Understanding and addressing vitamin D resistance

A Comprehensive Approach Integrating Genetic, Environmental, and Nutritional Factors

Abstract

Vitamin D resistance, a condition where the body inadequately responds to vitamin D, can manifest in both hereditary and acquired forms. This paper examines the complexities of vitamin D resistance, highlighting the multifactorial nature of the condition, which involves genetic predispositions, lifestyle factors, infections, hormonal imbalances, and micronutrient deficiencies. Hereditary forms, though rare, typically involve mutations in the vitamin D receptor (VDR), while acquired resistance is increasingly common and often associated with chronic illnesses and environmental factors.

The paper underscores the importance of understanding these diverse contributing factors to effectively address vitamin D resistance. The concept of whole-cell nutrition, which emphasizes the synergy between various nutrients, is presented as a crucial approach to mitigating vitamin D resistance. Furthermore, the paper advocates for integrative orthomolecular medicine, which optimizes health through precise nutrient balance, lifestyle modifications, detoxification, and advanced treatments such as bioidentical hormonal balance, photo-biomodulation therapy and stem cell transplantation. Through a holistic and integrative approach, it is possible to enhance the body’s ability to utilize vitamin D effectively, leading to improved health outcomes in conditions ranging from osteoporosis to autoimmune diseases.

1. Introduction

Vitamin D is essential for numerous biological functions, including calcium homeostasis, bone health, immune function, and cellular regulation. However, some individuals experience vitamin D resistance, where the body fails to respond adequately to normal or even elevated levels of vitamin D. This resistance can be categorized into two primary forms: hereditary and acquired. Understanding the underlying mechanisms and contributing factors is crucial for effective diagnosis and treatment.

2. Vitamin D Resistance, hereditary and acquired

While hereditary forms of vitamin D resistance, such as those caused by mutations in the vitamin D receptor (VDR), are rare, acquired vitamin D resistance is increasingly recognized and can be more common. This acquired form of resistance is often linked to chronic health conditions, lifestyle factors, and immune system dysregulation. Research suggests that a significant portion of individuals might not respond adequately to standard doses of vitamin D supplementation. Studies have shown that about 25% of individuals may be “low responders” to vitamin D, requiring higher or more individualized doses to achieve the desired physiological effects (1).

2.1 Hereditary Vitamin D Resistance

Hereditary vitamin D resistance, also known as Hereditary Vitamin D-Resistant Rickets (HVDRR), is a rare genetic disorder caused by mutations in the vitamin D receptor (VDR) gene. These mutations lead to a reduced ability of the VDR to bind to 1,25-dihydroxyvitamin D, the active form of vitamin D, or impair the receptor’s function, resulting in clinical manifestations such as rickets, hypocalcemia, and secondary hyperparathyroidism. HVDRR typically presents in early childhood, with symptoms including skeletal deformities, growth retardation, and in some cases, alopecia. Treatment usually involves high doses of calcitriol (the active form of vitamin D) and calcium supplements to overcome the resistance (2-7).

2.2 Acquired Vitamin D Resistance

Acquired vitamin D resistance occurs later in life and is not caused by genetic mutations. Instead, it results from a variety of external and internal factors that impair the body’s ability to utilize vitamin D effectively. This form of resistance is often associated with chronic illnesses, certain medications, or conditions that affect vitamin D metabolism. Recent research indicates that lifestyle factors including diet, sleep, exercise, toxins, nutrition and even hormonal imbalance can all contribute to vitamin D resistance. Examples of acquired vitamin D resistance include chronic kidney disease, which impairs the conversion of vitamin D to its active form, and certain autoimmune conditions, where inflammation and immune dysregulation can alter vitamin D metabolism and receptor function.

2.3 Diagnosis of Vitamin D Resistance

Vitamin D resistance is a diagnosis of exclusion and involves a combination of clinical assessment, laboratory tests (including serum levels of 25(OH)D and PTH) and monitoring the response to vitamin D supplementation. Elevated PTH levels in conjunction with sufficient vitamin D status are particularly indicative of resistance (1).

