# Nutrients

Source: https://synapse-lifestyle.com/en/reference-guide/nutrients

## Vitamin D3

Vitamin D (measured in blood as 25-hydroxyvitamin D) is a fat-soluble vitamin that, in addition to its classic role in bone and dental health, also has immunomodulatory and anti-inflammatory properties[1]. Deficiency (<20 ng/mL) and insufficiency (<30 ng/mL) are common and have been associated with a range of acute and chronic conditions.

However, there is considerable debate about optimal target values[2, 3]. The NICE guideline considers 50–75 nmol/L (approximately 20–30 ng/mL) sufficient, while endocrinologists[4] have recently recommended higher reference values (75–175 nmol/L, or 30–70 ng/mL).

Within Synapse, we align with these higher target values and apply the following cut-offs:

|  | 25-OH-Vitamin D |
| --- | --- |
| Severe deficiency (red) | ≤15ng/mL |
| Deficiency (orange) | 15-20ng/mL |
| Mild deficiency (yellow) | 20-30ng/mL |
| Optimal (green) | 30-70ng/mL |
| High (yellow) | 70-100ng/mL |
| Very high (orange) | exactly 100ng/mL |
| Very high (red) | >100ng/mL |

## Vitamin B12

There is considerable controversy about optimal cut-off values for vitamin B12. While guidelines generally recommend testing when clear symptoms or anaemia are present, non-specific symptoms such as dizziness, fatigue, and difficulty concentrating are also associated with vitamin B12 deficiency[5]. Since a lack of vitamin B12 can damage the nervous system and increase the risk of conditions such as Alzheimer's disease, vascular dementia, and other neurodegenerative diseases, early detection and correction is of great importance[6].

Vitamin B12 plays a crucial role in various metabolic pathways, which means that functional markers such as methylmalonic acid and homocysteine provide additional insight into effective biological availability. Looking at these functional markers, it has been shown that methylmalonic acid concentrations only reach optimal values[7] at a vitamin B12 level of approximately 250–260 pmol/L (approximately 340–350 ng/L). Synapse therefore applies a higher lower threshold for insufficiency than that advised by the NICE guidelines[8] or the Superior Health Council[9].

The upper bound of the optimal range differs per laboratory: Synapse uses the upper reference bound printed on your lab report, or 771ng/L when the report prints none.

Within Synapse, the following reference values apply[10]:

|  | Vitamin B12 |
| --- | --- |
| Deficiency (red) | ≤180ng/L |
| Insufficiency (orange) | 180-265ng/L |
| Mild insufficiency (yellow) | 265-350ng/L |
| Optimal (green) | 350ng/L to the upper reference bound |
| High (yellow) | the upper reference bound to 1500ng/L |
| Very high (orange) | ≥1500ng/L |

## Folate

As with vitamin B12, there is considerable debate[11] about optimal cut-off values for folate. While there is broad consensus on the need for folate supplementation during pregnancy, clear guidelines for the general population outside of pregnancy are harder to find.

To determine the optimal lower threshold for folate, Synapse uses functional markers[12] and applies stricter cut-offs than many existing guidelines. This approach enables early identification of suboptimal folate levels.

The cut-off values[13] we apply are:

|  | Folate |
| --- | --- |
| Deficiency (red) | ≤3ng/mL |
| Insufficiency (orange) | 3-3.75ng/mL |
| Mild insufficiency (yellow) | 3.75-4.5ng/mL |
| Optimal (green) | 4.5-16ng/mL |
| High (yellow) | 16-19ng/mL |
| High (orange) | 19-22ng/mL |
| Very high (red) | ≥22ng/mL |

## Homocysteine

Homocysteine is an intermediate amino acid in the methionine and folate metabolic pathways and serves as a functional integrator of B vitamin status (B2, B6, B9, B12) and choline[22]. In plain terms, it is a natural by-product that builds up when the body lacks certain B vitamins. A deficiency in one or more of these cofactors causes homocysteine levels to rise. In addition to nutritional factors, reduced kidney function (eGFR <60 mL/min) and genetic variants in the MTHFR enzyme (c.677C>T) also contribute to elevated values.

