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I'm planning for next monday a complete lab blood test, after many years.  I'm not going to do many fancy things since it's not insurance money, but I'd like a good compromise between info and money spent. Possibly targeted to my vegan regime. What would be other useful tests to carry out beyond these basic ones I'd like to order? I've yet to ask for a quotation so I may have to cut on some items.



  • CBC count
  • CMP 
  • Lipids panel
  • HbA1C
  • Serum iron
  • Ferritine
  • B12
  • folate (necessary?)
  • Vitamin D
  • TSH
  • IGF-1
  • Free Testosterone




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Good suggestions from TomBAvoider and Mechanism:  Zinc, hs-CRP,  homocysteine, adiponectin, lipid panel with particle size, lipoprotein (a),  apolipoprotein B, (and  apolipoprotein A1, fibrinogen etc.  I usually get an expanded package that has all those.)



Iodine might be a consideration if you are  not using iodized salt.


Michael Ray:  Because some of the richest sources of iodine in the American diet are dairy products, ocean fish, and iodized salt (a quarter teaspoon contains about 95 micrograms), and because many excellent vegan foods (soybeans, and cruciferous vegetables like broccoli, cabbage, mustard greens, and kale) contain compounds called goiterogens that inhibit the thyroid gland’s utilization of the mineral, it’s reasonable to be concerned about iodine levels if you’re vegan. Unfortunately, nutrition software doesn’t track it, because there aren’t enough foods with known iodine levels: deficiency is rare these days in North America, thanks to salt iodization, so testing hasn’t been a big priority.


The positive side to this is that if you’re using iodized table salt or Morton Lite Salt on a daily basis, which contains about 95 micrograms per quarter teaspoon, your iodine needs are probably being met; if not, you may want to take a supplement (say, 100 micrograms).







Serum phosphorus might be another consideration, given your high dietary phosphorus intake.


I was tested for calcium, magnesium, selenium and got some unexpected results.


DHEA-s would be interesting, but hardly "basic."

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Guys, thanks for all the suggestions, I think I'm going to do this: on monday, since the doc comes home to draw blood from my son, I'm going to take advantage of it and have a very few basic parameters analyzed, among which calcium, iron, D3, TSH and IGF-1. 


Then I'm going to schedule another extended panel, ask quotations, maybe I'll be able to do that on company insurance money.


Zinc, Iodine, I supplement regularly but yes, is that enough, or is that too much? I agree on checking those minerals and others anyway. 

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I would get fasting insulin and glucose in addition to HbA1c.


IGF-1 is important for people on CR, but you need to combine it with IGFBP-3.

Hcy is important if you're vegan; as Mech indicates, your folate intake is likely fine if you eat a lot of veggies.

Zinc is important for veg(etari)ans, but like most minerals, measuring serum levels tells you nothing about functional status. Similarly, serum calcium and magnesium are uninformative.

Serum selenium levels may be useful for Europeans, who often have low Se intake, tho' they're generally useless for North Americans, whose Se levels are almost always adequate.

"Lipid" (by which I take it Sibirak means "lipoprotein") particle size is at best a surrogate for LDL particle number, as explained here . If your insulin, fasting glucose, HbA1C, LDL-C and (especially) triglycerides are in the average range, you likely don't need any of these tests; if you're going to get one, get either apoB or NMR LipoProfile (LDL particle number), but not both — and then track the same value over time.


HDL particle number/size are not ready for prime time.

Adiponectin, lipoprotein (a),and  apolipoprotein A1, and fibrinogen  are all expensive, fancy-shmancy tests, of little use to most people: I certainly wouldn't put them on the high priority list without some specific reason to do so.

 You can ignore DHEA-s: it was on the CRS list originally because of some early data from the BLSA and the nonhuman primateas suggesting that it might be a biomarker of aging, but that's all fallen apart.

IF you're on CR (I take it you're not, McCoy) and are male, testosterone is a good idea, but you really want testosterone by LC/MS-MS: Life Extension offers LabCorp's test #070038 for $48, but you can't order it online: have to call in and ask the blood lab for it.


If you're on CR, get T3 and rT3 in addition to TSH.

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@ drewab   Selenium was quite high.



Michael Ray:  Adiponectin, lipoprotein (a),and  apolipoprotein A1, and fibrinogen  are all expensive, fancy-shmancy tests, of little use to most people: I certainly wouldn't put them on the high priority list without some specific reason to do so.


I agree, not high priority.     In my case,  I pay for all my tests out of pocket.  Costs are not too high in my location, and the additional tests were not much more on top of the basic ones.  


Btw,  I was discussing lipoprotein (a) in another thread,  and have done a bit of reading on it.   Controversies remain, but the emerging scientific consensus seems to be that Lp (a) is an independent and  likely causal risk factor for CVD and CAVS.


