Vitamin D

Vitamin D is important in the context of parathyroid disease because of its vital role in calcium regulation and its intricate involvement with PTH, calcitonin and calcium levels. Vitamin D deficiency is quite common and can contribute to parathyroid disease, particularly as a cause of secondary hyperparathyroidism.

Parathyroid hormone levels tend to rise with vitamin D deficiency (causing secondary hyperparathyroidism), but calcium levels do not change. If the serum calcium rises, then there is almost certainly a parathyroid tumour present.

Biology of Vitamin D

Vitamin D is a fat-soluble vitamin, with two major physiologically relevant forms: vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). The term Vitamin D can refer to either D₂ or D₃ or both, but usually concerns cholecalciferol, made in the body by the action of sunlight on the skin. Cholecalciferol is the major form of supplemental vitamin D currently available in Australia (Ostelin).

Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body, into the active form of the vitamin. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol or calcifediol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)₂D], also known as calcitriol (Fig. 1).

Fig.1: Vitamin D synthesis with actions of sunlight on the skin, and conversion in liver and kidney

Actions of Vitamin D

Calcitriol, the active form of Vitamin D, acts in a variety of ways, the most important of which seem to be mediated via the vitamin D receptor (VDR). It is involved in the regulation of between 200 and 1000 genes via the VDR and so has effects on numerous different tissues.

Vitamin D has three main functions:

• enhancing absorption of calcium and phosphate from the small intestine
• inhibiting parathyroid hormone synthesis and secretion
• mineralising the bone matrix

More recently low vitamin D has been linked to multiple sclerosis, diabetes (type 1 and type 2), various types of cancers (particularly colon cancer), heart disease, mental health conditions including schizophrenia, all cause mortality including cardiovascular mortality, worse outcomes in stroke, altered immunity and other auto‑immune diseases; however, more research is needed.

It is very important to maintain adequate Vitamin D levels, to: 

a) reduce the risk of falls and, together with calcium, the risk of fractures in the elderly 

b) prevent rickets in children, osteomalacia, and helps to prevent osteoporosis 

c) prevent some types of cancer, diabetes mellitus, and heart disease which have been linked to vitamin D deficiency, as well as syndromes with altered immunity including multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. 

Without sufficient vitamin D, only 10-15% of dietary calcium can be absorbed. Thus, bones can become thin, brittle, or misshapen. Adequate Vitamin D prevents rickets in children and osteomalacia in adults. Together with calcium, vitamin D also helps protect older adults from osteoporosis. 

Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation. Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D. Many cells have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)₂D.

Serum concentration of 25(OH)D is the best indicator of vitamin D status. It is easily measured and is the standard measurement of the vitamin D level. It reflects vitamin D produced cutaneously and that obtained from food and supplements and has a fairly long circulating half-life of 15 days. 25(OH)D functions as a biomarker of exposure, but it is not clear to what extent 25(OH)D levels also serve as a biomarker of effect (i.e., relating to health status or outcomes). Serum 25(OH)D levels do not indicate the amount of vitamin D stored in body tissues.

In contrast to 25(OH)D, circulating 1,25(OH)₂D is generally a poor indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate. Levels of 1,25(OH)₂D do not typically decrease until vitamin D deficiency is severe.

Screening for Vitamin D deficiency involves checking 25(OH)D level, along with calcium, phosphate, ALP, parathyroid hormone levels and renal function. 

Sources of Vitamin D

Sun exposure

Most people in Australia meet their vitamin D needs through exposure to sunlight. The National Health and Medical Research Council's recommended dietary intake for vitamin D in Australia assumes that most Australians receive sufficient sunlight to more than adequately meet their vitamin D requirements. 

Current lifestyle and work environments in developed countries, however, may be contributing to an increased prevalence of vitamin D deficiency, particularly in winter. Many people leave for work early in the morning, return home after dark, and drive to and from work, so that, during winter, they have limited sunlight exposure for five out of every seven days.

Recommended exposure of 5–15 minutes of sunlight 4–6 times a week outside the hours of 10 am–2 pm seems prudent. Certainly, avoidance of the most dangerous ultraviolet exposure in the middle of the day is appropriate, especially in summer, with responsible use of ultraviolet blocking agents. Guidelines on exposure to sunshine need to be tailored to the individual − one size does not fit all. Many factors need to be considered including geographical location such as latitude, season, time of day, skin colour, age and particularly clothing. The amount of sun exposure required in Melbourne for example, is about 7 minutes in summer and 25 minutes in winter for fair-skinned types.

Less vitamin D is synthesised in winter, in those who have dark skin or are older, and in those who dress with little potential for skin exposure to sunlight for cultural reasons or for sun protection. Therefore, serum vitamin D levels are lower in winter than in summer. 

Despite the importance of the sun for vitamin D synthesis, this conflicts with the anti-cancer message of limiting exposure of skin to UV radiation to prevent skin cancer. Guidelines on sun exposure must be tempered by the high prevalence of skin cancers in this country. Much controversy has surrounded the topic of how much sunshine is enough and how much is too much. It is a subject where there has often been a lack of consensus among medical specialists themselves and this problem is further compounded in transferring this message to the public.

Food

Very few foods in nature contain vitamin D. Rich sources are fatty fish, such as sardines, salmon, herring and mackerel; fish liver oils are also a good source. Other sources of importance are meat, milk and eggs, and fortified foods such as margarine. 