Elevated homocysteine is associated with increased all-cause mortality and with numerous conditions, particularly cardiovascular disease[23]. An independent and partly causal relationship has been described for venous thrombosis, peripheral arterial disease, coronary atherosclerosis, and stroke. The underlying mechanisms include oxidative stress, inflammation, and endothelial dysfunction, with reduced nitric oxide availability. Hyperhomocysteinaemia has also been causally linked to neural tube defects and is associated with cognitive decline and dementia.

Intervention focuses on optimising intake of vitamins B2, B6, B9, B12, and possibly choline or betaine, which can lower homocysteine levels[23, 24]. Homocysteine should be measured in the fasting state, as postprandial methionine intake can cause a transient rise and thereby overestimate the baseline value[22].

At Synapse, we apply the following cut-offs:

|  | Homocysteine (μmol/L) |
| --- | --- |
| Optimal | ≤8 |
| Normal | 8-10 |
| Mildly elevated | 10-12 |
| Elevated | 12-16 |
| Markedly elevated | >16 |

## Calcium

Calcium (Ca^2+) is the most abundant mineral in the human body (~1 kg). Approximately 99% is stored in bones and teeth; the remaining 1% circulates freely. This free (ionic) fraction is indispensable for muscle and cardiac contraction, nerve conduction, blood coagulation, enzyme activation, and hormonal signalling. Serum calcium is therefore kept under extremely tight regulation by parathyroid hormone (PTH), active vitamin D, and calcitonin.

Under normal circumstances, calcium levels remain fairly stable. The cut-off values[14] applied by Synapse are:

|  | Calcium |
| --- | --- |
| Severe deficiency (red) | ≤2.20mmol/L |
| Deficiency (orange) | 2.20-2.225mmol/L |
| Mild deficiency (yellow) | 2.225-2.25mmol/L |
| Optimal (green) | 2.25-2.60mmol/L |
| High (yellow) | 2.60-2.733mmol/L |
| High (orange) | 2.733-2.867mmol/L |
| Very high (red) | ≥2.867mmol/L |

## Magnesium

Magnesium is an essential mineral involved in more than 300 enzymatic reactions in the body. It supports muscle relaxation, nerve impulse transmission, cardiac function (including heart rhythm and blood pressure), bone mineralisation, and energy production. Deficiencies often arise from chronic stress, gastrointestinal disorders, a poor diet, or medication use.

While a low serum magnesium level (hypomagnesaemia) indicates deficiency, a normal level does not rule out depletion; a 24-hour urine measurement can provide additional information. Clinically, muscle cramps, cardiac arrhythmias, fatigue, weakness, difficulty concentrating, and increased stress sensitivity may indicate magnesium deficiency[15].

Under normal circumstances, magnesium levels remain fairly stable. The cut-off values[16, 17, 18] applied by Synapse are:

|  | Magnesium |
| --- | --- |
| Severe deficiency (red) | ≤0.5mmol/L |
| Deficiency (orange) | 0.5-0.625mmol/L |
| Mild deficiency (yellow) | 0.625-0.75mmol/L |
| Optimal (green) | 0.75-1.05mmol/L |
| High (yellow) | 1.05-1.233mmol/L |
| High (orange) | 1.233-1.417mmol/L |
| Very high (red) | ≥1.417mmol/L |

## Zinc

Zinc is an essential trace element found naturally in a variety of foods. It acts as a cofactor for hundreds of enzymes and is indispensable for immune function, protein and DNA synthesis, wound healing, cell division, and signal transduction. It also supports growth and development during pregnancy, childhood, and adolescence, and plays a role in taste perception[19]. Risk factors for deficiency include inadequate dietary intake, chronic alcohol use, and malabsorptive bowel diseases.

In clinical practice, serum or plasma zinc serves as the primary marker, although levels can vary with sex, age, time of sampling, infection, or hormonal changes. The cut-off values applied by Synapse are[20]:

| Zinc | Men | Women |
| --- | --- | --- |
| Severe deficiency (red) | ≤0.50μg/mL | ≤0.50μg/mL |
| Deficiency (orange) | 0.50-0.62μg/mL | 0.50-0.62μg/mL |
| Mild deficiency (yellow) | 0.62-0.70μg/mL | 0.62-0.70μg/mL |
| Optimal (green) | 0.70-1.178μg/mL | 0.70-1.08μg/mL |
| High (yellow) | 1.178-1.219μg/mL | 1.08-1.153μg/mL |
| High (orange) | 1.219-1.259μg/mL | 1.153-1.227μg/mL |
| Very high (red) | ≥1.259μg/mL | ≥1.227μg/mL |

