Vitamin D3 and the liver and kidneys: is it safe

Vitamin D3 is taken by millions of people, and increasingly in high doses. The editorial team examined the role the liver and kidneys play in vitamin D metabolism, when it can be harmful, and which tests help keep the situation under control.

The liver and kidneys — two activation stations for vitamin D

Vitamin D3 (cholecalciferol) is itself biologically inactive. To become a hormone, it goes through two stages of conversion. First, in the liver, a hydroxyl group is attached to the molecule, and 25-hydroxyvitamin D is formed — it is precisely its level that is measured in a blood test.

The second stage occurs mostly in the kidneys: the enzyme 1-alpha-hydroxylase converts 25(OH)D into calcitriol — 1,25-dihydroxyvitamin D. This stage is tightly regulated by parathyroid hormone, calcium and phosphorus levels, and the FGF23 factor.

So for vitamin D, both the liver and the kidneys are not "victims" but working organs. Therefore the question of safety has two dimensions: whether vitamin D harms these organs and how their diseases change the metabolism of the vitamin itself.

It is important to understand: hepatic 25-hydroxylation is weakly regulated, so at large doses the 25(OH)D level rises almost proportionally. This is exactly where the mechanism of possible intoxication lies.

The kidneys: the main risk is calcium

Vitamin D toxicity is realized not directly, but through calcium. At a very high 25(OH)D level, calcium absorption in the intestine and its release from bones increase. Hypercalcemia and hypercalciuria develop — an excess of calcium in the blood and urine.

For the kidneys this threatens the formation of stones, the deposition of calcium in the kidney tissue (nephrocalcinosis), dehydration due to impaired concentrating ability and, in severe cases, acute kidney injury. The cases of intoxication described in the literature are usually related to manufacturing errors in supplements, incorrect dosing, or many months of taking very large doses without monitoring.

In the large Women's Health Initiative study, combining calcium with a moderate dose of vitamin D was accompanied by a small increase in the incidence of kidney stones. This is a reminder that the risk is often related specifically to the combination of vitamin D and high doses of calcium.

At the same time, in the randomized VITAL study, in which participants took 2000 IU of vitamin D3 per day for years, no significant problems with the kidneys or hypercalcemia were recorded. In other words, moderate doses in the general population appear safe.

The liver: what is known about safety

No direct hepatotoxicity of vitamin D at ordinary doses has been described. The liver processes it, but this process is not accompanied by cell damage, and in supplement studies an increase in liver enzymes is not a characteristic side effect.

In chronic liver diseases, on the contrary, vitamin D deficiency occurs very often. The reasons are less time in the sun, poor absorption of fat-soluble vitamins in cholestasis, and reduced synthesis of vitamin D-binding protein. A low 25(OH)D level is associated with a more severe course of cirrhosis, although a cause-and-effect relationship has not been fully established.

In severe liver failure, the first stage of activation may theoretically suffer, but in practice, in most patients the main problem is a deficiency of the starting vitamin, which is corrected with ordinary cholecalciferol under a doctor's supervision.

So for the liver, vitamin D3 at recommended doses poses no known threat, and its level should be monitored in any chronic liver disease.

Norms, limits, and tests

Guidelines for safe intake are set by large regulatory bodies. They apply to healthy adults and do not replace individual prescriptions.

Intoxication is usually associated with 25(OH)D levels that significantly exceed the upper limit of the reference range, combined with hypercalcemia. A "high-normal" level on its own is not enough for a diagnosis.

During prolonged intake of doses above the recommended, it is reasonable to periodically monitor:

• 25(OH)D — to avoid an excess;
• total or ionized calcium;
• creatinine and GFR;
• if there is a history of stones — the daily excretion of calcium in the urine.

Special groups

In chronic kidney disease, vitamin D metabolism changes substantially: the formation of calcitriol decreases, and secondary hyperparathyroidism develops. The KDIGO recommendations provide for correcting 25(OH)D deficiency, but active forms of vitamin D (calcitriol, alfacalcidol) are prescribed only by a doctor because of the high risk of hypercalcemia.

People with a history of kidney stones should discuss both vitamin D and calcium supplements with a doctor, since it is precisely their combination that can increase the risk of recurrence.

Caution is needed in sarcoidosis and other granulomatous diseases, in which calcitriol is synthesized outside the kidneys without the usual control, as well as when taking thiazide diuretics, which reduce the excretion of calcium.

For a healthy athlete with ordinary test results, intake within the tolerable upper limit poses no known risk to the liver or kidneys.

Editorial conclusions

The liver and kidneys activate vitamin D, but at recommended doses it does not harm them.

The main mechanism of possible harm is hypercalcemia and hypercalciuria during a prolonged excess, which threatens the kidneys above all: stones, nephrocalcinosis, acute injury.

In liver and kidney diseases, vitamin D deficiency is more often observed, which is corrected under the supervision of a doctor and tests.

We also recommend reading our materials on omega-3 and the liver and kidneys, on the 25(OH)D test, and on magnesium and the kidneys.

References

1. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press; 2011.
2. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930.
3. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33–44.
4. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669–683.
5. Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, et al. Vitamin D toxicity — a clinical perspective. Front Endocrinol. 2018;9:550.
6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. Kidney Int Suppl. 2017;7(1):1–59.