Low Vitamin D Can Mask Hyperparathyroidism : Ever since food began to be fortified with vitamin D, the manifestations of pHPT have become less severe.

ARLINGTON, VA. — A level of vitamin D that is low but near or within the normal range may mask the presentation of patients with primary hyperparathyroidism, Dr. Shonni J. Silverberg reported at a conference sponsored by the American Society for Bone and Mineral Research.

In the United States, the presentation and epidemiology of primary hyperparathyroidism (pHPT) and vitamin D deficiency have developed concomitantly since food began to be fortified with vitamin D about 75 years ago. During this period, the prevalence of vitamin D deficiency has declined dramatically while the clinical manifestations of pHPT have become less severe. Symptomatic pHPT, or osteitis fibrosa cystica, has decreased because of lower levels of parathyroid hormone (PTH) in the disease. The weight and size of parathyroid adenomas also has declined substantially during this period, said Dr. Silverberg, professor of clinical medicine at Columbia University in New York.

“The question [was] whether or not calcium and vitamin D nutrition affects clinical expression of tumor growth in primary hyperparathyroidism. There has long been a hypothesis of 'double trouble,' which states that the clinical manifestations of primary hyperparathyroidism may be more severe in the presence of vitamin D deficiency,” she said.

Epidemiologic data show that classical pHPT still exists in areas of the world where vitamin D deficiency is endemic. When one analyzes the relationship between the two conditions in the United States and in developing countries where vitamin D deficiency is endemic, vitamin D (25-hydroxyvitamin D) levels are “somewhat inversely proportional” to the degree of PTH elevation, according to Dr. Silverberg. In this situation, people with very low vitamin D levels and pHPT may have PTH levels 15–20 times the upper limit of normal, but those with higher vitamin D levels—while still being in the lower range of normal—and pHPT may have PTH levels 1.5–2 times the upper limit of normal.

In patients with mild pHPT, sufficient—but still low-normal—levels of vitamin D oppose the hypercalcemic effect of excess PTH and thereby lower serum calcium levels and urinary calcium excretion back to their normal ranges.

Many of these people may be referred from doctors in the community who are reluctant to make a diagnosis of pHPT in patients with an elevated PTH level, normal serum calcium level, and a sufficient level of vitamin D, Dr. Silverberg said.

A study of women in New York and Beijing found that nearly all New Yorkers with pHPT were asymptomatic, whereas 94% of women with pHPT in Beijing were symptomatic and often had fractures and severe bone disease. There were very marked differences in serum levels of calcium, PTH, and vitamin D levels between women in the two cities (Int. J. Fertil. Womens Med. 2000;45:158–65).

In a study of 49 patients in Saudi Arabia (where vitamin D deficiency is endemic) who underwent a parathyroidectomy for pHPT, 19 patients had severe bone disease. These 19 patients had high levels of PTH and alkaline phosphatase, and increased thyroid gland size and weight, but their vitamin D levels were not significantly different from those without severe bone disease. The study investigators concluded that marked vitamin D deficiency may play a part in osteitis fibrosa cystica, but manifestation of bone disease with pHPT is multifactorial (J. Endocrinol. Invest. 2004;27:807–12).

A study in France showed that 38% of normal individuals were vitamin D insufficient (using a 20-ng/mL cutoff), compared with 91% of those with pHPT, regardless of its severity. The proportion of patients with pHPT who had vitamin D insufficiency also was similar regardless of whether their serum calcium level was lower or greater than 12 mg/dL (J. Endocrinol. Invest. 2006;29:511–5).

These results raise the question of whether there is a cutoff level of vitamin D at which pHPT becomes symptomatic, Dr. Silverberg said.

A study of patients with pHPT in Turkey found that individuals with vitamin D levels less than 15 ng/mL had significantly higher serum PTH, alkaline phosphatase, and parathyroid adenoma weight than did those with vitamin D levels of 15–25 ng/mL or more than 25 ng/mL (World J. Surg. 2006;30:321–6). Similar results were found in a study of U.S. patients.