• Clinical Symptoms: Patients may present with symptoms indicative of vitamin D deficiency or resistance, such as bone pain, muscle weakness, or signs of rickets or osteomalacia.
• Medical History: A comprehensive medical history should include an evaluation of dietary vitamin D intake, sun exposure, and any chronic illnesses such as oral/dental infections, chronic kidney disease or gastrointestinal disorders. Other lifestyle factors that may adversely affect vitamin D metabolism should also be considered.
• Serum 25-Hydroxyvitamin D (25(OH)D) Levels: Measure serum levels of 25(OH)D to determine vitamin D status. Low levels may indicate deficiency, but not necessarily resistance.
• Parathyroid Hormone (PTH) Levels: Elevated PTH levels despite adequate or high levels of 25(OH)D are a hallmark of acquired vitamin D resistance. This suggests that the body is not responding appropriately to vitamin D, leading to secondary hyperparathyroidism (1).
• Calcium and Phosphate Levels: Assess serum calcium and phosphate levels. In cases of vitamin D resistance, calcium absorption may be impaired, leading to hypocalcemia and altered phosphate metabolism (8,9). Corrected calcium has been used when low albumin is present. However, some authors argue against this practice (10).
• Vitamin D Receptor (VDR) Functionality: In some cases, genetic testing for polymorphisms in the vitamin D receptor or related genes may be indicated to assess potential hereditary factors contributing to resistance.
• Vitamin D Supplementation Trials: Administering high doses of vitamin D (e.g., as per the Coimbra protocol) and monitoring changes in serum 25(OH)D and PTH levels can help assess the body’s responsiveness. A lack of expected response may indicate resistance (1).
• Longitudinal Monitoring: Regular follow-up with repeat testing can help determine if the patient is a low responder to vitamin D therapy, which may require higher doses for therapeutic effects.

3. Factors Contributing to Vitamin D Resistance

3.1 Genetic Factors

In addition to HVDRR, several genetic polymorphisms significantly influence vitamin D metabolism and receptor function, contributing to variations in vitamin D resistance.

• CYP24A1 Variants: The gene CYP24A1 encodes an enzyme that degrades active vitamin D. Polymorphisms in this gene can lead to lower circulating levels of vitamin D and reduced effectiveness. Variants such as rs3886163 have been associated with decreased vitamin D levels, impacting overall vitamin D metabolism and related health outcomes (11,12).
• CYP2R1 Polymorphisms: The CYP2R1 gene is crucial for converting vitamin D into its active form. Variants in this gene, including rs10500804 and rs12794714, have been linked to lower serum levels of 25-hydroxyvitamin D (25(OH)D), indicating a significant role in vitamin D metabolism (12,13).
• Vitamin D Receptor (VDR) Polymorphisms: The VDR gene, which encodes the vitamin D receptor, also exhibits polymorphisms that can affect vitamin D signaling. Variants such as Fok1 and others in the 3′ UTR region may alter VDR expression and function, thereby influencing vitamin D’s biological effects (11,14).
• Impact on Health: Genetic variations in these pathways have been associated with various health conditions, including obesity and type 2 diabetes. Studies highlight the importance of these polymorphisms in understanding vitamin D deficiency and its broader implications for metabolic diseases (13,14).

3.2 Infections

Infections, particularly chronic ones, can contribute to vitamin D resistance. Dental infections, including those related to root canal-treated teeth (15,16), have been implicated in systemic inflammation that can alter vitamin D metabolism. Additionally, infections such as tuberculosis and chronic viral infections can interfere with VDR function and immune regulation, exacerbating vitamin D resistance (1,17-23).

3.3 Physiological Conditions

Obesity is a well-known factor contributing to vitamin D resistance. In obese individuals, vitamin D is sequestered in adipose tissue, reducing its bioavailability. This leads to lower circulating levels of vitamin D and an increased requirement for supplementation (24-26).

