Authors: Payal Bhandari M.D., Tejal

Contributors: Vivi Chador, Amer Džanković, Hailey Chin

Key Insights 

Vitamin D is a hormone that supports many body functions and helps prevent serious health issues. The two main forms, D2 and D3, are made from sunlight and depend on balanced blood acidity. Vitamin D can also be found in plant-based foods, fortified foods, and supplements, but it must be activated in the liver and kidneys. The liver turns D2 and D3 into 25(OH)D, and the kidneys convert it to the active form, 1,25(OH)2D.

The best way to check vitamin D levels is by measuring 25(OH)D. Changes in these levels help track conditions linked to vitamin D imbalances, like muscle cramps, fatigue, heart problems, kidney stones, and mood issues. Monitoring vitamin D helps with early treatment and tracking progress. Keeping levels balanced is key for good health.

What Is Vitamin D?

Vitamin D is an important fat-soluble nutrient that is different from most vitamins because it can be made by the body when exposed to sunlight, rather than just being obtained from food. This makes it more like a pro-hormone, which is an inactive hormone that activates and helps control minerals like calcium and magnesium, as well as hormones such as insulin and cortisol. Vitamin D is essential for strong bones, a healthy immune system, and good heart health. It also helps protect against conditions like chronic inflammation, infections, and certain cancers.

Role of Vitamin D in the Body

Vitamin D is important for strong bones, teeth, muscles, and nerves, as well as a healthy immune system. It helps absorb calcium, magnesium, and phosphorus, keeping bones strong and preventing osteoporosis.

Vitamin D also helps produce energy in cells by controlling calcium and phosphate levels. Calcium is needed for muscle and nerve function. Low calcium can cause muscle spasms, while phosphate helps create energy. Low phosphate can damage cells and lead to diseases like heart disease and cancer.

Active vitamin D works by binding to a receptor in cells, turning on genes that help fight infections and reduce inflammation.

Figure 1: Vitamin D has many important roles in the body. In the skin, it protects cells from damage. In the blood, it helps control inflammation and supports blood vessel health. The lab test for calcifediol is used to check vitamin D levels. When turned into calcitriol in the kidneys, it helps maintain calcium levels by supporting bone health and calcium absorption. Understanding vitamin D helps manage health issues linked to low or high levels.

Origin of Vitamin D Synthesis1 

Sunlight Synthesizes Vitamin D in the Skin

Your body makes most of its vitamin D (70-80%) from sunlight and gets the rest (20-30%) from food.

• Vitamin D2: Comes from plants and yeast.

• Vitamin D3: Comes from animals.

UV-B sunlight converts a skin compound (7-dehydrocholesterol) into pre-vitamin D3. Factors like sunlight strength, skin color, and age affect how much vitamin D your body makes:

• Darker skin: Takes longer to make vitamin D.

• Less sunlight: People in places like Alaska may lack vitamin D in winter.

• Near the equator: People make vitamin D year-round.

A 2-step process in the liver and kidneys activates vitamin D

After vitamin D3 is made in the skin, it binds to a protein and moves to the liver. Here, an enzyme changes it into 25-hydroxy vitamin D (25(OH)D), called calcidiol. In the kidneys, another enzyme turns calcidiol into calcitriol, the active form of vitamin D. Calcitriol works quickly but lasts only 4 hours in the blood. 25(OH)D (calcidiol) is the most reliable indicator of vitamin D levels because it stays in the blood for 2-3 weeks.

Figure 2: Cholesterol helps make vitamin D3. UV light turns it into provitamin D3, which travels in the blood to the liver. There, it becomes 25-hydroxyvitamin D (calcifediol). In the kidneys, it changes again into calcitriol, the active form of vitamin D.

Bile Salts Absorb Vitamin D

Bile salts help digest fats, absorb vitamins (A, D, E, K), and remove extra cholesterol. They are mostly organic and are essential for vitamin D3 to provide energy, support minerals like calcium, and protect tissues.

