Plasma ionized calcium and cardiovascular risk factors in mild primary hyperparathyroidism: effects of long-term treatment with active vitamin D (alphacalcidol).

Primary hyperparathyroidism (HPT) has been associated with hypertension, hyperinsulinaemia, hypertriglyceridaemia and hyperuricaemia. In the present study, plasma ionized calcium (Ca2+) was studied in relation to cardiovascular risk factors in 20 subjects with mild hypertension. Plasma Ca2+ was found to be negatively correlated with fasting serum insulin, triglycerides and urate, and with diastolic blood pressure (DBP). However, after the interaction of the different risk factors had been taken into account in the multiple regression analysis, only the relationship between Ca2+ and serum insulin was significant (r = 0.55, P less than 0.01). In a previous double-blind, placebo-controlled study 1 micrograms alphacalcidol, a synthetic analogue of 1,25 dihydroxy-vitamin D3, induced a decrease in blood pressure in mild HPT subjects. In the present study, the highest dose that did not further aggravate the hypercalcaemia was given in a long-term study over a 12-month period to 18 mild HPT subjects (average dose, 1.75 micrograms daily). The treatment induced a reduction in body weight of 0.9 kg (P less than 0.05) and an increase in serum urate from 330 +/- 92 to 380 +/- 104 mmol l-1 (P less than 0.01). A reduction in blood pressure was only observed at the end of the study, from 142 +/- 17/86.6 +/- 9.1 to 139 +/- 13/82.9 +/- 8.9 mmHg (P less than 0.05 for DBP). The reduction in systolic blood pressure was significantly correlated with the reduction in body weight induced by treatment (r = 0.63, P less than 0.02). No consistent changes in glucose or lipid metabolism were induced by treatment.

Serum levels of 1,25-(OH)2-vitamin D are not altered by long-term supplementation with alphacalcidol (1-OH-vitamin D3). A double-blind, placebo-controlled study.

The endogenous production of 1,25-(OH)2-vitamin D has been estimated to be 1.5 micrograms daily. Despite the use of alphacalcidol (1,25-(OH)2-vitamin D) during more than a decade the long-term effects of the serum levels of 1,25-(OH)2-vitamin D have been poorly investigated. When 1 microgram of alphacalcidol was given daily to 39 non-vitamin D deficient subjects in a double-blind, placebo-controlled study during 4 months no significant effects on the serum levels of 1,25-(OH)2-vitamin D or 25-(OH)-vitamin D were found. The treatment however induced a 50% increase in urinary excretion of calcium (p less than 0.01). In conclusion, long-term supplementation with a physiological dose of alphacalcidol does not influence the serum levels of 1,25-(OH)2-vitamin D, despite a marked effect on urinary calcium excretion.

Cardiovascular risk factors in primary hyperparathyroidism: a 15-year follow-up of operated and unoperated cases.

The need for treatment of mild and apparently asymptomatic primary hyperparathyroidism (HPT) is questioned, but a raised incidence of cardiovascular disease has been regarded as evidence in favour of surgery. While it is well known that several risk factors for cardiovascular disease (hypertension, hyperlipidaemia and diabetes mellitus/impaired glucose tolerance) are overrepresented in HPT, it is not known whether surgery provides long-term normalization in these respects and reduces the risk of premature death. In a 15-year follow-up of a cohort of 172 subjects in whom mild hypercalcaemia was initially detected during a health screening, it was found that 56 subjects had died. 17 individuals had been operated on for HPT, 47 individuals were persistently hypercalcaemic, while 45 subjects had serum calcium within the normal range (seven individuals were lost to follow-up). There had been no significant differences in blood pressure between these groups of mildly hypercalcaemic patients and age- and sex-matched controls at the initial screening, but at follow-up blood pressure was significantly higher not only in subjects with persistent hypercalcaemia, but also in those who had been successfully operated on for HPT. Neither of the hypercalcaemic groups showed any significant deviations from the controls with regard to indices of lipid or glucose metabolism. These findings suggest that there is no simple cause-and-effect relationship to account for the propensity toward high blood pressure in primary HPT. Consequently it cannot be assumed that surgery for HPT will eliminate the increased risk of cardiovascular disease in patients with mild HPT.

