Peer-Reviewed, Evidence-Based Analysis of Vitamin Dand Primary Hyperparathyroidism

Storm Weaver Æ David B. Doherty ÆCamilo Jimenez Æ Nancy D. Perrier

Published online: 24 March 2009

� Societe Internationale de Chirurgie 2009

Abstract

Background Research into the actions of vitamin D on

the human body has been increasing at an exponential rate,

as has understanding of the impact of vitamin D on various

aspects of the endocrine system. Primary hyperparathy-

roidism (PHPT) is a disease of the endocrine system that

can result in debility if not diagnosed. New understanding

about the effect of vitamin D on parathyroid hormone

regulation may provide an opportunity to better understand

the coexistence of PHPT and vitamin D deficiency.

Methods An evidence-based literature review was based

on a PubMed search for research involving vitamin D and

primary hyperparathyroidism, and evaluating existing

research on vitamin D. The PubMed search included

English-language articles published between 1977 and

2008, with a focus on research and analysis completed

between 2005 and the present. This study examined recent

developments in understanding the relationship between

vitamin D and PHPT. This review of existing literature

examined the impact of vitamin D insufficiency and defi-

ciency, including the impact on diagnosis of vitamin D

insufficiency/deficiency, diagnosis and management of

PHPT, and the impact on overall health. The level of evi-

dence was determined according to criteria proposed by

Sackett et al. and the grade of recommendation according

to the criteria proposed by Heinrich et al.

Results Level III and level IV evidence predominates the

vitamin D/PHPT based literature, with several notable

Heinrich grade A, B, and C studies available. Additional

evaluation of studies’ review is provided by reference and

by section.

Conclusions Vitamin D metabolism plays an important

role in PHPT etiology, diagnosis, and management. Care of

both conditions may have an important impact on overall

health in humans.

Introduction

Vitamin D, once poorly understood has been shown to be

highly involved in a number of human processes, from

calcium regulation to blood lipid regulation [1 (V)] . A fat-

soluble vitamin, vitamin D is present naturally in relatively

few foods but is added to some foods as a supplement. In

humans, vitamin D is produced through the conversion of

cholesterol during exposure to ultraviolet (UV)B radiation

on the skin.

Vitamin D deficiency is a common condition in the

United States and worldwide [2 (V), 3 (V), 4 (III)] likely

caused by the combination of diets sparse in vitamin D,

avoidance of ultraviolet B (UVB) sunlight, indoor con-

finement, and an increasingly elderly population. Primary

hyperparathyroidism (PHPT) is also common and largely

affects the elderly. The low 25-hydroxyvitamin D level

frequently seen in patients with PHPT is believed to be at

least partly a result of the metabolic sequelae of inherent

excess parathyroid hormone (PTH) converting 25-hydrox-

yvitamin D to 1,25-dihydroxyvitamin D [5 (II), 6 (II)].

However, other factors seem to contribute to the coexis-

tence of the two conditions [7 (III)].

S. Weaver � D. B. Doherty � N. D. Perrier (&)

Department of Surgical Oncology, The University of Texas

M. D. Anderson Cancer Center, PO Box 301402, Houston,

TX 77230-1402, USA

e-mail: nperrier@mdanderson.org

C. Jimenez

Department of Endocrine Neoplasia, The University of Texas

M. D. Anderson Cancer Center, Houston, TX, USA

123

World J Surg (2009) 33:2292–2302

DOI 10.1007/s00268-009-9966-9

The effects of a low preoperative vitamin D level in the

setting of PHPT remain unclear, particularly in patients

with mild PHPT. Differentiating primary autonomous PTH

production in the setting of mild hypercalcemia from sec-

ondary PTH elevation due to vitamin D deficiency is not

always straightforward. Some studies suggest that vitamin

D deficiency may worsen the manifestations of PHPT by

promoting more pronounced parathyroid gland prolifera-

tion [8 (III)]. The result is higher PTH elevation, larger

adenomas, and more frequent fractures compared with

patients who have vitamin D sufficiency [9 (V), 10 (I), 11,

12 (V)].

Vitamin D

The generic appellation ‘‘vitamin D’’ comprises multiple

forms of the vitamin, metabolized in the body in the

intestines and liver. Although vitamin D is created through

conversion of cholesterol in the skin, during exposure to

UVB radiation on the skin, vitamin D also can be ingested,

most often in one of two major types (vitamin D2 and

vitamin D3). Research on the function and metabolism of

vitamin D comprises a number of studies, ranging from

Sackett Level II through Sackett Level V investigations,

including both human and animal studies. Sackett Level III

investigations predominate, with a number of Sackett Level

V reviews evaluating accumulated evidence present.

Ingested vitamin D is converted to useful forms through

synthesis in the liver and/or intestines, where D2 and

D3 are converted to calcifediol (25-hydroxycholecal-

ciferol, also called calcidiol) in the liver, and/or calcitriol

(1, 25-dihydrovitamin D) in the kidneys and intestines.

As previously noted, there are two major types of vita-

min D: vitamin D2 (ergocalciferol) and vitamin D3

(cholecalciferol), most often provided in supplementation,

including fortification of food and dairy products. Until

recently, the most commonly fortified food product was

milk, and milk was typically fortified with vitamin D2, also

known as ergocalciferol. Ergocalciferol is primarily a

plant-based version of vitamin D, with a slightly different

structure and less biological activity in the human body

than vitamin D3 (cholecalciferol), due to a more complex

molecular bonding system. Double bonds on two of the

carbon side chains (C23 and C24), as well as the addition

of a methyl group on C24 act as inhibitors and slow met-

abolic transformation of D2 in the body.