The investigators of a separate case-control study that controlled for the effects of age, sex, body mass index, and season corroborated the finding that low vitamin D levels could worsen the clinical presentation of pHPT, but they did not find any association between low vitamin D levels and thyroid adenoma size. The percentage of patients with a vitamin D level less than 20 ng/mL varied significantly between the summer and winter months in the study's two control groups, but not among patients with pHPT (Clin. Endocrinol. [Oxf.] 2005;63:506–13).

Dr. Silverberg and her colleagues found that 53% of 124 U.S. patients with mild pHPT had an insufficient level of vitamin D (less than 20 ng/mL). The researchers also noticed a seasonal variation in the manifestation of pHPT in the summer in which vitamin D levels rose while PTH levels dropped. When the patients were split into tertiles based on vitamin D levels, the investigators found that serum PTH levels and alkaline phosphatase activity were significantly higher among patients in the lowest tertile of vitamin D (less than 16 ng/mL) than in patients in the middle (16–24 ng/mL) and highest tertiles (more than 24 ng/mL). Another analysis of the same data suggested that the relationship was valid throughout the range of levels for vitamin D and serum PTH. Histomorphometric studies of the patients' bones also were consistent with an enhanced effect of PTH in those with a low level of vitamin D (Am. J. Med. 1999;107:561–7). “It is very important, however, to remember that the results we are describing are [cross-sectional] … and that there is absolutely no way, based on anything that we or anybody else knows at this point, to infer a causal association in these data,” she said.

But another study of women with pHPT did not find any association between vitamin D levels and the severity of pHPT. In that study, low vitamin D levels were associated with age and renal function, but there was no association between vitamin D level and bone mineral density after investigators controlled for age, PTH excess, and body mass index (Clin. Endocrinol. [Oxf.] 2004;60:81–6).

The surgical literature shows that after patients with pHPT undergo a parathyroidectomy, a substantial percentage of patients have persistently elevated PTH levels despite others signs of being cured of their hyperparathyroidism. The most consistent finding across these studies is low vitamin D levels either just before or immediately after surgery. In this case, pHPT has become secondary HPT, she noted.

One small study of vitamin D repletion in patients with suspected pHPT did not provide conclusive results. In a study of 229 patients with osteoporosis, 15 had low vitamin D levels and concomitant high PTH levels (J. Clin. Endocrinol. Metab. 2000;85:3541–3). After a single treatment of 500,000 U of vitamin D₂, five patients still had elevated PTH levels and were presumed to have pHPT. But two of those five patients had serum calcium levels less than 9 mg/dL, “which certainly raises the question in my mind about the diagnosis,” Dr. Silverberg said.

In those five patients, the bone mineral density after 13 months had increased by 6% in the spine and 8% in the hip. Although the investigators concluded that the increase in BMD resulted from the effect of vitamin D on pHPT, the patients' calcium levels make the diagnosis of pHPT questionable, she said.

ARLINGTON, VA. — A level of vitamin D that is low but near or within the normal range may mask the presentation of patients with primary hyperparathyroidism, Dr. Shonni J. Silverberg reported at a conference sponsored by the American Society for Bone and Mineral Research.

In the United States, the presentation and epidemiology of primary hyperparathyroidism (pHPT) and vitamin D deficiency have developed concomitantly since food began to be fortified with vitamin D about 75 years ago. During this period, the prevalence of vitamin D deficiency has declined dramatically while the clinical manifestations of pHPT have become less severe. Symptomatic pHPT, or osteitis fibrosa cystica, has decreased because of lower levels of parathyroid hormone (PTH) in the disease. The weight and size of parathyroid adenomas also has declined substantially during this period, said Dr. Silverberg, professor of clinical medicine at Columbia University in New York.

“The question [was] whether or not calcium and vitamin D nutrition affects clinical expression of tumor growth in primary hyperparathyroidism. There has long been a hypothesis of 'double trouble,' which states that the clinical manifestations of primary hyperparathyroidism may be more severe in the presence of vitamin D deficiency,” she said.