No major metabolic alterations accompany the hypotensive effect of active vitamin D.

A hypotensive effect of active vitamin D treatment (alphacalcidol 1 mg daily) has previously been reported in three double-blind, placebo-controlled studies over 4-6 months in subjects with mild primary hyperparathyroidism (HPT), intermittent hypercalcemia and essential hypertension. The commonly used antihypertensive drugs, thiazides and betablockers, both induce impairments in both glucose and lipid metabolism and the thiazides are known to cause an elevation of serum urate. The effects of vitamin D treatment on these metabolic variables were recorded in these studies. Alphacalcidol did not induce any changes in fasting glucose HbA1c or insulin, serum triglycerides, cholesterol or serum urate in any of the treated groups. Neither was HDL cholesterol affected, except for a rise seen in the HPT subjects. It is therefore concluded that no major metabolic alterations in glucose or lipid metabolism or serum urate accompany the hypotensive effect of vitamin D.

Reduction in serum alkaline phosphatase levels by treatment with active vitamin D (alphacalcidol) in primary and secondary hyperparathyroidism and in euparathyroid individuals.

Raised levels of alkaline phosphatases (ALP) are seen in conditions with a high bone turn-over, such as in primary and secondary hyperparathyroidism (HPT). To study the effects of active vitamin D treatment on ALP, alphacalcidol (1-alpha-hydroxyvitamin D3), was given to patients with primary HPT as well as HPT secondary to chronic renal failure and also to healthy, euparathyroid subjects. Oral alphacalcidol (1 microgram daily) significantly reduced serum ALP (3.2 +/- 1.1 to 2.8 +/- 1.2 mu kat/l, p less than 0.05) in a 6-month double-blind, placebo-controlled study in patients with mild primary HPT, and alphacalcidol given intravenously to uremic subjects induced a reduction in serum ALP levels (3.5 +/- 3.1 to 2.6 +/- 1.7 mu kat/l, p less than 0.05) during a 4 months' study. A reduction in serum ALP was also seen in the euparathyroid subjects (2.4 +/- 0.77 to 2.2 +/- 0.64 mu kat/l, p = 0.03). This study indicates that treatment with active vitamin D is effective in reducing the increased bone turnover seen in subjects with both primary and secondary HPT.

Delayed hypersensitivity in primary and secondary hyperparathyroidism. Treatment with active vitamin D.

The vitamin D endocrine system, besides its traditional role in mineral metabolism, also affects the immune system. A recent study demonstrated that vitamin D supplementation restored a blunted delayed hypersensitivity response (DH) in elderly vitamin D-deficient subjects. In the present study the DH, as measured by the tuberculin test (PPD), was studied in two groups of patients with a disturbed vitamin D system, i.e. primary hyperparathyroidism (HPT) and secondary HPT due to chronic renal failure. A significant reduction in DH was found in the patients with chronic renal failure when compared to control subjects (4.1 +/- 5.3 vs 12 +/- 9.3 mm, p less than 0.05) whereas only a non-significant tendency to a reduced DH was seen in the HPT patients (9.5 +/- 9.2 mm). Treatment with alphacalcidol, a synthetic analogue to the active vitamin D metabolite over 3-6 months did not affect the DH in any of the hyperparathyroid patient groups. Thus it seems likely that other factors than vitamin D were involved in their reduced DH response.

Treatment with active vitamin D (alphacalcidol) in patients with mild primary hyperparathyroidism.