3.4 Prescription Drugs

Several prescription drugs can contribute to vitamin D resistance by either increasing the metabolism of vitamin D or interfering with its absorption.

• Antiepileptic Drugs (AEDs)
  • Phenytoin: This drug is known to induce cytochrome P450 enzymes, which accelerate the breakdown of vitamin D, leading to lower levels in the body (27,28).
  • Carbamazepine: Similar to phenytoin, carbamazepine increases the hepatic metabolism of vitamin D, resulting in deficiencies over time (27-29).
  • Phenobarbital: This medication also induces the metabolism of vitamin D, contributing to its deficiency (28,30).
• Cancer Treatments
  • Tamoxifen: Used in breast cancer treatment, tamoxifen has been associated with decreased vitamin D levels (29).
  • Cyclophosphamide and Taxanes (e.g., Paclitaxel): These chemotherapeutic agents can also disrupt vitamin D metabolism, though the exact mechanisms are less well-defined (27).
• Cardiovascular Medications
  • Calcium Channel Blockers (e.g., Verapamil, Diltiazem): These drugs may inhibit the conversion of vitamin D precursors, leading to lower serum levels of vitamin D (27).
  • ACE Inhibitors: Some studies suggest that these medications can be associated with lower vitamin D levels, although the relationship may be influenced by underlying health conditions (27).
• Other Medications
  • Antibiotics: Certain antibiotics, particularly rifampicin, can induce liver enzymes that metabolize vitamin D more rapidly (29,30).
  • Bile Acid Sequestrants (e.g., Cholestyramine): These can interfere with the absorption of fat-soluble vitamins, including vitamin D (28).
  • Orlistat: This weight-loss drug can reduce the absorption of dietary fats, which may also affect the absorption of vitamin D (28).
  • Steroids: Corticosteroids like prednisone can lead to decreased vitamin D metabolism and absorption, contributing to deficiencies (29).

3.5 Lifestyle Factors

Several lifestyle factors influence vitamin D metabolism and can contribute to vitamin D deficiency and resistance:

• High Carbohydrate Diet: High carbohydrate diets may negatively influence vitamin D status and contribute to vitamin D resistance, particularly in specific populations such as pregnant women. Research indicates that a higher carbohydrate intake (≥300 g/day) is significantly correlated with lower levels of 25-hydroxyvitamin D (25(OH)D), which is a key marker for vitamin D status (31). A study involving pregnant women found a significant negative correlation between carbohydrate intake and 25(OH)D levels, highlighting the potential impact of high carbohydrate consumption on vitamin D status (31). Other research indicates that low-carbohydrate diets are associated with higher levels of 25(OH)D, suggesting that reducing carbohydrate intake may be beneficial for improving vitamin D status (32,33).
  • Mechanisms of Interaction
    1. Body Composition and Fat Sequestration: Increased carbohydrate intake can lead to higher body fat composition, which may dilute vitamin D levels in the body. Fat tissue can sequester vitamin D, reducing its bioavailability and potentially impairing its metabolism in the liver (31,32).
    2. Insulin Resistance: High carbohydrate diets can promote insulin resistance, which has been associated with various metabolic disorders. Insulin resistance itself can affect the metabolism of vitamin D, leading to altered levels of its active forms in the body (34).
    3. Dietary Composition: Studies suggest that diets low in carbohydrates, such as ketogenic or low-carbohydrate high-fat (LCHF) diets, may enhance vitamin D status. These diets often include higher amounts of vitamin D-rich foods, which may contribute to better overall vitamin D levels compared to high carbohydrate diets (32,33).
• Toxins: Environmental toxins may also impair the function of enzymes involved in vitamin D activation.
  • Air Pollution and Chemical Exposure: A review article discusses how air pollution, environmental chemicals, and smoking can trigger vitamin D deficiency. The authors suggest potential mechanisms through which these factors may affect vitamin D metabolism, including the disruption of vitamin D synthesis in the skin and alterations in liver metabolism (35).
  • Impact of Nutritional and Environmental Factors: A study highlighted the prevalence of vitamin D deficiency among a population in Saudi Arabia, linking it to various factors, including dietary intake and environmental influences. The findings suggest that even in sunny regions, factors like obesity and limited sun exposure can exacerbate vitamin D insufficiency (36).
  • Endocrine-Disrupting Chemicals (EDCs): Substances like bisphenol A (BPA) and phthalates, commonly found in plastics, can disrupt endocrine functions, including those related to vitamin D. A study analyzed the relationship between urinary levels of phthalate metabolites and bisphenol A with vitamin D levels in U.S. adults. EDCs may alter the expression of enzymes responsible for vitamin D metabolism, leading to reduced efficacy of vitamin D in the body. These findings suggest that higher concentrations of these substances correlate with lower vitamin D levels, indicating that dietary toxins may play a role in vitamin D resistance (35).
• Ultra-Processed Foods (UPF): Recent studies have indicated a concerning relationship between the consumption of ultra-processed foods (UPFs) and vitamin D deficiency.
  • Impact on Vitamin D Levels:
    1. Association with Deficiency: A cross-sectional study conducted in Brazil found that high consumption of UPFs was significantly associated with an increased risk of vitamin D deficiency. Individuals who consumed more UPFs had a 2.05 times higher likelihood of being vitamin D deficient compared to those with lower intake levels. This suggests that UPFs may negatively impact serum vitamin D concentrations, contributing to deficiencies in the population studied (37).
    2. Micronutrient Content: Another study highlighted that diets high in UPFs were inversely related to the intake of several micronutrients, including vitamin D. It was observed that the micronutrient content in diets rich in UPFs was significantly lower than in those based on natural or minimally processed foods. Specifically, the study noted that the higher the proportion of UPFs in the diet, the lower the levels of vitamin D and other essential nutrients (38).
    3. Broader Nutritional Implications: The detrimental effects of UPFs extend beyond vitamin D, as they have been linked to inadequate intake of various micronutrients critical for health. This trend poses significant public health concerns, particularly in populations where UPF consumption is rising rapidly (39,40).
• Excess Seed Oils (Dietary Omega-6 PUFA): High dietary intake of omega-6 polyunsaturated fatty acids (PUFAs) (primarily found in seed oils) has been linked to vitamin D resistance, primarily due to the competitive metabolism of omega-6 and omega-3 fatty acids. Both omega-6 and omega-3 PUFAs are metabolized by the same enzymes, which can lead to an imbalance when omega-6 intake is excessively high compared to omega-3 intake. This imbalance can exacerbate inflammatory processes and potentially interfere with the body’s ability to utilize vitamin D effectively. The evidence suggests that high amounts of dietary omega-6 PUFAs can contribute to vitamin D resistance through mechanisms involving inflammation and metabolic dysregulation. A balanced intake of omega-3 and omega-6 fatty acids is crucial for maintaining optimal health and ensuring effective vitamin D metabolism.