Epidemiologic data show that classical pHPT still exists in areas of the world where vitamin D deficiency is endemic. When one analyzes the relationship between the two conditions in the United States and in developing countries where vitamin D deficiency is endemic, vitamin D (25-hydroxyvitamin D) levels are “somewhat inversely proportional” to the degree of PTH elevation, according to Dr. Silverberg. In this situation, people with very low vitamin D levels and pHPT may have PTH levels 15–20 times the upper limit of normal, but those with higher vitamin D levels—while still being in the lower range of normal—and pHPT may have PTH levels 1.5–2 times the upper limit of normal.

In patients with mild pHPT, sufficient—but still low-normal—levels of vitamin D oppose the hypercalcemic effect of excess PTH and thereby lower serum calcium levels and urinary calcium excretion back to their normal ranges.

Many of these people may be referred from doctors in the community who are reluctant to make a diagnosis of pHPT in patients with an elevated PTH level, normal serum calcium level, and a sufficient level of vitamin D, Dr. Silverberg said.

A study of women in New York and Beijing found that nearly all New Yorkers with pHPT were asymptomatic, whereas 94% of women with pHPT in Beijing were symptomatic and often had fractures and severe bone disease. There were very marked differences in serum levels of calcium, PTH, and vitamin D levels between women in the two cities (Int. J. Fertil. Womens Med. 2000;45:158–65).

In a study of 49 patients in Saudi Arabia (where vitamin D deficiency is endemic) who underwent a parathyroidectomy for pHPT, 19 patients had severe bone disease. These 19 patients had high levels of PTH and alkaline phosphatase, and increased thyroid gland size and weight, but their vitamin D levels were not significantly different from those without severe bone disease. The study investigators concluded that marked vitamin D deficiency may play a part in osteitis fibrosa cystica, but manifestation of bone disease with pHPT is multifactorial (J. Endocrinol. Invest. 2004;27:807–12).

A study in France showed that 38% of normal individuals were vitamin D insufficient (using a 20-ng/mL cutoff), compared with 91% of those with pHPT, regardless of its severity. The proportion of patients with pHPT who had vitamin D insufficiency also was similar regardless of whether their serum calcium level was lower or greater than 12 mg/dL (J. Endocrinol. Invest. 2006;29:511–5).

These results raise the question of whether there is a cutoff level of vitamin D at which pHPT becomes symptomatic, Dr. Silverberg said.

A study of patients with pHPT in Turkey found that individuals with vitamin D levels less than 15 ng/mL had significantly higher serum PTH, alkaline phosphatase, and parathyroid adenoma weight than did those with vitamin D levels of 15–25 ng/mL or more than 25 ng/mL (World J. Surg. 2006;30:321–6). Similar results were found in a study of U.S. patients.

The investigators of a separate case-control study that controlled for the effects of age, sex, body mass index, and season corroborated the finding that low vitamin D levels could worsen the clinical presentation of pHPT, but they did not find any association between low vitamin D levels and thyroid adenoma size. The percentage of patients with a vitamin D level less than 20 ng/mL varied significantly between the summer and winter months in the study's two control groups, but not among patients with pHPT (Clin. Endocrinol. [Oxf.] 2005;63:506–13).

Dr. Silverberg and her colleagues found that 53% of 124 U.S. patients with mild pHPT had an insufficient level of vitamin D (less than 20 ng/mL). The researchers also noticed a seasonal variation in the manifestation of pHPT in the summer in which vitamin D levels rose while PTH levels dropped. When the patients were split into tertiles based on vitamin D levels, the investigators found that serum PTH levels and alkaline phosphatase activity were significantly higher among patients in the lowest tertile of vitamin D (less than 16 ng/mL) than in patients in the middle (16–24 ng/mL) and highest tertiles (more than 24 ng/mL). Another analysis of the same data suggested that the relationship was valid throughout the range of levels for vitamin D and serum PTH. Histomorphometric studies of the patients' bones also were consistent with an enhanced effect of PTH in those with a low level of vitamin D (Am. J. Med. 1999;107:561–7). “It is very important, however, to remember that the results we are describing are [cross-sectional] … and that there is absolutely no way, based on anything that we or anybody else knows at this point, to infer a causal association in these data,” she said.