The parathyroid gland possesses receptors for 1,25-dihydroxyvitamin D3, the active metabolite of the vitamin D system, and in vitro experiments have shown that 1,25-dihydroxyvitamin D3 can inhibit the secretion of PTH. In this study 31 subjects who had displayed persistent mild hypercalcemia for 14 years and presumably had mild primary hyperparathyroidism (HPT) were challenged with 1.0 microgram alphacalcidol (1 alpha-(OH)-vitamin D3) over 6 months in a double-blind, placebo-controlled study. Before initiation of therapy, the hyperparathyroid subjects showed lower serum levels of 1,25-dihydroxyvitamin D in relation to PTH or calcium when compared with age- and sex-matched controls. Treatment induced a slight rise in serum calcium (0.05 mmol/l), but no significant decrease of the PTH levels. Eighteen of the subjects thereafter entered an open study with a higher dose of alphacalcidol (2.0 micrograms) over 1 year. Although this high dose induced a marked rise in serum calcium (0.17 mmol/l), there was only a transient reduction of the PTH levels. Thus, during long-term condition there was an escape from the suppressive action of the elevated calcium concentrations and no evidence of a specific inhibition of PTH secretion by a small oral dose of active vitamin D.

Reduction of blood pressure during long-term treatment with active vitamin D (alphacalcidol) is dependent on plasma renin activity and calcium status. A double-blind, placebo-controlled study.

Patients with essential hypertension, in particular those with low plasma renin activity (PRA), are reported to have lowered plasma-ionized calcium and elevated parathyroid hormone levels. In this study 1 microgram alphacalcidol (1 alpha-hydroxy-vitamin D3) was given in a double-blind, placebo-controlled fashion over four months to 39 subjects with mild to moderate hypertension. There was a significant rise in PRA in the treatment group when compared to placebo (P less than .05), but the mean blood pressure response was similar in the two groups. When the treatment group was divided according to pretreatment PRA it was, however, seen that subjects with low PRA displayed a reduction in diastolic blood pressure, whereas those with high PRA raised their blood pressure compared to placebo. Also subjects with low pretreatment values for plasma-ionized calcium and high levels of parathyroid hormone showed a reduction in diastolic blood pressure. This study supports the idea of a relationship between calcium metabolism and the renin-aldosterone system in essential hypertension and describes a beneficial effect of vitamin D supplementation on blood pressure in low-renin hypertension.

Hypertension in primary hyperparathyroidism--reduction of blood pressure by long-term treatment with vitamin D (alphacalcidol). A double-blind, placebo-controlled study.

Patients with primary hyperparathyroidism (HPT) often have raised blood pressure but a simple cause-and-effect relationship has not been established. In 33 persons with probable primary HPT and mild hypercalcemia detected in a health survey, diastolic blood pressure (DBP) was significantly higher than among age- and sex-matched, normocalcemic, controls (89.4 +/- 9.8 (SD) v 85.2 +/- 8.9 mm Hg; P less than 0.05). Among the hypercalcemic individuals, DBP was, in a multivariate analysis, inversely related to the serum calcium and plasma-ionized calcium concentrations and to the serum levels of parathyroid hormone. A prospective, placebo-controlled, double-blind, study evaluating the effects of active vitamin D, alphacalcidol, (1 microgram daily) was carried out in the hypercalcemic patients over a six-month period. This treatment caused a slight further increase (0.05 mmol/L) of both serum calcium and plasma-ionized calcium concentrations. At the same time there was a significant reduction of DBP with a mean of 6.7 mm Hg compared with placebo (P less than 0.05). The hypotensive action of the vitamin D compound was inversely related to the pretreatment serum levels of 1,25(OH)2D3 and additive to concomitant, unchanged, antihypertensive medications. The negative correlation between serum calcium and blood pressure is similar to that obtained in normocalcemic individuals and suggests that raised blood pressure, at least in the milder forms of primary HPT, is only independently associated with the disease. Active vitamin D, although it raises serum calcium, can lower blood pressure also in hypercalcemic patients as previously demonstrated in normocalcemic individuals.

Relation of serum calcium concentration to metabolic risk factors for cardiovascular disease.

Data from a health screening survey with over 18,000 adult participants were used to determine the relations between serum calcium concentration and the cardiovascular risk factors hypertension, hyperglycaemia, and hyperlipidaemia. Blood pressure and serum glucose and cholesterol concentrations were all positively related to each other independent of age, sex, kidney function, and obesity. Similar relations between the risk factors were found in subjects with hypertension or hyperglycaemia independent of the degree of overweight. These results suggested that there might be a metabolic syndrome of cardiovascular risk factors. Serum calcium concentration was positively related to systolic and diastolic blood pressures and serum glucose and cholesterol concentrations. Thus a common feature in the syndrome is an increased serum calcium concentration. The relations between serum calcium concentrations and the cardiovascular risk factors were not limited to the upper parts of the distribution, being seen over a wide range. Changes in calcium metabolism seem to be related to a metabolic syndrome of hypertension, impaired glucose tolerance, and hyperlipidaemia.