Low bile salts reduce vitamin D activity and increase harmful molecules (ROS), which can damage cells, DNA, and body functions. This leads to inflammation and harm to organs and blood vessels.

Regulation of Vitamin D Blood Levels

Cholesterol Synthesis in the Liver 

The body mostly makes vitamin D, with a small amount coming from food. Vitamin D2 is found in plants, fortified foods, and mushrooms, while vitamin D3 comes from animal products like dairy, eggs, fish, poultry, and oils.

Vitamin D is made from cholesterol, which is produced in the liver (20–25%) and other organs like the small intestine, adrenal glands, and reproductive organs (75–80%). Cholesterol production requires a lot of energy and happens in cells.

Liver cholesterol production is controlled by diet and hormones, while other tissues are less affected. The body makes about 9 milligrams (mg) of cholesterol per kilogram of body weight each day and transports 600–800 mg from tissues to the liver to be processed, in a process called reverse cholesterol transport (RCT).

Figure 3: Cholesterol Synthesis and Regulation. Multiple enzymes are involved in acetyl CoA’s undergoing numerous reactions and forming cholesterol. It is then converted to various steroid hormones, bile salts, vitamin D, and oxysterols (oxidized form of cholesterol) and incorporated into lipoproteins and an integral part of cell membranes.  

Calcium, Phosphate, Magnesium Blood Levels, and the Parathyroid Hormone

Vitamin D production depends on cholesterol in the liver and blood levels of calcium, phosphate, magnesium, and parathyroid hormone (PTH). Low calcium levels cause magnesium to release from bones and muscles, raising magnesium levels. This also triggers the parathyroid gland to produce PTH, which:

1. Breaks down bone to release calcium into the blood.

2. Helps the intestines absorb more calcium.

3. Activates vitamin D in the kidneys.

Active vitamin D (calcitriol) and PTH work to raise calcium levels. Calcitriol increases phosphate levels, while PTH lowers phosphate and increases magnesium loss in urine. Phosphate is essential for making ATP, the body’s energy source.

Magnesium is crucial for muscles, nerves, and hormones. Low magnesium can stop vitamin D activation, making it harder to regulate calcium, even with sunlight or PTH.

Causes of magnesium deficiency include:

• Dehydration.

• Poor diet or foods that block absorption.

• Gut damage from illness or surgery.

• Medications affecting digestion.

Low magnesium or vitamin D can cause weak bones, muscle cramps, fatigue, seizures, irregular heartbeat, and high blood pressure.

Figure 4: Vitamin D, PTH, phosphate, and calcium work together to balance minerals in the body. When calcium is low, PTH is released, causing calcium to be taken from bones and absorbed in the intestines. It also helps the kidneys keep calcium. Vitamin D helps absorb calcium and phosphate in the intestines and kidneys. When calcium is high, PTH levels drop, reducing calcium release and absorption.

Clinical Significance of Monitoring Low Vitamin D Blood Levels5 

Figure 5: The clinical manifestations of vitamin D deficiency include, but are not limited to vascular diseases, multiorgan damage, hormonal imbalances, bone and joint disorders, infections, cancers, kidney stones, and metabolic and autoimmune disorders. 

Vitamin D levels can be very low or high in people who live in cold areas with little sunlight, have gut imbalances (dysbiosis), or experience poor blood flow to organs (vasoconstriction). The gut microbiota helps with digestion, nutrient absorption, and waste removal. Vasoconstriction can slow digestion and reduce healthy gut bacteria, leading to dysbiosis.

Figure 6: A healthy gut microbiota is important for energy, hormones, and metabolism. It helps with digestion, nutrient absorption, and waste removal. Dysbiosis, or an imbalance in gut bacteria, can disrupt metabolism and raise levels of harmful pathogens, cancer cells, and other invaders, affecting the immune system.