Despite its drawbacks, vitamin D2 is more commer-

cially accessible and less expensive to produce, making it

more suitable for large-scale fortification of foodstuffs.

Fortification of foodstuffs has increased over time, making

access and affordability of D2 a significant factor in

increasing availability of vitamin D in the food supply.

Whereas it was primarily milk that was fortified with

vitamin D, the increase in research concerning the impact

of vitamin D deficiency on populations over time has

resulted in an increase, in the western world, in fortification

of any number of food products, including dairy, fruit/

vegetable juices, and baked goods.

Vitamin D3, also known as cholecalciferol, is the type of

vitamin D synthesized in the human body during exposure

of the skin to UVB radiation. Cholecalciferol is also pro-

duced in other animals, and although more difficult to

obtain, is more easily converted to calcifediol—the active

form of vitamin D used within the human body.

The process of conversion of cholecalciferol in the skin

is a result of the interaction between 7-dehydrocholoesterol

and UVB light within certain wavelengths (typically 270

and 300 nm). Peak synthesis occurs in a much narrower

band between 295 and 297 nm [13 (V), 14 (II)]. The rel-

evance of the wavelengths is particularly important: these

wavelengths are only present in sunlight at sea level when

the sun is[45� above the horizon or when the UV index is

[3 [15 (III)].

Individuals with fair skin can synthesize sufficient

vitamin D through 10–15 min of exposure of the arms,

hands, face, and/or back without sunscreen each day, pro-

vided that the proper solar elevation and/or UV index is

met. This exposure enables the synthesis of sufficient

cholecalciferol to meet the daily requirement of 400–

1000 IU recommended by nutrition researchers [15 (III),

16 (V), 17 (I), 18 (V)]. People with darker skin require

longer UVB exposure to synthesize sufficient cholecalcif-

erol. Once the body has created sufficient cholecalciferol to

attain equilibrium, additional vitamin D is degraded or

converted to other photosynthesized products as quickly as

it is generated.

Interestingly, the human body is exceptionally efficient

at synthesizing vitamin D, yet individuals with extensive

exposure to sunlight do not suffer from vitamin D intoxi-

cation (which can occur in individuals obtaining excessive

vitamin D through supplementation). It has been noted that

once the human body has synthesized sufficient vitamin D,

the synthesizing products (previtamin D3 and vitamin D3)

respond to the presence of sunlight by synthesizing further

into other photoproducts [16 (V)].

Although we are still working to understand the body’s

need for vitamin D, and establish accurate reference values

for vitamin D levels at different ages and health statuses,

some guidelines have been set regarding what reference

ranges of vitamin D constitute ‘‘deficiency,’’ ‘‘insuffi-

ciency,’’ and ‘‘normal.’’ As we understand more about the

relationship between vitamin D and health, these reference

ranges are shifting, but current ranges for 25(OH)D are

typically considered optimal if, 32.0–100.0 ng/ml [19 (V),

20 (III)].

World J Surg (2009) 33:2292–2302 2293

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Gross vitamin D deficiency, resulting in changes in the

body such as rickets, brought about the changes in the food

supply that encouraged supplementation. This was evident

especially in foods consumed by children.

As a fat-soluble vitamin, there has been concern among

medical practitioners over the level of vitamin D at which

vitamin D intoxication would occur. Side effects of vitamin

D intoxication, including hypercalcemia, can be serious,

and limited understanding of the metabolic cycle for vita-

min D possibly caused error on the side of caution where

fat-soluble vitamins were concerned. The current Recom-

mended Daily Allowance (RDA) of vitamin D, increased to

400 IU in 2007, but is still considered by some to be

insufficient for anything other than prevention of the most

visible side-effects of vitamin D deficiency. Holick and

others believe that the minimum requirements for vitamin

D are closer to 1000 IU per day [16 (V)]. In addition, with

the increased use of sunscreens and the reduced amount of

time spent outdoors for both children and adults, these

requirements must be met through supplementation, which

is a much less efficient method than the body’s own syn-

thetic process.

Due to supplementation at minimal values in the food

supply, which prevents the more visible symptoms of gross

vitamin D deficiency, vitamin D insufficiency, although

common, remains undetected in many patients. As we

understand more about the function of vitamin D in the

body, links are developing about the relevance of vitamin

D for immune function, maintenance of cognitive capacity

in elderly populations, cancer prevention and treatment,

and other vital matters of health. Despite the beneficial

aspects of campaigns to raise awareness about the dangers

of UV light, sun exposure, and the relationship to cancers,

such as melanoma, these campaigns, combined with

decreased exposure to natural sunlight, have contributed to

the prevalence of vitamin D insufficiency and chronic

marginal deficiency in western populations.

Vitamin D deficiency induces mild secondary hyper-

parathyroidism with a subsequent increase in bone

turnover, and, in elderly patients, an increased risk of

osteoporotic fracture, mainly at cortical sites [21 (IV)].