## Iron

Iron is a component of haemoglobin and is therefore essential for oxygen transport. It is also found in various enzymes (including cytochromes) and supports energy metabolism, growth, and neurological development. Globally, iron deficiency is the most common nutritional deficiency. It can occur both with anaemia (IDA = Iron Deficiency Anaemia) and without anaemia (IDWA = Iron Deficiency Without Anaemia). Although the latter is often missed, it can have a major impact on quality of life and, in conditions such as chronic heart failure, increases morbidity and mortality[21].

Because a single laboratory parameter can give a misleading picture, Synapse always evaluates an iron profile:

- **Transferrin saturation (TSAT):** Ratio of bound iron to transferrin.
- **Ferritin** Reflects iron stores, but rises with (chronic) inflammation.

The table below shows the thresholds we apply. Synapse reads a deficiency from ferritin; transferrin saturation only counts towards recognising iron overload.

| Result | Male | Female |
| --- | --- | --- |
| Iron deficiency (red) | Ferritin <15μg/L (Note: During acute inflammation (CRP, preferably hsCRP, above 10 mg/L) ferritin and saturation are unreliable. A ferritin below 30 μg/L then always counts as iron deficiency; a ferritin of 30 to 100 μg/L or a saturation below 20% is not reported as a deficiency but with a warning about the inflammation.) | Ferritin <15μg/L |
| Possible iron deficiency (orange) | Ferritin 15-30μg/L | Ferritin 15-30μg/L |
| Healthy (green) | Ferritin from 30μg/L, with a measured saturation | Ferritin from 30μg/L, with a measured saturation |
| Iron overload (red) | Saturation >50% and ferritin >300μg/L | Saturation >45% and ferritin >200μg/L |

If saturation was not measured, Synapse does not assess a ferritin of 30μg/L or more. Anyone who reports haemochromatosis always gets the result iron overload.

### Iron overload

This factor appears when a member reports haemochromatosis, or when the blood values point to iron overload: a transferrin saturation above 50 % (men) or 45 % (women) together with a ferritin above 300 μg/L (men) or 200 μg/L (women). Hereditary haemochromatosis, usually HFE C282Y homozygosity, has incomplete penetrance and is expressed earlier in men[25, 26]. The EASL guideline uses a fasting transferrin saturation above 45 % as the trigger for HFE genotyping[25]; the ACG guideline takes the same line[27].

A high ferritin more often means something else: metabolic hyperferritinaemia in overweight, insulin resistance and fatty liver is the most common cause, usually with a normal transferrin saturation[28]. Untreated iron overload leads to liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and cardiomyopathy; a ferritin above 1,000 μg/L signals a raised risk of advanced fibrosis. Venesection down to a ferritin of 50 to 100 μg/L is the treatment, and first-degree relatives are offered screening[25].

Developed and reviewed with the Synapse [medical advisory board](https://synapse-lifestyle.com/en/advisory-board).