A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies.

Tsimikas S

J Am Coll Cardiol. 2017 Feb 14



Evidence that elevated lipoprotein(a) (Lp[a]) levels contribute to cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) is substantial. Development of isoform-independent assays, in concert with genetic, epidemiological, translational, and pathophysiological insights, have established Lp(a) as an independent, genetic, and likely causal risk factor for CVD and CAVS




Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases

Florian Kronenbergcorrauth.gif

Cardiovasc Drugs Ther. 2016; 30: 87–100.
Published online 2016 Feb 20.
PMCID: PMC4789197

Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein that is under strong genetic control by the LPA gene locus. Genetic variants including a highly polymorphic copy number variation of the so called kringle IV repeats at this locus have a pronounced influence on Lp(a) concentrations. High concentrations of Lp(a) as well as genetic variants which are associated with high Lp(a) concentrations are both associated with cardiovascular disease which very strongly supports causality between Lp(a) concetrations and cardiovascular disease.
This method of using a genetic variant that has a pronounced influence on a biomarker to support causality with an outcome is called Mendelian randomization approach and was applied for the first time two decades ago with data from Lp(a) and cardiovascular disease. This approach was also used to demonstrate a causal association between high Lp(a) concentrations and aortic valve stenosis, between low concentrations and type-2 diabetes mellitus and to exclude a causal association between Lp(a) concentrations and venous thrombosis.
Considering the high frequency of these genetic variants in the population makes Lp(a) the strongest genetic risk factor for cardiovascular disease identified so far.


Edited by Sibiriak
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Blood drawn, after having evaluated all suggestions I ordered the following analyses:


  • Complete CBC
  • Lipid panel (classic)
  • Serum iron
  • Serum ferritine
  • Vit B12
  • Homocysteine
  • Glucose
  • HbA1c
  • Insuline
  • Vit D
  • TSH

I'm going to discuss the results when they'll be ready.

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Michael Ray:  Adiponectin, lipoprotein (a),and  apolipoprotein A1, and fibrinogen  are all expensive, fancy-shmancy tests, of little use to most people: I certainly wouldn't put them on the high priority list without some specific reason to do so.


I agree, not high priority. [...]   Controversies remain, but the emerging scientific consensus seems to be that Lp (a) is an independent and  likely causal risk factor for CVD and CAVS.



(My last name is not "Ray"). The question isn't whether Lp(a) is causally involved (tho' I don't think there's actually a consensus on that point either), but whether the test both meaningfully adds information about risk, and that steps taken lower measured Lp(a) values reduce risk — and that it adds incremental value to what can be determined and acted upon from established risk factors. There is certainly no consensus to that effect: neither the American Heart Association, nor the Canadian Cardiovascular Society, nor the European Society of Cardiology, or the American College of Cardiology, nor the US Preventive Services Task Force have thus far endorsed it as a primary screening test. The European Society of Cardiology guidelines say:


High concentrations of Lp(a)are associated with increased risk of CAD and ischaemic stroke and Mendelian randomization studies support a causal role in CVD for Lp(a). There is no randomized intervention study showing that reducing Lp(a) decreases CVD risk.362 At present there is no justification for screening the general population for Lp(a), but it may be considered in patients at moderate risk to refine risk evaluation or in subjects with a family history of early CVD.


Similarly, the Canadian guidelines suggest that "Measurement of Lp(a)might be of value in additional risk assessment in individuals with a family history of premature vascular disease and familial hypercholesterolemia." The American Heart Association/American College of Cardiology joint Guidelines say that


Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond a standard fasting lipid profile is not recommended for cardiovascular risk assessment in asymptomatic adults. ... The role of lipoprotein(a) [Lp(a)] in risk assessment has received attention as a potential additional risk marker. In the Emerging Risk Factors Collaboration, ... [using data from] Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality ... [including] 126 634 participants in 36 prospective studies and spanned 1.3 million person-years of follow-up ... Lp(a) concentration was weakly correlated with several conventional vascular risk factors and highly consistent within individuals over several years. ... This study demonstrated that there are continuous, independent, but modest associations of Lp(a) concentration with risk of CHD and stroke. As with previous individual reports, associations were only modest in degree, and detailed information on incremental risk prediction beyond traditional risk factors is still lacking. There have also been, and continue to be, concerns about measurement and standardization of measurement of Lp(a) in clinical settings (103). The writing committee therefore concluded that measurement of Lp(a) did not merit consideration for cardiovascular risk assessment in the asymptomatic individual.

... and the USPSTF says:




Fair-quality evidence indicates that lipoprotein(a) level predicts CHD events after adjustment for some Framingham risk factors, but no studies calculated a Framingham risk score, assessed predictive value beyond Framingham risk scoring, or assessed whether lipoprotein(a) contributes to reclassification from intermediate to another risk category. ...