Typically, insufficiency is determined at that point at which

there is insufficient calcidiol present in the blood to allow

serum parathyroid hormone homeostasis, noted as the point

at which serum PTH levels start to increase. Currently,

serum calcidiol levels are usually considered normal

when C30 ng/ml, insufficient between 25–30 ng/ml, and

deficient when \25 ng/ml [13 (V), 22 (V)]. This reference

range is currently being analyzed and may change as fur-

ther developments in understanding the role of vitamin D

in multiple systems of the body takes shape. The estab-

lishment of new reference ranges will be discussed in

upcoming sections.

Even slight deficiencies in vitamin D can impact the

immune and musculoskeletal systems by affecting bone

density and muscle strength [23 (V), 24 (III)]. Vitamin D

deficiency also has been implicated in the development and

progression of some cancers and chronic disorders, including

melanoma and diabetes [25] (I), 26 (V), 27 (IV), 28 (IV)].

Primary hyperparathyroidism

PHPT is a metabolic disorder characterized by autonomous

overproduction of PTH [29 (I)]. A biochemical diagnosis is

made when a patient has an elevated or high-normal serum

calcium level and an inappropriately elevated intact PTH

level (serum Ca levels C 10.2 mg/dl, intact PTH level [80 pg/ml).

Approximately 100,000 patients in the United States are

diagnosed with PHPT each year [30] (IV)]. Increased

screening for abnormal serum calcium levels during rou-

tine medical examinations and the routine use of

multichannel autoanalyzers have resulted in earlier and

increased PHPT detection [31](V)]. Eighty percent of

patients with PHPT are now diagnosed biochemically

before they develop ‘‘classic’’ PHPT symptoms, such as

nephrolithiasis, pancreatitis, or osteitis fibrosis cystica.

Despite the greater tendency for testing that has provided

beneficial early diagnosis, nonclassic and early symptoms

of PHPT, including fatigue, bone/joint pain, cognitive

difficulty, and sleep disturbances, among others, may be

insufficiently problematic to elicit documentation. These

symptoms are commonly dismissed by the patient and not

mentioned. In addition, because the majority of these

symptoms are difficult to quantify and often are subjective,

patients with PHPT who exhibit these symptoms are

commonly referred to as ‘‘asymptomatic.’’

PHPT prevalence increases with age. Perimenopausal,

menopausal, and postmenopausal women are at the greatest

risk of developing PHPT [32] (IV), 33 (V), 34 (II), 35 (III),

36 (V)]. One screening study found that approximately

14% of women older than aged 65 years have PHPT [37

(I)]. Because the population of elderly patients continues to

increase, with 20% of the U.S. population predicted to

be older than aged 65 years by 2030, PHPT is becoming an

increasingly important health issue. Furthermore, because

elderly patients are more likely to be confined to their

homes or extended care facilities, to have restricted diets,

and to have little exposure to UV radiation, they also are

the population most likely to be deficient in vitamin D

[1 (V), 18 (V), 38 (II)]. Therefore, it is not surprising that

PHPT and vitamin D deficiency coexist in many elderly

patients. In fact, a recent study revealed that up to 75% of

elderly patients with PHPT also have vitamin D deficiency

[39 (V)].

2294 World J Surg (2009) 33:2292–2302

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Mobility issues tend to increase as individuals age, and

loss of muscle strength and dexterity are more common in

elderly populations. Although inactivity and comorbidities

can contribute to loss of muscle strength in elderly patients,

some researchers have suggested that age-related changes

in hormonal status, specifically calcidiol and PTH, also

contribute to this loss. A substantial percentage of elderly

patients who experience loss of muscle strength, especially

those with weakness or fatigue and few additional symp-

toms, will have few overt symptoms of vitamin D

deficiency.

Untangling the connections between vitamin D

and PHPT

A complex regulatory network of vitamin D, calcium, and

PTH exists within the human endocrine system (Fig. 1) [2

(V)]. Vitamin D receptors on the parathyroid glands detect

levels of calcitriol, which inhibits the production of PTH,

the major regulator of renal 1-hydroxylase. In PHPT,

autonomous production of PTH, the result of tumor or

increased parathyroid glandular mass, supersedes the

normal feedback mechanism.

Current research by Sambrook et al., [40 (I)] among

others, recognizes the link between vitamin D insufficiency

and PHPT, and those individuals with undiagnosed vitamin

D insufficiency are being shown to have a more compli-

cated course in the resolution of PHPT.

This overview highlights a range of Sackett I-V evi-

dence in the examination of the connection between

vitamin D and PHPT. Some of the earliest studies of

vitamin D and PHPT investigated vitamin D metabolism

regulation by the parathyroid glands. In 1972, Garabedian

et al. found evidence that the removal of the parathyroid

glands significantly interfered with vitamin D metabolism

[41]. This group also found that replacing PTH with

parathyroid extract could nearly restore vitamin D metab-

olism. Furthermore, Garabedian et al. noted that vitamin D

levels controlled by release of PTH from the parathyroid

glands were independent of blood or intestinal calcium

levels, indicating that calcium homeostasis and the vitamin

D/PTH regulating mechanism are separate processes [41

(III)].

The search for novel ways to manage hypercalcemia—

the key symptom of PHPT—has led to further studies of

vitamin D and PHPT. In 1977, Kaplan et al. found that

increases in calcitriol levels were linked to increases in

fractional and urinary calcium levels, but that serum cal-

cium levels, serum phosphorus levels, and serum PTH

levels remained unaffected. The researchers also found that

abnormally high vitamin D levels are linked to increases in

intestinal calcium absorption, but they also noted that that

vitamin D metabolism related to parathyroid function may

have only a limited role in absorptive hypercalcemia.