  • Omega-6 PUFAs, particularly those derived from linoleic acid, tend to promote inflammation. Chronic inflammation can alter metabolic pathways, potentially leading to vitamin D resistance by affecting the expression of vitamin D receptors or the enzymes involved in vitamin D metabolism (41,42).
  • Nutritional Imbalance: The typical modern diet exhibits a high omega-6 to omega-3 ratio, often ranging from 20:1 to 50:1, which is significantly higher than the recommended ratio of 4:1 to 5:1. This excessive intake of omega-6 fatty acids can lead to an overproduction of pro-inflammatory eicosanoids, which may further contribute to metabolic dysregulation and vitamin D resistance (41,42).
  • Genetic Factors: Variants in genes responsible for fatty acid desaturation (like the FADS gene cluster) can influence how individuals metabolize these fatty acids, potentially leading to varied responses to dietary omega-6 and omega-3 intake. These genetic differences can affect the synthesis of eicosanoids and, consequently, the inflammatory response, which is linked to vitamin D metabolism (42,43).
• Sunshine and Exercise: Adequate sun exposure is crucial for endogenous vitamin D synthesis. However, modern lifestyles often limit sun exposure, contributing to deficiency and resistance. Regular exercise has been shown to improve vitamin D status by enhancing metabolism and reducing inflammation.
  • Lack of exercise can contribute to vitamin D resistance, primarily through its impact on muscle mass and vitamin D metabolism. Research indicates that regular physical activity, particularly resistance training, can enhance vitamin D status by increasing the expression of vitamin D receptors (VDRs) in muscle tissue and promoting the release of vitamin D from muscle cells into circulation (44,45).
  • Mechanisms of Vitamin D Resistance
    1. Muscle Mass and Vitamin D Storage: Resistance exercise is associated with increased muscle mass, which can serve as a reservoir for vitamin D. This muscle tissue can bind and store vitamin D, potentially leading to reduced serum levels of 25(OH)D (the main circulating form of vitamin D) if not adequately supplemented (44).
    2. Exercise-Induced Changes: Acute bouts of exercise have been shown to temporarily increase serum levels of 25(OH)D, indicating that physical activity can enhance vitamin D metabolism. For instance, studies have demonstrated that even a single session of exercise can elevate vitamin D concentrations shortly after the activity (45,46).
    3. Vitamin D Receptors: Regular exercise may upregulate VDR expression in muscles, enhancing the body’s ability to utilize vitamin D effectively. This is crucial because vitamin D plays a significant role in muscle function and overall physical performance (46,47).
    4. Seasonal and Environmental Factors: The benefits of exercise on vitamin D status can also be influenced by seasonal variations in sunlight exposure, which is the primary source of vitamin D. Individuals who are more sedentary may miss out on the natural vitamin D synthesis that occurs with outdoor physical activity (44,46).
• Sleep: Poor sleep quality can disrupt the circadian rhythm, which in turn affects hormone levels and vitamin D metabolism. Adequate sleep is essential for maintaining optimal vitamin D levels and reducing resistance.
  • Poor sleep has been linked to vitamin D resistance, with emerging evidence suggesting that vitamin D deficiency (VDD) may exacerbate sleep disorders and poor sleep quality. The interplay between poor sleep and vitamin D resistance highlights the importance of maintaining adequate vitamin D levels for optimal sleep health. While there is promising evidence linking VDD to sleep disorders, further high-quality studies are needed to establish causal relationships and clarify the mechanisms involved
  • Relationship Between Vitamin D and Sleep
    1. Epidemiological Evidence: Studies indicate that individuals with VDD are at a significantly higher risk of experiencing sleep disorders. A meta-analysis involving 9,397 participants found that those with low serum vitamin D levels had increased odds of poor sleep quality, short sleep duration, and excessive daytime sleepiness. Specifically, participants with serum 25(OH)D levels below 20 ng/mL had a 1.5-fold increased risk of sleep disorders (48,49).
    2. Biological Mechanisms: The association between vitamin D and sleep regulation is biologically plausible. Vitamin D receptors are present in the brain, and vitamin D may influence sleep through its role in regulating the serotonergic system, which is crucial for sleep-wake cycles (50,51).
    3. Interventional Studies: Some interventional studies have suggested that vitamin D supplementation can improve sleep quality. For instance, a randomized controlled trial reported that vitamin D supplementation in veterans increased sleep duration. However, results have been inconsistent across different studies, with some showing no significant improvement in sleep from vitamin D supplementation (49,52).
  • Implications of Poor Sleep on Vitamin D Levels
    1. Poor sleep can also affect vitamin D metabolism and its effectiveness in the body. Chronic sleep deprivation may lead to alterations in metabolic processes, including those involved in vitamin D synthesis and utilization, potentially contributing to a cycle of deficiency and resistance (48,51).