In Australia, there is mandatory fortification of table edible oil spreads (eg, low-fat spreads) and table margarine, and voluntary fortification of modified and skim milks, and powdered milk, yoghurts and cheese. However, dietary sources account for only 5-10% of daily intake in most Australians.

Dietary supplements

Vitamin D2 (ergocalciferol) is only available in combination vitamin products and may be less effective in raising and maintaining serum 25(OH)D levels compared with Vitamin D3 (cholecalciferol). Guidelines for treating deficiency are detailed below, but generally involves treatment with oral cholecalciferol 3000 - 5000 units daily for 6 to 12 weeks followed by a maintenance dose of 1000 - 2000 units daily. The dose is tailored to the level of deficiency.

Cholecalciferol capsules (1000 units/0.2mL liquid) are readily available in Australia. 

Vitamin D deficiency in Australia

Several studies have assessed vitamin D status in Australia and New Zealand. The prevalence of deficiency varies, but is acknowledged to be much higher than previously thought.

Vitamin D deficiency can be detected using the 25-OHD radioimmunoassay. While there is debate as to ideal concentrations, the following could be used to guide a clinical approach:

• vitamin D sufficiency > 75 nmol/L
• sub-optimal levels 50-75 nmol/L
• vitamin D insufficiency 25-50 nmol/L
• vitamin D deficiency 15-25 nmol/L
• severe vitamin D deficiency < 15 nmol/L.

The highest rates of frank deficiency occur in dark-skinned, veiled, pregnant women (80%), with similarly high rates found in mothers of infants treated for rickets. Another high-risk group is the elderly, with marginal deficiency rates of 76% in nursing home residents, and 53% in hostel residents. Other studies assessing younger adults have reported marginal deficiency rates of 23% and 43%, with 8% of young women (20–39 years) found to have frank deficiency at the end of winter in Geelong (Victoria, latitude 38°S).

Circulating 25-OHD and 1,25-(OH)2D levels decrease with age. This may be a result of age-related factors, such as reduced capacity to produce vitamin D, diminished sunlight exposure, reduced intake, decline in renal function, disorders associated with abnormal gut function, or reduced synthesis or enhanced degradation of 25-OHD.

Mild vitamin D deficiency: Defined as serum 25-OHD levels in the range 25–50 nmol/L, mild deficiency leads to increased parathyroid hormone secretion and high bone turnover.

Moderate vitamin D deficiency: Defined as serum 25-OHD levels of 15–25 nmol/L, moderate deficiency has been associated with reduced bone density, high bone turnover and increased risk of hip fracture in older people.

Severe vitamin D deficiency: Serum 25-OHD levels of < 15 nmol/L, resulting in osteomalacia, are rare in Australia and New Zealand. Patients with severe deficiency may present with bone and muscle pains, weakness and pseudofractures. Severe deficiency results in secondary hyperparathyroidism.

Recommendations for management of vitamin D deficiency states

Adapted from Source: Vitamin D and adult bone health in Australia and New Zealand: a position statement

High-risk groups

• Elderly people, particularly in residential care

• People hospitalised or institutionalised long-term

• People with skin cancers or skin-related conditions where avoidance of sunlight is required

• Dark-skinned people

• People wearing covering clothing for religious or cultural reasons, particularly veiled women

• Patients with fat malabsorption syndromes, including cystic fibrosis, coeliac disease, inflammatory bowel disease

• People with occupations such as office workers, taxi drivers, factory workers and night-shift workers

• People with medical conditions or medications affecting vitamin D metabolism: e.g. obesity, end-stage liver disease, renal disease, drugs that increase degradation such as rifampicin/anticonvulsants

Minimum sun exposure to prevent deficiency

• For most people, exposure of hands, face and arms to 1/3 minimal erythemal dose (MED) most days

• Older people require more frequent exposure

Dietary vitamin D required to prevent deficiency

• At least 200 IU (5 μg) (age < 50 years) or 600 IU (15 μg) (age > 70 years) per day

• Those with substantial sun avoidance may require higher doses

Vitamin D supplementation required to reduce fracture risk in the elderly

• About 1000 IU (25 μg) per day

Vitamin D required to treat moderate to severe deficiency

• 3000–5000 IU (75–125 μg) per day for at least 6–12 weeks; this will usually return serum 25-hydroxyvitamin D levels to the reference range, and allow ongoing treatment with a lower dose (eg, 1000 IU per day).

• Cholecalciferol (vitamin D₃) 1000 IU or 25 μg is the supplement most commonly used in Australia and costs approximately 11–16 cents per capsule. It is not subsidised by the Pharmaceutical Benefits Scheme. Multivitamin supplements with 32–200 IU per tablet are not adequate to treat or prevent vitamin D deficiency.

  Calcitriol (1,25-dihydroxyvitamin D₃) is generally not suitable for treatment of vitamin D deficiency as it has a narrow therapeutic window resulting in an increased risk of hypercalcaemia or hypercalciuria. This is especially true in nursing home residents who often have quite severe vitamin D deficiency. Calcitriol has a role in the treatment of vitamin D deficiency in renal failure where there is inability to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Serum calcium concentrations and renal function must be monitored closely under these circumstances.

• Most patients will need ongoing treatment with a lower dose (eg, 1000 IU per day).