Furthermore, Kaplan et al. [42 (II)] found that intestinal

calcium absorption exceeded the levels that would be

expected in the setting of increased serum calcitriol levels.

In 1991, Vieth et al. [30] found that serum calcitriol

levels are useful in the diagnosis of PHPT. Their study

revealed that vitamin D metabolites were not dependent on

PTH and were stable in patients diagnosed with PHPT as

well as in serum samples from patients without PHPT.

Metabolites of vitamin D did not fluctuate despite changes

in PTH. However, levels of 1,25(OH)2D were significantly

higher in patients with PHPT. Ninety-fifth percentile of

1,25(OH)2D levels were reached in 65% of patients with

PHPT. It was concluded that making the elevated levels of

1,25(OH)2D were a good tool for evaluating patients with

potential PHPT. Vieth et al. also found that the PTH-

dependent metabolite calcitriol increased 100-fold. The

group found a significant correlation between serum cal-

citriol levels and serum calcidiol levels in patients with

PHPT (r = 0.5; P \ 0.05) but not in patients who did not

have PHPT (r = 0.02), suggesting that high serum calci-

triol levels indicate the need for further testing for PHPT

[30 (IV)].

Several important questions about the complex rela-

tionship between vitamin D and PHPT have been

addressed, including questions about the role of vitamin D

in PHPT homeostasis and the impact of vitamin D on

serum calcium levels in patients with PHPT. It seems that

the severity of PHPT increases when the disease and

vitamin D insufficiency occur concurrently.

Among the questions being examined, there is the

question of whether PHPT may be a result of parathyroid

gland stimulation from vitamin D insufficiency. It is pos-

sible that vitamin D insufficiency could predispose patients

to PHPT, but not all patients with PHPT are vitamin D-

deficient. Decreased vitamin D levels can lead to fewer

vitamin D receptors (VDR), which are created in response

to active 1,25(OH)2D stimulating expression of the VDR

on the parathyroid glands. This impedes the feedback

inhibition by calcitriol on PTH [40 (I), 7 (III)].

To effectively manage concomitant PHPT with under-

lying vitamin D insufficiency or deficiency, there are

several other issues that need to be addressed, which are

being explored in current research or have yet to be

explored, including: 1) the definition of a ‘‘normal’’ PTH

value in patients with concomitant PHPT and vitamin D

insufficiency/deficiency, particularly elderly patients; 2)

the role and effect of preoperative vitamin D replacement

therapy in patients with concomitant PHPT and vitamin D

deficiency; 3) the role of post-parathyroidectomy vitamin

World J Surg (2009) 33:2292–2302 2295

123

D replacement therapy; 4) the correlation of vitamin D

deficiency and postoperative PTH levels in eucalcemic

patients; 5) the relationship of vitamin D status and

resected parathyroid gland weight; and 6) the significance

of coexisting morbidities in PHPT and vitamin D

insufficiency.

Need to establish ranges for normal PTH values

in concomitant disease

The normal PTH range has not been clearly defined for

patients with vitamin D insufficiency or marginal defi-

ciency, particularly for the elderly. Research, including a

Fig. 1 A normal PTH-Vit D regulatory network showing complex

balance between serum calcium (Ca??) and Vit D, which regulates

PTH. 2 Vit D enters the bloodstream, and is converted in the liver to

25(OH)D [calcidiol]. Kidneys produce renal 1-hydroxylase, for

conversion of 25(OH)D to 1,25(OH)D. Parathyroid glands produce

PTH. : PTH levels trigger renal 1 hydroxylase, converting 25(OH)D

to I,25(OH)D. 1,25(OH)D ? small intestine (duodenum) to release

Ca?? stores. Too little Ca?? for levels of 1,25(OH)D = increased

bone turnover to supplement blood Ca?? levels. : levels of

1,25(OH)D and Ca?? are detected by the Vit D receptors (VDRs)

on the parathyroid glands, inhibiting production of PTH. A PTH-

producing tumor on the parathyroid gland = failed regulation process.

: levels of PTH produced by the tumor = the normal increase in

Ca?? and I,25(OH)D. : PTH levels trigger rapidly accelerating

Ca?? release, and skeletal Ca?? is demanded to attempt to balance

the system

2296 World J Surg (2009) 33:2292–2302

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full range of evidence in which Sackett III evidence pre-

dominates, marks a strong interest in this area.

Secondary hyperparathyroidism (SHPT), caused by low

serum calcidiol levels, may be misdiagnosed as eucalcemic

PHPT in patients who have a high normal serum calcium

level, an elevated intact PTH level, and concomitant vita-

min D insufficiency or deficiency. Several factors impact

proper diagnosis, and without thorough screening, can

result in borderline cases having improper management.