Chronic Dysbiosis-Induced Atherosclerosis

Chronic dysbiosis (gut bacteria imbalance) can cause nutrient deficiencies that affect protein needed for vitamin D. It also raises stress hormones (like cortisol and adrenaline), which can turn food into glucose, slow fat metabolism, and break down muscle. This leads to:

1. Toxic byproducts from protein breakdown increase blood acidity, reducing energy and damaging cells.

2. Poor gut function lowers nitric oxide (NO), which is needed for healthy blood flow and nerve communication.

3. Excess fat in organs like the pancreas disrupts hormone and enzyme production, leading to diabetes.

4. Lower protein production reduces vitamin D synthesis.

Low vitamin D is linked to more cholesterol in arteries, causing plaque buildup and atherosclerosis.

Figure 7: Atherosclerosis is when fat, scar tissue, and platelets build up in the artery walls, causing them to thicken. This limits blood flow, raises blood pressure, and causes blood to back up into organs like the liver, heart, and pancreas .  

If vitamin D deficiency is not treated, it can cause ongoing damage to blood vessels and tissues. This can harm various organs and lead to symptoms like irregular heart rate, heart attack, stroke, coma, or even sudden death.

Brain and Nerve Damage 

The brain has more cholesterol than other parts of the body, and it makes its own cholesterol since lipoproteins can’t cross the blood-brain barrier. Low vitamin D can damage the blood-brain barrier, affecting brain cells and increasing dementia risk. This damage also prevents the clearing of harmful proteins like beta-amyloid, which causes problems in the brain, leading to:

• Learning disabilities

• Brain blood vessel issues

• Mild cognitive impairment

• Dementia

• Mental health problems like depression and anxiety

• Ear disorders like vertigo, ear infections, and hearing loss

A 2017 study shows higher vitamin D levels may lower dementia risk, but benefits above 35 nanograms per milliliter are unclear. A 2014-2024 review links low vitamin D to more ear issues. It affects calcium levels and brain inflammation, worsening hearing loss and balance problems. Testing vitamin D levels can help treat ear, brain, and nerve disorders.

Autoimmune Disorders

Without enough active vitamin D, immune cells get misdirected, attacking the body’s own tissues. This can lead to autoimmune diseases like Crohn’s, celiac disease, and rheumatoid arthritis (RA). A study showed that people with RA have a 50% higher risk of heart disease, similar to the risk in diabetic patients.

Infections and Cancer

Vitamin D deficiency causes white blood cells (WBCs) to become overactive and work with harmful microorganisms and cancer cells. This helps remove toxins but also supports infections, cancer growth, and blood clots. Low vitamin D is linked to cancers like pancreatic, colorectal, breast (in overweight or obese people), prostate, liver, lung, ovarian, and chronic lymphocytic leukemia (CLL).

Figure 8: Vitamin D deficiency is linked to high levels of oxidized cholesterol in tumor cells, which helps cancer grow and spread. Damaged blood vessels allow tumor cells to bind to cholesterol and interact with platelets. Neutrophils, which protect blood vessel integrity, also shield tumor cells from being destroyed. Tumor cells trigger platelets to form clots and support new blood vessel growth. Natural killer (NK) cells, which normally destroy tumor cells and pathogens, are blocked from doing so. The inflammation from these processes creates a cycle that encourages infections and cancer growth.

Metabolic, Endocrine, and Hormonal Disorders 

Vitamin D deficiency is linked to metabolic and endocrine disorders that affect the structure and function of organs. Factors like age, sex, body mass index, high blood pressure, and genetics can influence this. Temporary changes in hormone levels, such as during pregnancy, surgery, stress, or trauma, can also disrupt vitamin D production and metabolism, often leading to deficiency.

Diabetes 

Diabetes is when blood sugar is too high due to lack of insulin (Type I) or insulin resistance (Type II). Vitamin D plays a key role in both types of diabetes. It helps lower inflammation and controls a gene called Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), which regulates fat, sugar, and inflammation.