The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors studied to screen asymptomatic men and women with no history of CHD to prevent CHD events ... including] (hs-CRP), ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness (carotid IMT), coronary artery calcification (CAC) score on electron-beam computed tomography (EBCT), homocysteine level, and lipoprotein(a) level.


Now, only the European guidelines are very recent (USPSTF is from 2009), and all of these guidelines will be revised in future as more evidence accumulates — but as of now, the consensus is that Lp(a) is not a useful test for low-risk or asymptomatic adults.

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FWIW, Michael Lustgarten, who has sometimes been discussed on these boards, has a website, and has an interest in optimizing some biomarkers, though not necessarily all those a CRONie might have interest in. You can search around his website to see which biomarkers he focuses on (he mostly uses diet as the modifying factor):



Edited by TomBAvoider
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I've got the results, they are...interesting, not always following expectations.


Serum Iron, ferritin, CBC.


I'm checking now and my 6-months average dietary iron intake is 320% RDA (290% last month). 42%of it is from cacao powder, 31% from soy milk and yogurt, 27% from spinach.

Now, the iron I eat sounds huge, but, aside from the fact that it is non haeme, it encounters a very hostile environment: lots of fibers, tannins, flavanols, phytates... The same cacao which provides 42% of iron exhibits huge amounts of tannins. By the way, very often I ingest vit C together with iron containing foods. And B12 is 263 pg/ml, pretty well inside the normal range of 193-982.


Overall result is that my serum iron is at the lower level of the normal range: 67 micrograms/dL (normal range is 65-175). Ferritin is better off, at 83 ng/ml (normal range is 30-350). It is confirmed that most iron ingested gets bound to fibers, tannins, flavanols, phytates...

Now, RBC and hemoglobin count are exactly at the lower bound of the normal range. This may be interpreted as a desirable status, no anemia and lowest non-hazardous oxydative action of iron, but I regard it as a potentially hazardous state in case of emergency and conspicuos blood loss. I don't know though if I'm going to be able to ingest 500% dietary RDA.

RBC parameters are all good, so definitely no anemia there.

Edited by mccoy
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Vitamin D total.


This is a pretty unexpected result: 32 ng/ml, well inside the normal range of 30-100, but close to its lower bound.


Now, I've been eposing regularly to UVB rays when they are most intense for the latest 3 months. Up to 1.5 hours per day, in swim trunks. June has the most powerful sun radiation across the year. Even though I live at 42° latitude, UVB radiation is pretty strong now, especially so in clear days and extremely so at the beach, on the sea surface. Of course, the tan developed works as a UVB screen and the age is such that the D3 synthesis is lowered.


However, I would have expected a value within the range of 40-60 ng/ml. If I'm a slow synthetizer of vit D, or if my body is an avid user of it, I probably need lots of supplementation during the winter.

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Glucose, insuline, HOma-IR, HbA1C


Thanks to Michael Rae I asked for insulin concentration together with glucose, so that I was able to calculate my HOMA-IR index.


Fasting glucose was 83 mg/dl, pretty normal value and below the 100 mg/dl associated to a prediabetic condition.

Fasting insuline was 4 microU/ml, very low value, below the normal range of 4-25.


Resulting HOMA-IR index is 0.8, which suggests pretty good insuline sensitivity. This allows for a low Insuline baseline in glucose homeostasis, with all its advantages.


HbA1 c is 5.6%, within the normal range of 4.5-6.5%, but a little high. Although, from previous posts and Dean's research, it turns out that a normal-high value in healthy individuals may have many causes not related to an unhealthy glucose homeostasis.


Since I'm following a vegan regime. , my net carbs tend to be pretty high, at 216 g/d 6-months average, of which 140 g are simple sugars, equally divided into glucose, fructose, sucrose.

(edit: last month my average values were lower, 156 g net carbs, 104 g simple sugars).


The above consumption of simple sugars doesn't seem to compromise glucose homeostasis, although at times my fasting glucose is higher than 90 mg/dl

Edited by mccoy
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This hormone was an uncertain outcome. Being vegan I eat very little dietary iodine, so I've been supplementing with 100-200 micrograms/d iodine plus iodized salt. Iodine, similarly to iron, encounters an hostiler environment of soy isoflavones, glycosides and other binding molecules. hence the uncertain outcome. However, the result was good at 3.6 microIU/ml, with a normal range of 0.25-5.

I might keep the 200 micrograms/d supplementation, increasing it when I'll eat more soy products.