But another study of women with pHPT did not find any association between vitamin D levels and the severity of pHPT. In that study, low vitamin D levels were associated with age and renal function, but there was no association between vitamin D level and bone mineral density after investigators controlled for age, PTH excess, and body mass index (Clin. Endocrinol. [Oxf.] 2004;60:81–6).

The surgical literature shows that after patients with pHPT undergo a parathyroidectomy, a substantial percentage of patients have persistently elevated PTH levels despite others signs of being cured of their hyperparathyroidism. The most consistent finding across these studies is low vitamin D levels either just before or immediately after surgery. In this case, pHPT has become secondary HPT, she noted.

One small study of vitamin D repletion in patients with suspected pHPT did not provide conclusive results. In a study of 229 patients with osteoporosis, 15 had low vitamin D levels and concomitant high PTH levels (J. Clin. Endocrinol. Metab. 2000;85:3541–3). After a single treatment of 500,000 U of vitamin D₂, five patients still had elevated PTH levels and were presumed to have pHPT. But two of those five patients had serum calcium levels less than 9 mg/dL, “which certainly raises the question in my mind about the diagnosis,” Dr. Silverberg said.

In those five patients, the bone mineral density after 13 months had increased by 6% in the spine and 8% in the hip. Although the investigators concluded that the increase in BMD resulted from the effect of vitamin D on pHPT, the patients' calcium levels make the diagnosis of pHPT questionable, she said.

ARLINGTON, VA. — A level of vitamin D that is low but near or within the normal range may mask the presentation of patients with primary hyperparathyroidism, Dr. Shonni J. Silverberg reported at a conference sponsored by the American Society for Bone and Mineral Research.

In the United States, the presentation and epidemiology of primary hyperparathyroidism (pHPT) and vitamin D deficiency have developed concomitantly since food began to be fortified with vitamin D about 75 years ago. During this period, the prevalence of vitamin D deficiency has declined dramatically while the clinical manifestations of pHPT have become less severe. Symptomatic pHPT, or osteitis fibrosa cystica, has decreased because of lower levels of parathyroid hormone (PTH) in the disease. The weight and size of parathyroid adenomas also has declined substantially during this period, said Dr. Silverberg, professor of clinical medicine at Columbia University in New York.

“The question [was] whether or not calcium and vitamin D nutrition affects clinical expression of tumor growth in primary hyperparathyroidism. There has long been a hypothesis of 'double trouble,' which states that the clinical manifestations of primary hyperparathyroidism may be more severe in the presence of vitamin D deficiency,” she said.

Epidemiologic data show that classical pHPT still exists in areas of the world where vitamin D deficiency is endemic. When one analyzes the relationship between the two conditions in the United States and in developing countries where vitamin D deficiency is endemic, vitamin D (25-hydroxyvitamin D) levels are “somewhat inversely proportional” to the degree of PTH elevation, according to Dr. Silverberg. In this situation, people with very low vitamin D levels and pHPT may have PTH levels 15–20 times the upper limit of normal, but those with higher vitamin D levels—while still being in the lower range of normal—and pHPT may have PTH levels 1.5–2 times the upper limit of normal.

In patients with mild pHPT, sufficient—but still low-normal—levels of vitamin D oppose the hypercalcemic effect of excess PTH and thereby lower serum calcium levels and urinary calcium excretion back to their normal ranges.

Many of these people may be referred from doctors in the community who are reluctant to make a diagnosis of pHPT in patients with an elevated PTH level, normal serum calcium level, and a sufficient level of vitamin D, Dr. Silverberg said.

A study of women in New York and Beijing found that nearly all New Yorkers with pHPT were asymptomatic, whereas 94% of women with pHPT in Beijing were symptomatic and often had fractures and severe bone disease. There were very marked differences in serum levels of calcium, PTH, and vitamin D levels between women in the two cities (Int. J. Fertil. Womens Med. 2000;45:158–65).