A pilot study of metabolic effects of intravenously given alpha-calcidol in patients with chronic renal failure.

Disturbances of calcium homeostasis might be involved in the pathogenesis of the metabolic derangements associated with uraemia. Indices of glucose and lipoprotein metabolism as well as blood pressure were measured in nine patients with chronic renal failure who were on regular hemodialysis. Seven of them thereafter received alpha-calcidol (a synthetic analogue to active vitamin D) intravenously for three months. Prior to therapy the patients had, compared with age and sex matched controls, impaired glucose tolerance, hyperlipoporteinemia and raised blood pressure. Treatment with alpha-calcidol reduced elevated serum levels of parathyroid hormone (PTH). Concomitantly there was a reduction of fasting blood glucose and HbA1C (glycosylated hemoglobin) concentrations and an improvement of the glucose tolerance, whereas insulin concentrations were unaffected. There was a reduction of whole serum triglycerides and an increase of HDL cholesterol. A significant decrease was also observed for systolic blood pressure. This pilot study suggests that treatment with active vitamin D, probably through its effects on calcium metabolism, is beneficial with regard to the metabolic disturbances in uraemia.

Suppression of serum parathyroid hormone levels by intravenous alphacalcidol in uremic patients on maintenance hemodialysis. A pilot study.

Seven patients on chronic hemodialysis were given alphacalcidol (1 alpha-OH-vitamin D3) intravenously in a pilot study during 3 months. Before treatment all patients had serum calcium values within the normal range, but elevated levels of parathyroid hormone (PTH). When serum calcium was raised above the normal range by treatment with alphacalcidol, all patients displayed marked suppression of PTH levels with a mean reduction of 40 +/- 20% (SD; p less than 0.01). When the dose of alphacalcidol was reduced so that the serum calcium values were kept at the upper limit of the normal range, a partial return towards pretreatment values of PTH was seen but the levels were still lowered (p less than 0.05). Thus, intravenous administration of the vitamin D compound appeared to be useful for the management of secondary hyperparathyroidism in patients on dialysis. A direct effect of alphacalcidol on the parathyroid glands could, however, not be distinguished from the calcemic action.

Treatment with clodronate in patients with hypercalcemia secondary to malignancy.

Dichloromethylene bisphosphonate (clodronate, Cl2MDP) is a synthetic analogue to pyrophosphate, which inhibits increased bone resorption. This drug was given to 12 patients with hypercalcemia secondary to advanced malignant disease. Clodronate in a daily dose of 1.6 to 3.2 g generally caused a return of the serum calcium values to normal within 5-10 days with a concomitant improvement of symptoms related to the hypercalcemia. Side effects were few. Thus, clodronate appears to be a valuable adjunct for the medical management of patients with malignancy-associated hypercalcemia.

Blood pressure is lowered by vitamin D (alphacalcidol) during long-term treatment of patients with intermittent hypercalcaemia. A double-blind, placebo-controlled study.

There is epidemiologic evidence of a relationship between calcium deficiency and hypertension. The present study evaluated the effects of alphacalcidol, a synthetic analogue of active vitamin D, given to 29 patients with marginal, intermittent hypercalcaemia. Before therapy there was an inverse relationship between serum calcium levels and diastolic blood pressure (p less than 0.02). Treatment with 1 microgram alphacalcidol raised the serum calcium by 0.07 mmol/l during a 6-month, double-blind, placebo-controlled trial and caused a significant reduction of diastolic blood pressure by 9.2 mmHg compared with placebo (p less than 0.01). The study extends previous observations, in normocalcaemic subjects, of inverse relationships between serum calcium and blood pressure indicating a primary disturbance of calcium homeostasis in hypertension. The observation that a physiologic amount of active vitamin D has hypotensive effects agrees with such a concept and suggests a new principle for the treatment of hypertension.