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I'm not a doctor, I just read a bunch of med papers out of curiosity/hobby, so take my remarks with a grain of salt. Your iron status is fine, from the numbers. RBC and hemoglobin count at the lower end is not as good - it's better toward the higher end. HbA1c would be better at 5.4% than 5.6%, but it's a tricky and unreliable biomarker, as discussed before. Your insuline number looks good - unless you have diabetes, lower values are better, less chance to get cancer.

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Correct me if I’m wrong (I did a only quick search),  but  it seems there is still no mainstream health/medical association consensus that   vitamin D testing and/or supplementation are recommended for the general population.   Of course,  mainstream health association recommendations are directed at  society-wide medical practice and are  influenced in part by institutional, ideological, financial and social cost-effectiveness considerations.   Individual decision-making exists on a different level and follows different dynamics.


USPSTF: No Evidence for Routine Vitamin D Screening  [Nov. 2014]



The US Preventive Services Task Force (USPSTF) has issued its first-ever guidance on the routine screening of asymptomatic patients for vitamin D deficiency. The recommendation is now final following the issue of draft guidance in June. There simply is no evidence on the specific pros and cons of screening for vitamin D deficiency, so routine screening cannot be advised at the current time, say the authors of the recommendation statement, led by Dr Michael L LeFevre (University of Missouri, Columbia) and colleagues.



U.S. Preventive Services Task  Force [Nov. 2014]



No national primary care professional organization currently recommends population-wide screening for vitamin D deficiency. The American Academy of Family Physicians concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency.18 The Endocrine Society recommends screening for vitamin D deficiency only in persons at risk and states that there is no evidence showing benefits of screening at a population level.19 It defines vitamin D deficiency as total serum 25-(OH)D levels of less than 50 nmol/L (<20 ng/mL) and vitamin D insufficiency as 52.5 to 72.5 nmol/L (21 to 29 ng/mL) and recommends treatment of persons with a vitamin D deficiency.


Other organizations, including the American Congress of Obstetricians and Gynecologists,20 the American Geriatric Society,21 and the National Osteoporosis Foundation,22 recommend testing for vitamin D as part of osteoporosis management or falls prevention.


The Institute of Medicine does not have formal guidelines on screening for vitamin D deficiency, but it has published a report on the recommended dietary allowance (RDA) for vitamin D.12 The RDA is the estimated requirement to meet or exceed the vitamin D needs of 97.5% of the adult population. Assuming minimal sun exposure, the Institute of Medicine’s RDA for vitamin D is 600 IU/day for adults aged 19 to 70 years and 800 IU/day for adults older than 70 years.


Furthermore, it concluded that total serum 25-(OH)D levels of 40 nmol/L (16 ng/mL) meet the needs of approximately half of the population, and levels of 50 nmol/L (20 ng/mL) or greater meet the needs of nearly all of the population. However, it is not necessary to evaluate 25-(OH)D levels before discussing RDA with patients.





Am Fam Physician. 2018 Feb 15;97(4):226-227.


Vitamin D Screening and Supplementation in Primary Care: Time to Curb Our Enthusiasm


KENNETH W. LIN, MD, MPH, Georgetown University Medical Center, Washington, District of Columbia



Recent trends in vitamin D testing and supplementation strongly suggest that physicians and patients believe that identifying and correcting vitamin D deficiency improves health outcomes. From 2000 to 2010, the volume of serum 25-hydroxyvitamin D (25-OH-D) tests reimbursed by Medicare Part B increased 83-fold.1 In 2000, four out of 1,000 U.S. adults 70 years or older reported taking a daily vitamin D supplement of at least 1,000 IU, compared with four out of 10 in 2014—a 100-fold increase.2


In contrast, LeFevre and LeFevre's review of the evidence for vitamin D screening and supplementation in adults in this issue of American Family Physician determined that these commonplace practices have virtually no established health benefits.3 The American Society for Clinical Pathology recommends against screening for vitamin D deficiency in the general population.4 The U.S. Preventive Services Task Force found insufficient evidence that vitamin D supplementation prevents cardiovascular disease, cancer, or fractures in community-dwelling adults.57 An umbrella review of more than 100 systematic reviews and meta-analyses of observational studies and randomized controlled trials found only a handful of “probable” relationships between serum vitamin D concentrations and clinical outcomes, and concluded that vitamin D supplementation does not increase bone mineral density or reduce the risk of fractures or falls in older adults.8


What factors explain the disconnect between the research on vitamin D and the great enthusiasm for screening and supplementation in clinical practice? First, vitamin D is a vitamin—by definition, something the body needs. To many adults, a relationship between vitamin D levels and general health seems plausible because they spend most of their time indoors and are counseled by clinicians to minimize sun exposure to reduce skin cancer risk.9 Second, earlier research had suggested positive effects that were not subsequently borne out. For example, observational studies often make news by publicizing associations between low vitamin D levels and chronic conditions such as cardiovascular disease,8 but subsequent randomized controlled trials showing negative results may be less widely reported.10 Clinicians may misapply evidence that vitamin D supplements reduce fall rates in institutionalized older adults11 to community-dwelling populations. Finally, physicians may misinterpret serum 25-OH-D concentrations of 20 to 30 ng per mL (50 to 75 nmol per L) as representing a deficiency that requires correction, when the National Academy of Medicine (formerly the Institute of Medicine) considers 97.5% of individuals with levels greater than 20 ng per mL to have adequate vitamin D for bone health.12