In a study of 49 patients in Saudi Arabia (where vitamin D deficiency is endemic) who underwent a parathyroidectomy for pHPT, 19 patients had severe bone disease. These 19 patients had high levels of PTH and alkaline phosphatase, and increased thyroid gland size and weight, but their vitamin D levels were not significantly different from those without severe bone disease. The study investigators concluded that marked vitamin D deficiency may play a part in osteitis fibrosa cystica, but manifestation of bone disease with pHPT is multifactorial (J. Endocrinol. Invest. 2004;27:807–12).

A study in France showed that 38% of normal individuals were vitamin D insufficient (using a 20-ng/mL cutoff), compared with 91% of those with pHPT, regardless of its severity. The proportion of patients with pHPT who had vitamin D insufficiency also was similar regardless of whether their serum calcium level was lower or greater than 12 mg/dL (J. Endocrinol. Invest. 2006;29:511–5).

These results raise the question of whether there is a cutoff level of vitamin D at which pHPT becomes symptomatic, Dr. Silverberg said.

A study of patients with pHPT in Turkey found that individuals with vitamin D levels less than 15 ng/mL had significantly higher serum PTH, alkaline phosphatase, and parathyroid adenoma weight than did those with vitamin D levels of 15–25 ng/mL or more than 25 ng/mL (World J. Surg. 2006;30:321–6). Similar results were found in a study of U.S. patients.

The investigators of a separate case-control study that controlled for the effects of age, sex, body mass index, and season corroborated the finding that low vitamin D levels could worsen the clinical presentation of pHPT, but they did not find any association between low vitamin D levels and thyroid adenoma size. The percentage of patients with a vitamin D level less than 20 ng/mL varied significantly between the summer and winter months in the study's two control groups, but not among patients with pHPT (Clin. Endocrinol. [Oxf.] 2005;63:506–13).

Dr. Silverberg and her colleagues found that 53% of 124 U.S. patients with mild pHPT had an insufficient level of vitamin D (less than 20 ng/mL). The researchers also noticed a seasonal variation in the manifestation of pHPT in the summer in which vitamin D levels rose while PTH levels dropped. When the patients were split into tertiles based on vitamin D levels, the investigators found that serum PTH levels and alkaline phosphatase activity were significantly higher among patients in the lowest tertile of vitamin D (less than 16 ng/mL) than in patients in the middle (16–24 ng/mL) and highest tertiles (more than 24 ng/mL). Another analysis of the same data suggested that the relationship was valid throughout the range of levels for vitamin D and serum PTH. Histomorphometric studies of the patients' bones also were consistent with an enhanced effect of PTH in those with a low level of vitamin D (Am. J. Med. 1999;107:561–7). “It is very important, however, to remember that the results we are describing are [cross-sectional] … and that there is absolutely no way, based on anything that we or anybody else knows at this point, to infer a causal association in these data,” she said.

But another study of women with pHPT did not find any association between vitamin D levels and the severity of pHPT. In that study, low vitamin D levels were associated with age and renal function, but there was no association between vitamin D level and bone mineral density after investigators controlled for age, PTH excess, and body mass index (Clin. Endocrinol. [Oxf.] 2004;60:81–6).

The surgical literature shows that after patients with pHPT undergo a parathyroidectomy, a substantial percentage of patients have persistently elevated PTH levels despite others signs of being cured of their hyperparathyroidism. The most consistent finding across these studies is low vitamin D levels either just before or immediately after surgery. In this case, pHPT has become secondary HPT, she noted.

One small study of vitamin D repletion in patients with suspected pHPT did not provide conclusive results. In a study of 229 patients with osteoporosis, 15 had low vitamin D levels and concomitant high PTH levels (J. Clin. Endocrinol. Metab. 2000;85:3541–3). After a single treatment of 500,000 U of vitamin D₂, five patients still had elevated PTH levels and were presumed to have pHPT. But two of those five patients had serum calcium levels less than 9 mg/dL, “which certainly raises the question in my mind about the diagnosis,” Dr. Silverberg said.

In those five patients, the bone mineral density after 13 months had increased by 6% in the spine and 8% in the hip. Although the investigators concluded that the increase in BMD resulted from the effect of vitamin D on pHPT, the patients' calcium levels make the diagnosis of pHPT questionable, she said.