## References

1. Walawska-Hrycek, A., Hrycek, E., Galus, W., Jędrzejowska-Szypułka, H. & Krzystanek, E. Does Systematic Use of Small Doses of Vitamin D Have Anti- Inflammatory Effects and Effectively Correct Deficiency Among Healthy Adults? Nutrients 17, 352 (2025). https://doi.org/10.3390/nu17020352
2. Dietary Reference Intakes for Calcium and Vitamin D. (National Academies Press, Washington, D.C., 2011). https://doi.org/10.17226/13050
3. Holick, M. F. et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 96, 1911– 1930 (2011). https://doi.org/10.1210/jc.2011-0385
4. Amrein, K. et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr 74, 1498–1513 (2020).5. https://doi.org/10.1038/s41430-020-0558-y
5. Aparicio-Ugarriza, R., Palacios, G., Alder, M. & González-Gross, M. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clinical Chemistry and Laboratory Medicine (CCLM) 53, (2015). https://doi.org/10.1515/cclm-2014-0784
6. Lachner, C., Steinle, N. I. & Regenold, W. T. The Neuropsychiatry of Vitamin B 12 Deficiency in Elderly Patients. J Neuropsychiatry Clin Neurosci 24, 5–15 (2012). https://doi.org/10.1176/appi.neuropsych.11020052
7. Muskiet, F. A. J. & Mathus-Vliegen, E. M. H. Commentaar Op Het ‘NHG-Standpunt Diagnostiek van Vitamine-B 12-Deficiëntie’. Ned Tijdschr Klin Chem Labgeneesk vol. 40 (2015).
8. G. Jans & R. Devlieger, C. M. Vitamine B12 - Onmisbaar voor jong en oud. https://www.nice-info.be/nutrinews/vitamine-b12-onmisbaar-voor-jong-en- oud#:~:text=Aanbevolen%20dagelijkse%20hoeveelheid%20vitamine%20B12,4%2C5 %20%C2%B5g%20per%20dag.
9. Hoge Gezondheidsraad (HGR). Voedingsaanbevelingen voor België - 2016. Brussel: HGR; 2016. Advies nr. 9285.
10. Abildgaard, A., Knudsen, C. S., Hoejskov, C. S., Greibe, E. & Parkner, T. Reference intervals for plasma vitamin B12 and plasma/serum methylmalonic acid in Danish children, adults and elderly. Clinica Chimica Acta 525, 62–68 (2022). https://doi.org/10.1016/j.cca.2021.12.015
11. Pfeiffer, C. M. et al. Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population. Am J Clin Nutr 104, 1607–1615 (2016). https://doi.org/10.3945/ajcn.116.138529
12. Khan KM, J. I. Folic Acid Deficiency. StatPearls [Internet]. Treasure Island (FL): StatPearls (2023).
13. Vos, M. J. et al. Folate reference interval estimation in the Dutch general population. Pract Lab Med 16, e00127 (2019). https://doi.org/10.1016/j.cca.2021.12.015
14. Office of Dietary Supplements. Calcium Fact Sheet for Health Professionals.
15. National Institutes of Health. National Institutes of Health - Office of Dietary Supplements. Magnesium - Fact Sheet for Health Professionals.
16. Rosanoff, A. et al. Recommendation on an updated standardization of serum magnesium reference ranges. Eur J Nutr 61, 3697–3706 (2022). https://doi.org/10.1007/s00394-022-02916-w
17. Yee, J. Magnesium: An Important Orphan. Adv Chronic Kidney Dis 25, 217–221 (2018). https://doi.org/10.1053/j.ackd.2018.04.001
18. Azem, R. et al. Serum magnesium, mortality and disease progression in chronic kidney disease. BMC Nephrol 21, 49 (2020). https://doi.org/10.1186/s12882-020-1713-3
19. Qu, X. et al. Serum zinc levels and multiple health outcomes: Implications for zinc- based biomaterials. Bioact Mater 5, 410–422 (2020). https://doi.org/10.1016/j.bioactmat.2020.03.006
20. National Institutes of Health - Office of Dietary Supplements. Zink - Fact Sheet for Health Professionals.
21. Al-Naseem, A., Sallam, A., Choudhury, S. & Thachil, J. Iron deficiency without anaemia: a diagnosis that matters. Clinical Medicine 21, 107–113 (2021). https://doi.org/10.7861/clinmed.2020-0582
22. Refsum, H. et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 50, 3–32 (2004). https://doi.org/10.1373/clinchem.2003.021634
23. Smith, A. D. & Refsum, H. Homocysteine – from disease biomarker to disease prevention. J Intern Med 290, 826–854 (2021). https://doi.org/10.1111/joim.13279
24. Lever, M. & Slow, S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem 43, 732–744 (2010). https://doi.org/10.1016/j.clinbiochem.2010.03.009
25. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol 77, 479–502 (2022). https://doi.org/10.1016/j.jhep.2022.03.033
26. Olynyk, J. K. & Ramm, G. A. Hemochromatosis. N Engl J Med 387, 2159–2170 (2022). https://doi.org/10.1056/NEJMra2119758
27. Kowdley, K. V. et al. ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol 114, 1202–1218 (2019). https://doi.org/10.14309/ajg.0000000000000315
28. Valenti, L. et al. Consensus Statement on the definition and classification of metabolic hyperferritinaemia. Nat Rev Endocrinol 19, 299–310 (2023). https://doi.org/10.1038/s41574-023-00807-6