Screening for vitamin D deficiency leads to hundreds of millions of dollars wasted in testing costs annually.3 Low-level daily supplementation with calcium and vitamin D can increase the risk of kidney stones,13 and higher monthly doses of vitamin D increased the risk of falls in a randomized controlled trial of older adults with vitamin D deficiency.14 The National Academy of Medicine has noted that vitamin D intakes above the tolerable upper limit of 4,000 IU per day may cause toxic effects such as renal impairment, hypercalcemia, or vascular calcification.15 In 2014, 3% of all U.S. adults and 6.6% of adults older than 60 years reported taking a vitamin D supplement of 4,000 or more IU per day.2


It is time for clinicians and patients to curb our enthusiasm for vitamin D screening and supplementation. Strategies to decrease unnecessary testing could include distributing the patient handout on vitamin D tests created by Consumer Reports for the Choosing Wisely campaign (http://www.choosingwisely.org/patient-resources/vitamin-d-tests/) and implementing clinical decision support for ordering laboratory tests. In Alberta, Canada, the number of vitamin D tests decreased by more than 90% during the first 12 months after implementation of a paper and electronic requisition form that required physicians who were ordering laboratory tests to select one of several approved indications (e.g., metabolic bone disease, abnormal blood calcium levels, malabsorption syndromes, chronic renal disease, chronic liver disease).16 Family physicians should also counsel patients on the recommended dietary allowance for vitamin D (600 IU per day in adults 70 years and younger, and 800 IU per day in adults older than 70 years), and discourage most patients from using supplements, especially in dosages near or above the tolerable upper limit of 4,000 IU per day.




The issue of optimal vitamin D levels (+ calcium and Vitamin K2 intake etc.)  has been extensively discussed in the CR forums,  and I do not want  to re-open that topic.


I'm just pointing out that If  the mainstream medical community’s society-level perspective on vitamin D testing were actually determinative, then a person without confirmed “approved indications”  would be advised not to seek Vitamin D testing. Nevertheless,  such a person, from an individual perspective, could very well have completely valid reasons to get tested.

Edited by Sibiriak
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Sibiriak, interesting considerations on the mainstream medical views on vit D testing. As usual, many of us will choose the precautionary principle and have themselves tested anyway. But it is good to remind that even if we have less than 60 ng/ml , we may still be pretty healty, fads around this vitamin tend to abound.


As a matter of fact, I've been often pondering about the Senegalese people living here. They are very dark, some of'em extremely dark, pitch black (especially so the Wolof populace), since they are 1st generation Africans, no blood mixing. They don't get any D3 from sun exposure, since I've seen none of'em in swim trunks under the sun and they are so dark anyway. Most probably they don't eat seafood, since it is very expensive here (only exception is canned sardines) and they are all on a budget. Their traditional food is rice and chicken, cous cous and chicken, they also eat traditional Italian cuisine like pasta, very cheap, little nourishing.


So, the final question: why aren't all these Senegalese people dead or very ill?

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I'm not a doctor, I just read a bunch of med papers out of curiosity/hobby, so take my remarks with a grain of salt. Your iron status is fine, from the numbers. RBC and hemoglobin count at the lower end is not as good - it's better toward the higher end. HbA1c would be better at 5.4% than 5.6%, but it's a tricky and unreliable biomarker, as discussed before. Your insuline number looks good - unless you have diabetes, lower values are better, less chance to get cancer.


TomB, thanks for your comments. I'll have to find out how to increase hemoglobine and RBC count.


The very low baseline insuline in my case explained why I lost inexorably weight by going low carb. Even if it was relatively low carb:  50-100 g carbs per day.  Having an already low insuline baseline, evidently the decrease in carbs caused a drastic decrease in the insuline spikes hence in a very low value of the AUC of the insuline concentration function with time. This, paired with moderate protein, resulted in a continuos underamplification of systemic mTOR by the paucity of the Leucine signal and the lack of the IGF-1/insuline-Akt cascade.


Even by doing resistance exercise, I lost slowly weight until i returned to my normal regime of about 200-300 g net carbs per day.