Established patient history of current or previous use of

agents known to affect bone and/or calcium metabolism,

such as glucocorticoids, anticonvulsants, thiazide diuretics,

furosemide, lithium, estrogen or estrogen/progesterone,

bisphosphonates, antiresorptive treatments, calcium sup-

plements, and/or vitamin D supplements, must be taken

into consideration, because these agents can impact serum

calcium levels and impede regulation of PTH. A thorough

medical history should be taken to elicit information about

fractures, nephrolithiasis, endocrinopathies, and any situa-

tion that induced a period of immobilization lasting more

than 2 months, particularly in elderly patients with poten-

tial diagnosis of SHPT or PHPT [43 (III)]. Laboratory

evaluation of vitamin D levels can assist in the process of

diagnosis, particularly for patients in whom significant

insufficiency or marginal deficiency may be impacting

symptomology, as demonstrated by Silverberg et al. in

1999 [7]. In this work, Silverberg et al. studied 124 patients

with mild hyperparathyroidism and found that patients in

the lowest vitamin D tertile had significantly higher PTH

levels than did patients in the other two tertiles. However,

there was no correlation between PTH and vitamin D levels

in patients with a vitamin D level [25 ng/ml, and no

correlations between PTH and calcidiol or calcitriol level

(III).

Souberbielle et al. [44 (II)] have performed considerable

research defining a normal reference range for PTH. His

group noted that there is a need to reevaluate current nor-

mative values, because developments in understanding the

association between vitamin D levels and PTH levels is

expanding. This sentiment was echoed by Bilezikian et al.,

who stated in a 2002 workshop on asymptomatic PHPT

that ‘‘better-defined normative values for age, gender,

menopausal status, and race for both PTH and calcium

would be helpful’’ [45 (V)].

Although serum PTH levels are typically higher in black

patients and elderly patients than in young and white

population, serum calcidiol levels are usually lower in

black and elderly patients [46] (II), 47 (III)]. This lower

vitamin D status may partly explain the higher PTH values

found in black patients and elderly patients [48 (III)].

Before 2004–2005, and recent reassessment of existing

PTH reference ranges based on developing information

about the relationship between PTH and vitamin D status,

the upper limit of the normative PTH range was set at

65 ng/ml. As information on the impact of vitamin D

insufficiency on PTH levels has become more apparent, it

has been realized that the reference ranges considered

‘‘normal’’ were based on insufficient information. On the

basis of a study of 708 consecutive, osteopenic, vitamin D-

sufficient patients, Souberbielle et al. proposed an upper

limit for the reference range for PTH of B46 ng/ml, by

Allegro assay. When 46 ng/ml was used as the cutoff for

‘‘normal’’ in patients the number of false negatives was

significantly reduced, compared with the number of false

negatives using the 65 ng/l upper limit. The number of

false positives did not increase in those patients. This

showed a net improvement in the percentage of patients

with surgically proven PHPT. Souberbielle et al. concluded

that this new range enabled diagnoses of normocalcemic

PHPT after all other possibilities, including malabsorptive

diseases, had been ruled out. The concept of the impact of

vitamin D on the previously accepted upper limit for nor-

mal serum PTH levels was further emphasized by Ozbey

et al., who also found that vitamin D may affect serum

calcium levels, leading to a normocalcemic presentation of

PHPT [49 (V)].

Souberbielle et al. [44] (II)] also sought to redefine

serum PTH reference ranges in elderly patients. Using two

different assays to measure PTH levels in 280 healthy 60-

to 79-year-old patients, Souberbielle et al. found that

vitamin D-deficient patients tended to be older and have

higher PTH levels and that patients with low vitamin D

levels had PTH levels above the 97th percentile. The

researchers concluded that the reference range for PTH

group may depend on vitamin D status.

Vitamin D deficiency and postoperative PTH levels

Untch et al. [50 (III)] evaluated the impact of calcidiol

deficiency (\25 ng/ml) on intraoperative and postoperative

PTH kinetics and outcomes after parathyroidectomy in 93

patients who underwent parathyroid adenoma resection for

PHPT. PTH and serum calcidiol levels were recorded at six

perioperative time points. Untch et al. found that calcidiol-

deficient patients had significantly higher preoperative

serum calcium, alkaline phosphatase, and PTH levels and

significantly higher PTH levels at incision and at 1 week

and 1–3 months after surgery. The mean decrease in

PTH ?tul?> level 5 minutes after resection was 79 ± 14% in

the calcidiol-deficient group and 72 ± 22% in the noncal-

cidiol-deficient group (P = 0.03). The researchers also

found that calcidiol levels were inversely correlated with

adenoma weight (P = 0.03) and postoperative PTH mea-

surements (P = 0.008). The authors concluded that

calcidiol-deficient patients have higher baseline and

World J Surg (2009) 33:2292–2302 2297

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postoperative PTH levels but that calcidiol is not correlated

with alterations in intraoperative PTH kinetics. These find-

ings suggest that preoperative vitamin D deficiency is

associated with higher postoperative PTH levels, which can

indicate a higher risk for development of postoperative

hypocalcemia. Ozbey et al. also noted that postoperative

PTH levels were significantly higher in patients with low

preoperative vitamin D levels, suggesting a negative corre-

lation between serum PTH and serum calcidiol levels [49

(V)].

In a retrospective study, Wang et al. assessed persistently

elevated intraoperative and postoperative PTH levels in 816

patients who underwent parathyroidectomy [51 (IV)].

Patients’ preoperative vitamin D levels were unknown.

Wang concluded that patients with postoperative vitamin D

levels on the lower tertile of the reference range were likely

to have elevated postoperative PTH levels. Lower postop-

erative vitamin D levels also were correlated with smaller

percentage decreases in intraoperative PTH levels. The

authors suggested that a minimally invasive parathyroidecty

that depends on intraoperative PTH to determine extent of

surgery might not be as effective in patients with preexisting,

unresolved vitamin D insufficiency.

