Vitamin D Deficiency

Introduction

Vitamin D is labeled as the “sunshine vitamin,” as it is produced in the skin on sun exposure. Vitamin D is required to maintain serum calcium concentration within the normal physiologic range for musculoskeletal health.

The Endocrine Society, National and International Osteoporosis Foundation, and American Geriatric Society define vitamin D deficiency as the level of 25-hydroxyvitamin (25 OH D) of less than 30 ng/mL. The Endocrine Society recommends a preferred range of 40-60 ng/mL. To maintain this level, the Endocrine Society recommends intake of 400 to 1000 International Units (IU) daily for infants less than one year, 600 to 1000 IU for children and adolescents from 1 to 18 years and 1500 to 2000 IU for all adults.

Associated Anatomy

The production of vitamin D3 in the skin involves a series of reactions initiating with 7-dehydrocholesterol. Upon exposure to ultraviolet B (UVB) radiation between the wavelengths of 290-315 nm, 7-dehydrocholesterol is converted to previtamin D3, which is then converted to vitamin D3 after a thermally induced isomerization reaction in the skin. From the skin, newly formed vitamin D3 enters the circulation by binding to vitamin D binding protein (DBP). In order to become active, vitamin D requires 2 sequential hydroxylations to form 1,25-dihydroxyvitamin D (1,25[OH]₂ D).

Vitamin D is initially hydroxylated in the 25 position by the hepatic microsomal and/or mitochondrial enzyme vitamin D 25-hydroxylase. The second hydroxylation occurs in the kidney and is performed by the P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase.

Upon entering the cell, the 1,25(OH)₂ D hormone binds to the vitamin D receptor (VDR). The bound vitamin D receptor then forms a heterodimer with the retinoic acid X receptor (RXR). This heterodimer then goes to the nucleus to bind deoxyribonucleic acid (DNA) and increases transcription of vitamin D–related genes.

Causes

Vitamin D deficiency arises from multiple causes including inadequate dietary intake and inadequate exposure to sunlight. About 50% to 90% of vitamin D is absorbed through the skin via sunlight while the rest comes from the diet. Twenty minutes of sunshine daily with over 40% of skin exposed is required to prevent vitamin D deficiency. Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, and cystic fibrosis may also lead to vitamin D deficiency. Moreover, medications such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin induce hepatic p450 enzymes which speed up the degradation of vitamin D. Lastly, people with chronic liver disease and chronic kidney disease are at high risk for vitamin D deficiency due to the steps of enzymatic hydroxylation by the liver and kidney to activate vitamin D.

Differential Diagnosis

Conditions to be considered in the differential diagnosis of vitamin D deficiency include the following:

• Lack of dietary intake
• Inadequate sunlight exposure
• Malabsorptive diseases – Celiac sprue, short bowel syndrome, cystic fibrosis
• Use of antiepileptic medications that accelerate vitamin D metabolism – Phenytoin, phenobarbital
• End-stage liver disease

Drugs

Ergocalciferol (Calciferol, Drisdol)

Ergocalciferol is the most widely available form of vitamin D. This agent stimulates calcium and phosphate absorption from the small intestine and promotes calcium release from bone into the blood.

Epidemiology

It is important to note that vitamin D deficiency is a major global public health issue. About 1 billion people worldwide have vitamin D deficiency, while 50% of the population has vitamin D insufficiency.The prevalence of patients with vitamin D deficiency is highest in the elderly, the obese patients, nursing home residents, and hospitalized patients. Prevalence of vitamin D deficiency was 35% higher in obese subjects irrespective of latitude and age. In the United States, about 50% to 60% of nursing home residents and hospitalized patients had vitamin D deficiency. Vitamin D deficiency may be related to populations who have higher skin melanin content and who use extensive skin coverage, particularly in Middle Eastern countries. In the United States, 47% of African American infants and 56% of Caucasian infants have vitamin D deficiency, while over 90% of infants in Iran, Turkey, and India have vitamin D deficiency. In the adult population, 35% of adults in the United States are vitamin D deficient whereas over 80% of adults in Pakistan, India, and Bangladesh are Vitamin D deficient. In the United States, 61% of the elderly population is vitamin D deficient whereas 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran were vitamin D deficient.

Natural Progression

With prolonged, severe vitamin D deficiency, there is reduced intestinal absorption of calcium and phosphorus and hypocalcemia occurs, causing secondary hyperparathyroidism, which leads to phosphaturia, demineralization of bones, and when prolonged, osteomalacia in adults and rickets and osteomalacia in children. Associated symptoms may then include bone pain and tenderness, muscle weakness, fracture, and difficulty walking. Patients with nutritional osteomalacia, from either a gastrointestinal disorder or suboptimal nutrition and inadequate sun exposure, tend to have serum 25(OH)D levels <10 ng/mL (25 nmol/L).