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More results of my blood tests: homocysteine


Detected value (plasma homocysteine): 14.4 micromol/lt

Reference range for teh relevant age interval: up to 13.2  micromol/lt


So I turn out to be slightly above the upper bound interval of the normal range. According to some experts, like Chris Masterjohn, the optimum rnge woudl be 5 to 9 micromol/lt, so I'd be definitely outside the optimum.


Potential reasons for value out of range:


  • deficiency in methil donors: Not B12, tested at 263 pg/ml, probably not folate, untested but at 170% RDA in the latest 6 months. choline though, might be a prob, at 57% the RDA, the only nutrient consistently below the RDA which I do not supplement
  • other candidates: B6, not a problem at 160% RDA average, or other B-complex vitamins, which are all above RDA but which I do supplement since sometimes I fall below B3 and B4 RDAs levels (for example, when not having much hunger, not eating nmushrooms...)


So, I'm already looking up the amazon supplement pages for choline. Even though I might have a sub-optimal absorption of folate, which I should test next time.

Wonder if any of you guys experienced the same high homocysteine problem.

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Hi mccoy,  I'm short on time at the moment so I'm just throwing this stuff out without commentary-- it may or may not be relevant:

MTHFR gene polymorphism, homocysteine and cardiovascular disease


Homocysteine is an emerging new risk factor for cardiovascular disease. It is a thiol compound derived from methionine and involved in two main metabolic pathways: the cycle of activated methyl groups, requiring folate and vitamin B12 as cofactors,and the transsulfuration pathway to cystathionine and cysteine requiring vitamin B6as cofactor. The homocysteine metabolism represents an interesting model of gene-environment interaction. Elevations in homocysteine may be caused by genetic defects in enzymes involved in its metabolism or by deficiencies in cofactor levels. A common polymorphism in the gene coding for the 5,10-methylene tetrahydrofolate  reductase (MTHFR) (C677T, Ala-->Val) is associated with a decreased activity of the enzyme due to thermolability. In case of homozygosity for the Val allele, a relative deficiency in the remethylation process of homocysteine into methionine leads to a mild-to-moderate hyperhomocysteinemia, a condition recognized as an independent risk factor for atherosclerosis. The genetic influence of the MTHFR polymorphism on homocysteine levels is attenuated in females in premenopausal age and is not significant in subjects who exhibit serum levels of folate and/or vitamin B12 above the 50th percentile of distribution in the general population.


The prevalence of the Val/Val genotype varies among different ethnic groups. It is very low in African populations, whereas in Europe and North America it ranges between 5% and 15%.  In Italy an even higher prevalence has been reported in some regions.   [see Table 1 MTHFR Val/Val genotype prevalences in different regions of Italy. ]


The question whether the MTHFR polymorphism might be per se an independent contributor to cardiovascular risk is debated. The interaction between this or other genetic factors and environmental/nutritional conditions (i.e. intake of vitamins such as folate) is a key determinant for homocysteine concentrations in healthy conditions as well as in some disease (i.e. in renal disorders). Another example of gene/environment interaction in the field of atherosclerosis is given by the apolipoprotein E polymorphism and its influence in response to diet. The presence of a high prevalence of risk-related allelic variants of such candidate genes within a certain population could serve to locally reinforce the recommendations concerning nutrient intake.

The Homocysteine Controversy

2011 Feb; 34(1): 93–99.  PMID: 20567905



Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease.


Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.

The metabolism and significance of homocysteine in nutrition and health


An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B6, B12 and folate or by feeding Met enriched diets. Additionally, some of the pharmaceuticals currently in clinical practice such as lipid lowering, and anti-Parkinsonian drugs are known to elevate Hcy levels. Studies on supplementation with folate, vitamins B6 and B12 have shown reduction in Hcy levels but concomitant reduction in certain associated pathologies have not been definitive. The enormous importance of Hcy in health and disease is illustrated by its prevalence in the medical literature (e.g. > 22,000 publications).


Although there are compelling data in favor of Hcy as a modifiable risk factor, the debate regarding the significance of Hcy mediated health effects is still ongoing. Despite associations between increased levels of Hcy with several pathologies being well documented, whether it is a causative factor, or an effect remains inconclusive. The present review though not exhaustive, is focused on several important aspects of Hcy metabolism and their relevance to health.

Role of homocysteine in the development of cardiovascular disease

Nutr J. 2015; 14: 6.


The question therefore exists if homocysteine is a biomarker or a risk factor? Current guidelines have not classified homocysteine as cardiovascular disease risk stratification. The analyses by Veeranna et al. [14] prospectively validated and showed the incremental value of homocysteine level in predicting adverse cardiovascular disease events beyond the FRS. Therefore this paper states that homocysteine fulfils the criteria to classify it as a “novel” marker [14]. Although lowering homocysteine levels in individuals with pre-existing cardiovascular disease has not shown any benefit, medications as part of a primary prevention strategy need to be evaluated further for confirmation [14]. Therefore, it seems unfair to underestimate the utility of homocysteine in cardiovascular disease risk prediction solely because interventions to lower plasma homocysteine levels have not shown a favourable outcome regarding the risk of cardiovascular disease incidence [14]. Yet there is always room for more research to validate homocysteine as a risk factor and this is absolutely necessary for the sake of solid evidence.


