients that perhaps they have one of the 2000 or so PNs, when in reality it's just a less-than-perfect TTS surgical outcome, whether due to scar tissue, the tension on the nerve not coming out exactly right, or whatever, and not necessarily even the doc's fault. A few months after my TTS release, my foot got much worse in one respect, to the point of having trouble coping and not being able to tolerate shoes, and the doc suggested I may have one of the PNs. Well, it took 3 years to settle down to the point I now call the surgery a success, so I guess I don't have any PN after all.

There certainly is merit for those with continuing trouble to get tested for the major PNs, possibly try a few of the more common supplements and keep on the lookout for any unusual symptoms that may help oneself or a doc zone in one of the rarer PNs. But without more to go on, I'd be reluctant to take too many medications, vitamins or supplements hoping for a lucky stab in the dark: there may be no PN at all, and, aside from cost, some of these medications, vitamins and supplements are not without risk either, which, knowing nothing more, possibly outweighs the potential gain. Of course, if I ever need to zone in on a PN, I'll give you a buzz. :-)


Re: For Dr. Ed

Bev on 5/08/03 at 11:38 (118101)

Friday when you have your lab work done, are you going to have them check for all of these things you have been discussing these past several days? Just think, in another week , hopefully, you will have those labs back and you will finally have some more answers. Some labs may take 2 weeks though. How are your hands & arms doing, the numbness in them?

Re: For Dr. Ed

Sharon W on 5/08/03 at 11:41 (118102)


You made a very good point. If what I had were actually the remnants of TTS after a surgery that's not completely successful, it wouldn't be that unusual to get diagnosed -- three times in a row -- with PN that I didn't really have.

Which brings up something I've been harping on lately. If there's one thing I've learned in the past two years, it's that diagnoses are only doctors' OPINIONS -- and of course, opinions often vary. What many doctors seem to do is take the easy route, just make a best guess based on whatever info they already have available to them (especially when the patient has a previous diagnosis), typically without bothering to do any additional tests or follow-up exams to confirm their opinions.

The problem is, if you don't have an accurate and complete diagnosis, you can receive all the treatments in the book (sometimes even surgery!) but since those treatments are for a problem you don't really have, they won't do you any good at all!

It is quite possible that I don't have PN at all - it could be something else. I do think it's highly PROBABLE that some of the problems in my right foot are after-surgery remnants of TTS...

However, TTS doesn't cause problems with controlling your hands. And it doesn't cause your thighs to get all weak and wobbly sometimes. And it doesn't usually play havoc with your balance to the point that sometimes you bump into walls.


Re: For Bev

Sharon W on 5/08/03 at 12:07 (118105)


Actually, what my doctor plans to do tomorrow is more thoroughly check out the COMMON causes for PN -- she said she'd order glycosated hemaglobin and glucose tolerance test (for pre-diabetic neuropathy), TSH and free T3 and free T4 (for hypothyroid neuropathy). And if I can talk her into it, I would like her to do the MMA, just to be SURE I don't have any B-vitamin deficiency.

After that, if all of THOSE tests come back absolutely normal, I'm going to TRY to seek out a PN specialist. I'm not giving up on finding the cause, but I can't expect my family doctor to keep pursuing this on her own, and none of the local neurologists seem to be interested in doing anything besides increasing my Neurontin! (...Duh... WHAT did I just say?... I can't remember...) #-o =P~


Re: Elliott

Dr. Z on 5/08/03 at 12:52 (118107)

Didn't you also have some posterior tibial tendonitis problems in addition to TTS. I don't have your chart in front of me. It is possible that this healed and that was the problem after the TTS surgery. IF this isn't your case just forget this

Re: Elliott

elliott on 5/08/03 at 14:53 (118110)

Dr. Z, that was the other foot, which has confounded experts up and down the east coast. Surgery in that foot left me with instability I didn't have before. It's diagnosis is complicated by the fact that I pass the single heel rise and resistance tests looking for PTT dysf. Of four big-name docs, two didn't know and two came up with the same diagnosis. But each of these last two proposed radically different surgeries (three bone procedures vs one bone and four tissue procedures) and each more or less explained why the other's proposed surgery won't work. Just great. So even getting a subconsensus on a diagnosis has not helped. The other two docs aren't convinced of the diagnosis either. I might still seek more opinions. I'm hoping if I wait long enough it will recover sufficiently to avoid risky surgery. My foot is a drop better than it was last year (I'm going on four come August since surgery), so at this rate, about 10 years after death due to old age, my foot will fully recover.