How PPAR-γ works:

• Fat Metabolism: PPAR-γ controls fat storage and balance in the body.

• Glucose Regulation: It helps the body use insulin better and manage blood sugar levels.

• Energy Balance: It helps control how the body uses and stores energy.

• Anti-Inflammatory Effects: It reduces inflammation, lowering the risk of diseases like heart disease.

Without enough vitamin D, fat metabolism and glucose uptake are impaired, leading to higher blood sugar. This can damage pancreatic cells that control blood sugar and digestion.

Pancreatic Cells:

1. Endocrine Cells:

   • Alpha Cells: Release glucagon to raise blood sugar.

   • Beta Cells: Release insulin to lower blood sugar.

   • Delta Cells: Balance insulin and glucagon.

   • Gamma Cells: Regulate pancreatic functions.

   • Epsilon Cells: Stimulate appetite.

2. Exocrine Cells:

   • Acinar Cells: Produce digestive enzymes.

   • Ductal Cells: Release bicarbonate to protect the digestive system.

Vitamin D helps regulate these cells, manage blood sugar, and support digestion. Low vitamin D also disrupts glucose control in the liver, damaging pancreatic cells and causing long-term health problems like high blood pressure and organ damage.

Proliferative Diabetic Retinopathy

Low vitamin D levels are linked to eye damage in people with diabetes, called proliferative diabetic retinopathy. This condition occurs when blood vessel damage causes inflammation, leading to fluid buildup in the macula and new blood vessels that can bleed and hurt vision.

A 2015 study of 715 people with diabetic retinopathy found that lower vitamin D levels are linked to more eye problems. Vitamin D helps prevent the growth of harmful blood vessels in the retina.

Bone Disorders and Secondary Hyperparathyroidism

High animal protein diets can lower levels of active vitamin D, which is important for calcium absorption. This can lead to low calcium levels in the blood. To fix this, the body releases a hormone called PTH, which boosts calcium absorption but also causes the kidneys to lose magnesium and phosphate.

Low levels of calcium, phosphate, and magnesium affect energy, muscles, nerves, and bones. In children, this can cause rickets; in adults, it can lead to osteomalacia, where bones become soft. Vitamin D deficiency can weaken bones, cause muscle pain and weakness, lead to bone deformities, and increase the risk of fractures and falls. It can also cause seizures due to nerve problems.

Thyroid Disorders

A diet high in animal protein can cause vitamin D and phosphate deficiencies, reducing the body’s energy production. This triggers an increase in reactive oxygen species (ROS), or heat, which raises thyroid-stimulating hormone (TSH) levels. TSH makes the thyroid produce thyroid hormones (T3 and T4), boosting energy and heat.

Short-term thyroid hormone use can increase fat and cholesterol metabolism, but long-term use or thyroid issues can slow fat metabolism. This leads to stored fat and less energy production. Undigested food in the blood causes inflammation, reducing red blood cells’ ability to deliver oxygen and preventing the liver from making vitamin D.

Excess Androgens (Hyperandrogenism)

A diet high in animal protein increases certain hormones (LH and FSH) but lowers vitamin D. LH triggers ovaries to make androgens, while FSH helps produce estrogen. High androgen levels (like in PCOS) or hormone therapy raise an enzyme that makes cholesterol, which also lowers HDL cholesterol and vitamin D. Too much fat and harmful cholesterol in the blood can cause fat buildup in organs and blood vessels, leading to inflammation. Vitamin D deficiency can cause fatty liver, diabetes, muscle loss, and heart disease.

Losing 5-10% of excess fat can boost vitamin D and reduce risks of diabetes and PCOS. Fat stores vitamin D, so weight loss helps release it, improving inflammation and insulin sensitivity.