Pathophysiology

Individuals with darker skin pigmentation have increased amounts of melanin in their skin which decreases the efficacy of vitamin D absorption; this is why African Americans and Hispanics are at greater risk. Once ingested or absorbed through the skin, the liver transforms vitamin D into 25-hydroxyvitamin D which is a necessary precursor to the active form. People with chronic liver disease and cirrhosis may not form the precursor leading to vitamin D deficiency. If transformed, the kidneys are then responsible for transforming 25-hydroxyvitamin D to 1,25-hydroxyvitamin D, which is the active form of Vitamin D in the body. People with kidney disease may not make the active form of vitamin D leading to vitamin D deficiency. Another cause may include malabsorption syndromes such as inflammatory bowel disease, celiac sprue, short bowel syndrome, celiac disease, and cystic fibrosis.

Possible Complications

Vitamin D deficiency can lead to a loss of bone density, which can contribute to osteoporosis and fractures.

Severe vitamin D deficiency can also lead to other diseases. In children, it can cause rickets. Rickets is a rare disease that causes the bones to become soft and bend. African American infants and children are at higher risk of getting rickets. In adults, severe vitamin D deficiency leads to osteomalacia. Osteomalacia causes weak bones, bone pain, and muscle weakness.

Researchers are studying vitamin D for its possible connections to several medical conditions, including diabetes, high blood pressure, cancer, and autoimmune conditions such as multiple sclerosis. They need to do more research before they can understand the effects of vitamin D on these conditions.

Possible Treatment

The Endocrine Society, along with the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation, published a clinical practice guideline in 2011 titled “Evaluation, Treatment and Prevention of Vitamin D Deficiency.” The committee recommended screening of only those individuals who are at high risk for vitamin D deficiency, including patients with osteoporosis or a malabsorption syndrome, as well as black and Hispanic individuals, obese persons (BMI >30 kg/m²), and those with several other medical conditions.

The daily maintenance dose of vitamin D varies by age, but most children and adults generally require 600-2000 IU of vitamin D daily. For vitamin D-deficient children and adults, higher doses of vitamin D given either daily or weekly are recommended, followed by an increase in the daily dose of vitamin D.

In a population-based study, the electronic medical records of more than 1,200,000 members of a health maintenance organization (HMO) were analyzed to determine the upper limit of vitamin D beyond which there is an increased risk of acute coronary syndrome (ACS) or mortality. The lowest risk of mortality and morbidity was reported in members with vitamin D levels in the 20-36 ng/mL range. The hazard ratio increased not only below but also above this range, with adjusted hazard ratios of 1.88 among subjects with vitamin D levels lower than 10 ng/mL, 1.25 among those with levels of 10-20 ng/mL, and 1.13 among those with levels higher than 36 ng/mL (P < 0.05).

Sun Exposure

Sensible sun exposure, especially between the hours of 10:00 am and 3:00 pm produces vitamin D in the skin that may last twice as long in the blood compared with ingested vitamin D. If sun exposure produces slight pinkness, the amount of vitamin D produced in response to exposure of the full body is equivalent to ingesting 10,000-25,000 IU. A variety of factors reduce the skin’s vitamin D-3 production, including increased skin pigmentation, aging, and the topical application of a sunscreen. A clinical study from Sweden comparing full body irradiation with UVB lamps 3 times a week for 6 weeks to a daily vitamin D₃ supplement of 1,600 IU daily for 6 weeks found UVB therapy to be more efficacious in raising serum 25(OH)D concentrations. This suggests that UVB therapy may be a useful therapeutic approach in selected individuals. 

Diet

Individuals who do not have exposure to sunlight are at risk for vitamin D deficiency if they do not ingest adequate amounts of foods that contain vitamin D.

However, most dietary sources of vitamin D do not contain sufficient amounts of the vitamin to satisfy daily requirements. Foods thought to contain high amounts of vitamin D3 are oily fish, such as salmon, mackerel, and blue fish, as well as fortified milk and other dairy products.

A single serving (3.5 oz) of wild-caught salmon has 988 ± 524 IU of vitamin D3, an amount that remains unchanged after baking but that decreases by 50% if the salmon is fried in vegetable oil.  In comparison, farm-raised salmon has only 25% of the vitamin D3 content found in the flesh of wild salmon. Blue fish and mackerel have vitamin D3 levels of 280 ± 68 IU and 24 IU, respectively. 

Fortified milk may contain less than the stated amount of vitamin D3 on the product (in some cases less than 80% of the amount). Vegetables are not a good source for vitamin D.