Beyer et al. [52 (II)] noted that after undergoing curative

parathyroidectomy for PHPT, as many as 43% of patients

have normocalcemia but elevated intact PTH levels that

could be due to an absolute or relative vitamin D defi-

ciency. In the study by Beyer et al., 86 patients who had

undergone parathyroidectomy for PHPT were divided into

two groups. Group 1 consisted of 26 patients who received

oral calcitriol and calcium carbonate postoperatively.

Group 2 consisted of 60 patients who did not receive cal-

citriol postoperatively (some received calcium carbonate at

the surgeon’s discretion). Eighty-five patients (99%)

achieved a postoperative cure with a sustained reduction in

serum calcium. At the 30-day postoperative evaluation,

serum PTH normalization was present in both group 1 and

group 2 (mean PTH, 41 ± 31 pg/ml and 39 ± 31 pg/ml,

respectively; P = 0.91). At 1–3 months postoperatively,

the mean serum calcium levels remained similar for group

1 and group 2 (9.5 ± 0.7 pg/ml and 9.3 ± 0.5 pg/ml,

respectively; P = 0.39), but the mean serum PTH level

was significantly higher in group 2 (67 ± 45 pg/ml, P =

0.02). At 4–6 months, the mean PTH remained higher in

group 2 (36 ± 22 pg/ml vs. 67 ± 35 pg/ml; P = 0.3),

even though the mean calcium levels remained normal in

both groups. The incidence of postoperative normocalce-

mic PTH elevation was therefore significantly higher in

group 2 at 1–3 months (39% vs. 14% in group 1; P = 0.04)

and at 7–12 months (83% vs. 22%; P = 0.04). Beyer et al.

concluded that vitamin D supplementation after parathy-

roidectomy for PHPT reduces the incidence of postoperative

eucalcemic PTH elevation.

Vitamin D deficiency also may be a risk factor for

postoperative hypocalcemia [53] (IV)]. In 2005, Stewart

et al. evaluated 190 patients with PHPT who had under-

gone minimally invasive parathyroidectomy for excision of

a single adenoma. Patients were divided into two groups:

those who were hypocalcemic after surgery (40% of

patients), and those who were not (60%). Stewart et al.

found that postoperative serum calcidiol levels were sig-

nificantly lower in patients who became hypocalcemic after

surgery. Sackett III, IV, and V level evidence are heavily

weighted in this area, and larger studies at the Sackett I and

II level are necessary to confirm existing evidence and

establish improved understanding of the involvement of

vitamin D in this area.

Vitamin D deficiency and increased gland weight

Some studies have examined the relationship between

vitamin D status and parathyroid gland weight in patients

with PHPT. Rao et al. [10] (I)] found a significant inverse

correlation between the mean serum calcidiol level and

mean parathyroid gland weight in 148 patients with PHPT.

The authors also noted a weak direct correlation between

parathyroid gland weight and calcitriol level and a weak

inverse correlation between gland weight and age. Serum

PTH levels and adjusted serum calcium levels were all

significantly higher in vitamin D-deficient patients. The

researchers concluded that parathyroid gland weight

depends on calcidiol levels in PHPT patients. Other studies

support this conclusion; for example, Beyer et al. found

that vitamin D-deficient patients had significantly larger

parathyroid glands (mean, 1757 g) than nonvitamin

D-deficient patients (mean, 524 g; P = 0.005) [52 (II)].

Moosgaard et al. [54] (II)] studied 170 patients with

surgically proven parathyroid adenomas and found that

parathyroid adenoma weight and calcidiol levels were

inversely correlated but that adenoma weight and calcitriol

levels were not related. Low calcidiol levels also were

related to higher PTH levels and higher PTH-to-adenoma

weight ratios. The group concluded that vitamin D defi-

ciency, particularly deficiency of circulating 25(OH)D,

calcidiol, potentially increases PTH secretion but that

neither PTH secretion nor adenoma weight is associated

with serum calcitriol levels. Similarly, Ozbey et al. found

an inverse relationship between parathyroid weight and

serum calcidiol levels [49 (V)]. In contrast, Silverberg et al.

found no correlation between vitamin D and gland weight

and noted that postoperative pathological examination of

parathyroid adenomas and glandular tissue did not show

any significant variation among patients with different

calcidiol levels [7 (III)]. Several strong (Sackett I or II)

studies confirm the strength of evidence in this area,

2298 World J Surg (2009) 33:2292–2302

123

backed by reviews that link evidence and present directions

for future research.

Vitamin D deficiency and PHPT severity

It is possible that vitamin D deficiency increases PHPT

severity, as postulated by Ozbey et al [49] (V)]. Silverberg

et al. [7 (III)] proposed that the PTH gene, which is abnor-

mally active in PHPT, is even less constrained in the setting

of vitamin D deficiency and that the lack of regulatory

feedback normally provided by vitamin D could account for

increased PHPT severity in vitamin D-deficient patients.

Raef et al. [55 (III)] studied the effect of vitamin D status

on the severity of bone disease and other PHPT features in

49 patients from a vitamin D-deficient region in Saudi

Arabia. Patients who had undergone bone mineral densi-

tometry were divided into two groups. Group A consisted of

19 patients who had severe bone changes indicating oste-

oporosis, and group B consisted of 23 patients with mild or

no bone changes. Ninety-four percent of the patients in

group A were in the bottom two vitamin D tertiles for the

general population. Patients in group A also were on aver-

age 14 years younger than patients in group B.