Enzymatic sulphation of bile salts in man. Bile salt sulphotransferase activity in percutaneous liver biopsy specimens from patients with liver disease.

Bile salt sulphation in liver disease was investigated by measuring the bile salt sulphotransferase level in percutaneous liver biopsy specimens from 27 patients. The same magnitude of mean specific enzyme activity was found in patients with cholestatic and non-cholestatic liver disease. No significant difference of the mean bile salt sulphotransferase activity was found when patients with and without reduced liver function as evidence from the intravenous galactose tolerance test were compared. The present results indicate that induction of liver bile salt sulphotransferase does not occur to a significant extend in clinical conditions with cholestasis.

Enzymatic sulphation of bile salts in man.

An investigation of the occurrence of glycolithocholate sulphotransferase in the human gastrointestinal tract and kidney is described. In addition to in the liver, glycolithocholate sulphotransferase was found in the small intestine, but no activity could be detected in the gastric mucosa, colonic mucosa, or kidney.

Primary sclerosing cholangitis associated with fibrosis of the submandibular glands and the pancreas.

A new syndrome of primary sclerosing cholangitis associated with fibrosis of the submandibular glands and the pancreas is described in a 43-year-old male. The sclerosing cholangitis was diagnosed at laparotomy because of cholestasis and the fibrosis of the submandibular glands and pancreas confirmed at microscopical investigation of biopsy specimens. The cholangitis responded well to treatment with a low dose of prednisolone (7.5--10 mg) and an endoscopic retrograde cholangiopancreaticographic examination 10 months after the operation revealed normal bile ducts.

Enzymatic sulphation of bile salts in human liver.

An enzyme catalyzing the transfer of the sulphate group from 3' -phosphoadenosine-5' -phosphosulphate to lithocholate and glycolithocholate is identified in the cytosol of human liver. The rate of sulphation was greatest with unconjugates lithocolate. Km values for lithocholate and glycolithocholate were 2 . 10(-6) and 3.3 . 10(-6) M, respectively. No enzyme activity was found in human kidney cytosol. A simple method for quantitative assay of the enzyme in percutaneous liver biopsy specimens is described.

Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen.

Twenty patients being treated with thiazides were found among 95 subjects (21%) with hyercalcemia verified in repeated determinations in a health screening of 15,903 persons. There were 1,034 patients treated with thiazides in this total health screening. The prevalence of hypercalcemia in the patients treated with thiazides in this total health screening. The prevalence of hypercalcemia in the patients treated with thiazide (1.9%) was considerably higher than the prevalence of hypercalcemia found in the entire health-screened population (0.6%). The thiazide treatment was withdrawn in the 20 hypercalcemic subjects after an examination, and the patients were observed at intervals during a follow-up period of one year. The necks of 14 were explored during or after the follow-up period because of an initial serum calcium level greater than 3.0 mmole/liter or persistent hypercalcemia. Parathyroid adenomas were seen in all patients receiving surgery. Single adenomas predominated in surgical findings. The finding of the present high number of patients with primary hyperparathyroidism may be associated with elevated blood pressure resulting in thiazide treatment after detection.

Blood pressure in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening programme.

Primary hyperparathyroidism was the most likely diagnosis in sixty-eight non-thiazide treated patients with hypercalcaemia detected in a health screening. The group included fifty-five females and thirteen males with a mean +/- SEM age of 55.0 +/- 0.7 years. On a pair basis, these patients were compared with a series of sixty-eight age- and sex-matched normocalcaemic subjects selected from the health screening register. Five subjects in each group were receiving medication for hypertension. Systolic and diastolic blood pressures were significantly higher in the hypercalcaemic subjects in the remaining fifty-eight pairs (P less than 0.001). This difference was unrelated to impaired renal filtration and many other factors associated with hypertension. It is concluded that hypercalcaemia and/or other effects of deranged parathyroid function per se may result in a blood pressure elevation on which need not necessarily attain the level of hypertension.