Kidney Stones and Chronic Kidney Disease

Vitamin D deficiency reduces the body’s ability to absorb calcium and phosphorus, causing more of these minerals to be excreted in urine. This can lead to high levels of calcium in the urine, increasing the risk of kidney stones. Over time, kidney stones can block urine flow, damage tissues, and raise the risk of infections and kidney problems (chronic kidney disease, or CKD). As CKD progresses, calcium can build up in other tissues, causing damage and disrupting normal body functions.

Clinical Significance of Monitoring High Vitamin D Blood Levels

Vitamin D is important, but too much can cause toxicity. High levels of Vitamin D can raise calcium in the blood, leading to damage in organs like the heart, kidneys, and brain. This can upset the balance of calcium, magnesium, and phosphorus, harming cells and the microbiota, and increasing inflammation, which raises the risk of infections and other diseases.

Kidney Stones and Kidney Damage

Vitamin D toxicity (hypervitaminosis D) is rare but can happen from taking high doses of vitamin D supplements, especially in people with chronic kidney disease (CKD). High vitamin D levels increase calcium absorption in the intestine and bones, leading to high blood calcium. This reduces parathyroid hormone (PTH) levels. To balance calcium, the kidneys try to remove more calcium in urine, causing increased bathroom trips. If the cause of vitamin D toxicity and low PTH isn’t treated, high blood calcium can harm the kidneys, cause kidney stones, and damage kidney cells.

Cardiovascular, Brain, and Nervous System Damage 

High calcium levels can cause the body to lose water and minerals. Over time, this leads to calcium deposits in blood vessels and heart valves, narrowing them, raising blood pressure, and damaging heart cells. This damage can lead to atherosclerosis, where plaque builds up and blood flow is blocked, increasing the risk of heart attacks, irregular heart rhythms, strokes, and brain damage.

Granulomas in the Lungs and Other Tissues

Vitamin D toxicity can raise blood calcium levels, causing poor blood flow to organs, cell damage, and heat production. Granulomas, or lumps, form in organs like the lungs and produce calcitriol, raising calcium in the blood. This can harm the kidneys and cause water and electrolyte imbalances. Over time, it lowers energy and damages blood vessels and tissues.

Symptoms of Vitamin D toxicity include:

• Frequent urination

• Excess thirst

• Nausea and vomiting

• Loss of appetite

• Fatigue

• Abdominal or pelvic pain

• Swelling in hands, feet, or ankles

• High blood pressure

• Muscle cramps

• Dark skin patches

• Puffy eyes

• Dry, itchy skin

• Trouble sleeping or concentrating

• Sexual dysfunction

Prevalence and Statistics of Abnormal Vitamin D Blood Levels

A CDC survey found that 8% of Americans were at risk of vitamin D deficiency, and 25% had insufficient levels. Vitamin D deficiency was defined as a blood level below 30 nmol/L, and insufficiency was 30 to 49 nmol/L. Certain groups, like older women and non-Hispanic Black Americans, were more at risk. Pregnant and breastfeeding women were less likely to be deficient. People with darker skin may have trouble making vitamin D from sunlight.

Vitamin D deficiency is rising due to gut health issues, poor nutrition, and conditions like obesity and diabetes, which affect the body’s ability to produce it.

Globally, 1 billion people have vitamin D deficiency. In Europe, 40% are affected, 68% in South Asia, and 80% in the Middle East. Limited sunlight, indoor lifestyles, traditional clothing, poor diets, and obesity contribute to the problem. Cultural beliefs and lack of healthcare also make it harder to address.

Conclusion

To address low or high vitamin D levels, it’s important to make lifestyle changes. These include eating a plant-based diet rich in vitamin D, staying hydrated, exercising regularly, practicing mindfulness, avoiding recreational drugs, managing side effects from medications, and reducing excess fat. Sometimes, vitamin D and magnesium supplements may be needed to bring levels back to normal and reduce health risks. It’s also important to check other levels, like magnesium, calcium, and cholesterol, along with vitamin D, to get a full picture of health risks linked to blood vessel damage and tissue injury.

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