Furthermore, group A patients had higher PTH levels and

larger parathyroid tumors than group B patients and thus

required more medical treatment after parathyroidectomy.

Sambrook et al. [40 (I)] evaluated the effects of an

elevated PTH level and vitamin D deficiency in frail,

elderly PHPT patients. In this prospective study, 842

patients’ biochemical parameters, including serum

25(OH)D, serum calcium, serum PTH, and bone ultrasound

attenuation, were assessed in relation to 5-year mortality.

PTH was found to affect mortality independent of vitamin

D and kidney function. The authors concluded that aging is

associated with the decreased responsiveness of renal 1-

hydroxylase to PTH. The researchers also noted that

hypercalcemic patients, such as those with PHPT, feared

worsening their hypercalcemia with vitamin D and thus

avoided it.

Beyer et al. [52 (II)] also suggested that vitamin D

insufficiency in patients with PHPT may be associated

with greater disease severity, higher incidence of multi-

gland disease, and elevated postoperative serum PTH

levels. Patients with suboptimal serum vitamin D levels

(B20 ng/ml) had a significantly higher mean serum cal-

cium level (11.3 ± 1.2 mg/dl vs. 10.8 ± 0.9 mg/dl;

P = 0.012) and mean serum PTH level (204 ± 138 pg/ml

vs. 156 ± 179 pg/ml; P = 0.006) than patients with opti-

mal serum vitamin D levels ([ 20 ng/ml). Patients with

vitamin D insufficiency also had a significantly higher

mean bone-specific alkaline phosphatase level than patients

without vitamin D insufficiency (P = 0.006). However, the

two groups had similar postoperative serum calcium levels,

serum PTH levels, eucalcemia rates, and postoperative

eucalcemic PTH elevation rates. Beyer et al. concluded

that, based on preoperative serum calcium and PTH levels,

bone markers, and gland size, PHPT patients with vitamin

D insufficiency have significantly greater PHPT severity

than PHPT patients without vitamin D insufficiency. The

researchers also noted that postoperative achievement of

eucalcemia seems to be independent of vitamin D status.

Pradeep et al. [56 (V)] evaluated 82 Indian patients with

PHPT who underwent parathyroidectomy to ascertain the

impact of vitamin D on postoperative outcome. Preopera-

tive calcidiol levels were available for 70 patients; 59

(84%) of these patients were vitamin D-deficient. Of the 32

patients for whom postoperative calcidiol levels were

available, 24 (75%) were vitamin D-deficient. To assess

recovery patterns in target organs, patients underwent

biochemical (serum calcium, phosphorus, and alkaline

phosphatase measurements) and radiological (bone mineral

densitometry) investigations at 3 weeks, 3 months,

6 months, and annually thereafter. Ultrasonography was

used to assess renal and pancreatic changes at 6 months

and annually thereafter. Follow-up ranged from 2 to

13 (median, 3) years. After surgery, 24 (75%) of 32

patients had persistent vitamin D deficiency (mean,

12.15 ± 5.45 ng/ml). Radiologic evaluation of all patients

revealed vigorous but disorderly bone remineralization

during 3 months. Bone pain and weakness disappeared

quickly in all patients. Kidney disease was evaluated in 43

patients; of these, 31 (74%) became symptom-free during

follow-up, 9 (21%) had no change in renal symptoms, and

3 (7%) had progression to end-stage renal failure. Seven

patients developed pancreatitis postoperatively. Six

patients (94.6%) became symptom-free during follow-up.

Pradeep et al. concluded that, in India, PHPT presents as

advanced disease with concomitant vitamin D deficiency.

The authors also concluded that persistent vitamin D

deficiency delays bone recovery, and that supplementation

to maintain non-deficient vitamin D status is necessary on

an ongoing basis to improve chances of recovery from

advanced PHPT, including the attendant renal and pan-

creatic issues found in advanced cases. Although Sackett

III-V evidence predominates in this area, several Sackett I,

Grade A and Sackett II, Grade B studies show great

promise for understanding the role of vitamin D in PHPT

severity.

Vitamin D repletion in patients with PHPT undergoing

parathyroidectomy

The role of vitamin D replacement therapy before and/or

after parathyroidectomy in patients with biochemical

World J Surg (2009) 33:2292–2302 2299

123

evidence of PHPT and low serum calcidiol levels has been

debated.

In 1999, Silverberg et al. [7 (III)] recommended that

vitamin D repletion not be used in patients with concom-

itant PHPT and vitamin D deficiency, because severe

hypercalcemia could occur. In 2005, Grey et al. [8 (III)]

evaluated vitamin D repletion for 1 year in 21 vitamin D-

deficient patients with mild PHPT undergoing clinical,

nonoperative management. All patients had baseline serum

calcium levels \ 12 mg/dl. Patients’ serum vitamin D

levels were normal at 6 months and had not increased at

12 months, and their serum calcitriol levels and serum

calcium levels did not change significantly from baseline to

6 or 12 months. Although patients’ intact PTH levels

decreased 25% during vitamin D repletion, the levels

remained abnormally elevated.