The published literature indicates that homocysteine is an independent cardiovascular disease risk factor modifiable by nutrition and exercise. However, it is now widely accepted that food sources alone cannot consistently supply the levels of nutrients necessary to sustain optimal homocysteine metabolism. In fact, emerging studies are uncovering novel nutritional strategies for lowering high homocysteine levels offering new possibilities for preventing cardiovascular disease.


The speculation of this peculiar correlation continues to contribute to the perplexity of the scientific society. Though most research work suggests a relationship, yet there seems to be other evidence that still prevents its inclusion as a biomarker. With every ten steps forward, we might have to face a step or two backward, but this should only further increase the enthusiasm of research in this field. This field definitely needs more research input until a definitive proof is available to cast off any shadow of doubt regarding the correlation between homocysteine and cardiovascular disease. Nevertheless, the present review should provide some insight into the role of homocysteine in the development of cardiovascular disease summarizing both central and peripheral effects of homocysteine. The authors feel that it is necessary to combat the ill effects of hyperhomocysteinemia as it has a pivotal influence on the pathology of the diseased process.

Can black tea influence plasma total homocysteine concentrations?

Am J Clin Nutr. 2003 Apr;77(4):907-11.


Elevated plasma total homocysteine (tHcy) concentrations are associated with an increased risk of atherothrombotic cardiovascular disease. This association is independent of other risk factors and is dose related, and there is increasing evidence that it is causal (1). Homocysteine is an amino acid derived from the demethylation of dietary methionine. The metabolism of homocysteine is influenced by several dietary factors, including folate, vitamin B-12, vitamin B-6, and betaine (2), and may be influenced by the intake of polyhydroxylated phenolic compounds (polyphenols) (3; Figure 1).


Dietary polyphenols were found to increase tHcy concentrations (3). Some of the richest dietary sources of polyphenols are beverages, including tea and coffee. Coffee is one of the main dietary factors implicated in increasing tHcy concentrations. Population studies showed that coffee is associated with elevated tHcy concentrations (4–10), and in controlled intervention studies, regular, chronic ingestion of coffee resulted in clinically relevant increases in tHcy concentrations (11, 12). The effect of coffee to increase tHcy concentrations is predominantly due to chlorogenic acid (3), which is a phenolic acid and the major polyphenol present in coffee. A controlled intervention study showed that very high doses of tea also increase tHcy concentrations (3). This may be due to polyphenols present in tea, including gallic acid, which is the major phenolic acid present in tea. However, results of cross-sectional population studies do not support a tHcy-increasing effect of tea. These studies generally showed inverse associations of tea intake with tHcy (4–7), which were attenuated after adjustment for coffee intake and other potential confounders (5–7). The effect on tHcy of a dose of tea that is more representative of ordinary population intakes has not been investigated in an intervention study.


It has been suggested that dietary polyphenols may contribute to an elevation in tHcy concentrations by acting as acceptors of methyl groups (3; Figure 1). If dietary polyphenols can alter tHcy concentrations, then the overall effects of a polyphenol-rich beverage may relate to polyphenol metabolism. Individual differences in the degree of O -methylation of polyphenols may influence tHcy concentrations. If this hypothesis is correct, then a greater degree of O-methylation of a specific dose of polyphenols should be associated with higher tHcy concentrations.

Association between Coffee Consumption and Its Polyphenols with Cardiovascular Risk Factors

Nutrients. 2017 Mar; 9(3): 276.PMCID: PMC5372939


A positive association, in a dose-dependent manner between homocysteine concentrations and coffee consumption, was reported in a cross-sectional study [44] and has confirmed in randomized controlled trials [45,46]. Grubben et al. [45] have suggested that 10% higher concentration of homocysteine is associated with very high intake of unfiltered coffee (1 L/day), but it is not clear whether the serum lipid fraction, i.e., cholesterol-raising diterpenes present exclusively in unfiltered coffee, is the only factor responsible for the increase in homocysteine concentration. Although the authors were not able to conclude whether this association depends on the brewing method, it seems that unfiltered coffee is more likely to increase total homocysteine than filtered coffee. They speculated that the effect of coffee, mediated by caffeine, on increased plasma homocysteine concentrations could be due to a decrease in blood vitamin B6 concentration, a vitamin related to homocysteine metabolism, whose deficit results in higher production of homocysteine. Additionally, chlorogenic acid, a polyphenol that is present in coffee, may also be partly responsible for the increase of the homocysteine production through increased methylation reactions [47].