The following foods contain the indicated amounts of vitamin D, as reported by the US Department of Agriculture’s (USDA’s) Nutrient Data Laboratory:

• Fortified milk (8 oz) – 100 IU
• Fortified orange juice (8 oz)  – 100 IU
• Fortified cereal (1 serving) – 40-80 IU
• Pickled herring (100 g) – 680 IU
• Canned salmon with bones (100 g) – 624 IU
• Mackerel (100 g) – 360 IU
• Canned sardines (100 g) – 272 IU
• Codfish (100 g) – 44 IU
• Swiss cheese (100 g) – 44 IU
• Raw shiitake mushrooms (100 g) – 76 IU
• Most multivitamins (1 tab) – 400 IU

It should be kept in mind that the potency of vitamin D supplements from different manufacturers can vary widely. In one study, pills from sealed bottles of over-the-counter cholecalciferol supplements (1000 IU, 5000 IU, and 10,000 IU) contained 52-135% of the dose listed on the labels. Analysis of bottles with the same lot number revealed that potency ranged from 57% to 138% of what was on the bottle. Compounded 50,000-IU pills contained 52-105% of the expected dose, and 1000-IU compounded pills contained 23-146%.

Primary Prevention

It is recommended that the level of the circulating form of vitamin D (25-hydroxyvitamin D) is checked at least twice a year: once in spring which will reflect low levels after the winter, and once in fall which will reflect higher levels after the summer and the dose should be adjusted accordingly.

Risk factors

The risk factors of vitamin D deficiency can be categorized into three main groups; non-modifiable risk factors, modifiable risk factors, and also factors that are related to mothers’ conditions.

Non-modifiable risk factors

• Age
• Ethnicity: non-western ethnicity like African, Asian, Turkish, and Moroccan children are at greater risks than children of western ethnic background.
• Dark skin color
• Season: late fall, winter, and spring
• Geography: higher latitude, lower altitude, cloudy weather

Modifiable risk factors

• Life style including sedentary behavior, high child television watching, and less outdoor activities
• Less sun exposure including use of sunscreen or clothing
• Obesity
• Being underweight
• Less milk drinking
• Not taking vitamin D supplements
• Exclusive breastfeeding

Maternal risk factors

• Lower maternal age
• Lower household income
• Multiparity
• Higher maternal BMI

Secondary Prevention

After correction of their vitamin D status with oral vitamin D, patients should have a repeat test of their 25(OH)D level to confirm that they are in the normal range. If the 25(OH)D concentration remains persistently low despite several attempts at correction with oral vitamin D, a trial of UVB light therapy (ie, by tanning lamps) may be considered to improve vitamin D status.

Signs or Symptoms

Some symptoms of a deficit in vitamin D include:

• thinning or brittle bones, osteoporosis, or frequent bone fractures
• muscle weakness, particularly if there is an unexplained change in muscle strength
• anxiety or depression, mood changes
• chronic pain, as vitamin D plays a key role in supporting bone, muscle, and cell health
• high or rising blood pressure
• exhaustion, even with enough sleep
• decreased endurance
• unexplained infertility

Studies

Active Not Recruiting

Number of studies: 24

Link

Completed

Number of studies: 428

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Enrolling by Invitation

Number of studies: 8

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Not Yet Recruiting

Number of studies: 23

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Recruiting

Number of studies: 83

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Results Available

Number of studies: 79

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Results Not available

Number of studies: 612

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Suspended

Number of studies: 3

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Terminated

Number of studies: 34

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Withdrawn

Number of studies: 22

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Types

The severity of vitamin D deficiency is divided into mild, moderate, and severe. A level of less than 20 ng/mL of 25-hydroxyvitamin D is considered mildly deficient. A level of less than 10 ng/mL of 25-hydroxyvitamin D is considered moderately deficient. A level of less than 5 ng/mL of 25-hydroxyvitamin D is considered severely deficient.

Typical Test

Physical examination

The majority of patients with vitamin D deficiency are asymptomatic; however, some symptoms to watch for are generalized weakness, fatigue, muscle aches, muscle twitching (fasciculations), osteoporosis, osteomalacia, and depression. In children, irritability, lethargy, developmental delay, bone changes, or fractures are important symptoms of vitamin D deficiency.

Laboratory workup

Measurement of serum 25-hydroxyvitamin D is the test of choice to determine vitamin D deficiency. Levels of 25(OH)D less than 20 ng/mL indicate vitamin D deficiency while levels below 30 ng/mL indicate vitamin D insufficiency. Levels of 25(OH)D greater than 50 ng/mL show optimal levels. Measurement of serum PTH may help distinguish secondary hyperparathyroidism in certain patients. It is important to screen for vitamin D deficiency in those at high risk, including patients with osteoporosis, malabsorption syndrome, obese individuals, African Americans, Hispanics, and patients with chronic kidney or chronic liver disease.

References:

https://www.ncbi.nlm.nih.gov/books/NBK532266/
https://www.ncbi.nlm.nih.gov/books/NBK441912/
https://www.uptodate.com/contents/vitamin-d-deficiency-in-adults-definition-clinical-manifestations-and-treatment#H20
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012634/
https://clinicaltrials.gov/
https://emedicine.medscape.com/article/128762-overview