Our group recently reported similar findings in a large

cohort of patients with PHPT. We queried a prospective

database of 301 patients with PHPT who were treated at

The University of Texas M. D. Anderson during a 3-year

period. Before parathyroidectomy, 118 patients (39%)

had a vitamin D level C30 ng/ml (sufficient), 71 (24%)

were vitamin D-deficient, and 112 (37%) were vitamin

D-deficient but underwent vitamin D replacement ther-

apy. The median duration of replacement was 28 days,

and the standard ergocalciferol dose given was 400,000

U. Of the 112 patients who underwent vitamin D

repletion, 91 (81%) had mean serum calcium levels that

decreased or remained relatively unchanged after reple-

tion. Parathyroid gland size was smallest in patients who

were vitamin D-sufficient before surgery and largest in

patients who were vitamin D-deficient and did not

undergo vitamin D replacement therapy. PTH levels

measured 1 and 6 months postoperatively were signifi-

cantly lower in the initially vitamin D-sufficient group

than in the other two groups (P = 0.05 and P = 0.009,

respectively). We did not observe any postoperative

differences in PTH levels between vitamin D-deficient

patients who did or did not undergo vitamin D repletion.

Only six patients developed worsened hypercalcemia, but

the highest increase in serum calcium was 0.6 mg/dl. We

concluded that preoperative vitamin D replacement

therapy is safe for patients with PHPT and does not

increase serum calcium levels. Although preoperative

vitamin D status affects gland size and postoperative

PTH level, vitamin D repletion in vitamin D-deficient

patients does not seem to have an effect that persists

postoperatively. Sackett III evidence predominates in this

area, and the relationship between vitamin D repletion,

when repletion may be effective, and the level of effect

it may have would benefit from extended high-Sackett-

level research.

Working toward the future

Efforts to understand the relationship of vitamin D and

various body systems are providing better understanding of

this once understudied vitamin. Even research that is not

directly related to PHPT is providing insights into symp-

tomology associated with vitamin D deficiency that can

coexist with, complicate, or confuse the diagnostic picture

for patients who are being examined for the possibility of

PHPT.

Dawson-Hughes has played a key role in researching the

impact of vitamin D levels on outcomes in patients, with

particularly interesting research on the issue of vitamin D

and elderly populations, which also is a key population

dealing with PHPT. She postulated that vitamin D has

measurable clinical benefits for elderly patients’ musculo-

skeletal systems and that bone mass, bone loss, muscle

performance, fall risk, and fracture incidence were associ-

ated with serum calcidiol levels [18 (V)]. She determined

that a mean serum vitamin D concentration C65 nmol/l

improves muscle performance and reduces the risk of falls

and that a serum vitamin D concentration of C75 nmol/l

reduces the risk of fractures. She proposed consistent ter-

minology to define vitamin D deficiency as serum calcidiol

concentrations \25 nmol/l, vitamin D insufficiency as

serum calcidiol concentrations of 25–74 nmol/l, and vitamin

D sufficiency as C75 nmol/l. Dawson-Hughes’ work cites

the National Health and Nutrition Examination Survey III,

which estimated that 30% of persons aged 60 years or older

who reside in lower latitudes (30� N and below) experience

vitamin D insufficiency during the winter months and that

26% of people aged 60 years or older who reside in higher

latitudes (45� N and above) experience vitamin D insuffi-

ciency, even during the summer months where sunlight

levels are highest. Dawson-Hughes and her colleagues

suggested that future research should more precisely define

how vitamin D affects muscles and identify the amount of

calcidiol needed to promote optimal muscle function and the

population of older patients who are most likely to respond

favorably to vitamin D supplementation.

Research impacting our understanding of the role of

vitamin D in endocrine function is developing, and our

understanding of this field is improving, in part through

ongoing research with potentially far-reaching impact on

our understanding of the links between nutrition and

endocrine function.

In one ongoing study, von Hurst et al. [57 (I)] have

determined that vitamin D receptors in the endocrine

pancreas may play a role in insulin secretion. The

researchers found limited evidence that vitamin D influ-

ences insulin resistance and early-stage type 2 diabetes.

Hannan et al. [17 (I)] examined the relationship between

2300 World J Surg (2009) 33:2292–2302

123

serum calcidiol levels and bone mineral density by eth-

nicity. In a population-based, observational study of 1,114

patients, the researchers found that compared with white

men, a higher percentage of black men (44%) and Hispanic

men (23%) had calcidiol levels in the lowest quartile

(P \ 0.001). The authors recommended further research

into biological mechanisms for the differences in serum

calcidiol levels between ethnic groups.

Conclusions

Although reduced vitamin D and calcium-sensing receptors

have been demonstrated in parathyroid adenomas, the ways

in which vitamin D depletion influences adenoma growth

in circumstances of suboptimal VDR development remains

unclear. Dietary restriction of calcium has a trivial effect

on serum calcium levels but is accompanied by increased

bone resorption. Much work remains to elucidate the

relationship between vitamin D, endocrine, and other dis-

eases of suboptimal nutrition, and diseases such as PHPT,

which appears to have a hitherto poorly explored nutri-

tional/environmental component in the impact of vitamin D

on the health of the parathyroid and the management of

PHPT.

Acknowledgments This work has been generously supported by

The American Geriatrics Society Jahnigen Scholars Program. The

authors thank Linda McGraw, Program Coordinator, Department of

Surgical Oncology, Section of Surgical Endocrinology for assistance

with manuscript preparation.

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