On the other hand, moderate coffee consumption among healthy subjects did not significantly increase the homocysteine concentration [48], and a population based-study described that coffee was no longer associated with plasma homocysteine after adjustment for plasma folate concentration [49]. In addition, Mursu et al. [50] found similar results and showed that the consumption of filtered coffee has neither short- nor long-term detectable effects on lipid peroxidation nor on plasma homocysteine concentrations in healthy non-smoking men. More recently, according to Corrêa et al. [51] in Brazilian population, no changes were observed for plasma total homocysteine, after the consumption of three or four cups of paper-filtered coffee per day. The inconsistencies between the above-mentioned epidemiological studies suggest that not all types of coffee brew have the same effect on plasma homocysteine concentrations or that the effect is spurious.


In the current study, we reported that individuals who were consuming more than three cups of filtered coffee per day had lower odds (even not significant) for hyperhomocysteinemia, and moderate consumption of filtered coffee and the polyphenols intake from coffee were inversely associated with hyperhomocysteinemia.
Edited by Sibiriak
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Thanks Sibiriak for having done the homework in my stead, LOL.


I'll have to ponder about the info, if there is a MTFHR gene polymorphism involved, in theory, according to the article posted, I might be able to bring down Hcyst levels by upping my B12 supplements (blood levels should be > 50th percentile, now it seems to be located at about the 20th percentile), adding some folate supplements, or even taking choline, betaine/TMG. Maybe I'm going to do just that and then test again...   B12 seems to have very high tolerability even at 1000 micrograms per day dosages.


But at the end the CVD risk seems to remain higher even if Hcyst level is lowered, so maybe the Hcyst hypothesis of increased CVD risk is just a matter of reverse causation. An effect rather than a cause.


Bottom line: given the controversy, i'm probably not going to worry much about that.

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There is some  evidence that homocysteine may interact with lipoprotein(a) [Lp(a)] to increase cardiovascular disease risk.


Lipoprotein(a) and Homocysteine Potentiate the Risk of Coronary Artery Disease in Male Subjects


Circulation Journal 76(8):1953-7 · April 2012  (PDF Available)



Depending on the microenvironment of the vascular tree, Lp(a) may change its structural characteristics and thus promote several pathophysiological mechanisms leading to the development of atherosclerosis or triggering thrombosis. In fact, it has been reported that the presence of Hcy [homocysteine] in amounts as low as 8 μmol/L increases by 20-fold the affinity between
Lp(a) and plasmin-treated fibrin.


The polymorphism of apo(a) when incorporated into the Lp(a) lipoparticle differentially affects the fibrin-binding affinity of Lp(a). Thus, small apo(a) isoforms have a higher affinity for fibrin.44 However, when apo(a) is dissociated from Lp(a) or is produced by recombinant technology, all isoforms display a similar affinity for fibrin, independent of size, and all of them are capable of producing an important antifibrinolytic effect.45 It is important to note that the free forms of apo(a) may arise as a result of the reducing environment generated by the presence of high concentrations of Hcy.21


Both molecules influence hemostatic function either by altering the endothelium or platelet function or by favoring a thrombotic-prone condition. The presence of both Lp(a) and Hcy is a risk factor that cannot be classified as additive or multiplicative. It potentiates the risk. Lp(a) and Hcy interact to increase the risk of CAD more than 10-fold compared with a 5-fold increase when only the Lp(a) is increased.

We believe that these findings highlight the importance of identifying individuals with the dual risk factor of elevated Hcy and Lp(a) to focus on preventive measures that might decrease the risk of atherothrombotic disease.


Conclusions   Lp(a) is an independent risk factor for CAD in the studied population. There is an interaction between Lp(a) and Hcy that significantly potentiates the risk of CAD.


Role of homocysteine and lipoprotein (A) in atherosclerosis: An update


Biomedical Research (2011) Volume 22, Issue 4



These findings support the hypothesis that tHcy and Lp (a) interact to increase the risk of CAD. A high tHcy level may act in concert with a high Lp (a) level to promote atherosclerosis and or vascular disease. These data provide an interesting hypothesis-generating finding regarding the differential interactive effects of 2 emerging cardiovascular risk factors and may have important implications for the prevention and treatment of CAD in select high-risk populations.



The current understanding of atherosclerosis is as a chronic inflammatory process, developing in response to some metabolic disorders (dyslipidemia, insulin resistance), infections and environmental processes that initiate and promote lesion development to the point of acute thrombotic complications. The growing knowledge about the interplay between homocysteine and lipoprotein (a) has many far reaching implications. Their synergism calls for more stringent treatment modalities in subjects having high homocysteine as well as lipoprotein (a) levels.

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