Diagnosis of patients with raised serum calcium level in primary care, Sweden

Abstract

Objective. To study the diagnosis of hypercalcaemic patients and to evaluate whether frequent analyses of serum calcium can detect more patients with hypercalcaemia. Design. Retrospective study of serum calcium analyses performed during the time period 1992–2000 and of the medical records of patients with elevated serum calcium levels between 1995 and 2000. Setting. Primary care in Tibro, Sweden. Subjects. Patients from the local community attending the primary healthcare centre. Main outcome measures. Frequency of serum calcium analyses, hypercalcaemic patients, and their diagnosis. Results. Doubling the number of serum calcium analyses did not increase the detected number of raised calcium levels. On the other hand, more frequent parathyroid hormone (PTH) analyses resulted in a corresponding increase in detected high PTH levels. In Tibro, 15% (n = 22) of the patients with hypercalcaemia were diagnosed with primary hyperparathyroidism, giving a rate of 0.22%. This is comparable to the prevalence in other population studies. Over 40% (n = 9) of patients with primary hyperparathyroidism in the study had only slightly raised serum calcium levels (2.55–2.60 mmol/l). In 70% (n = 99) of the cases, the cause of hypercalcaemia was unknown. The second most common diagnosis was skeletal disorders followed by kidney disease. Conclusion. An increase in the number of serum calcium analyses did not result in increased detection of raised calcium levels. In contrast, an increase in the number of PTH analyses resulted in increased detection of primary hyperparathyroidism. Therefore, PTH analyses should be used more frequently.

• Family practice
• hypercalcaemia
• parathyroid hormone
• primary care
• primary hyperparathyroidism

Primary hyperparathyroidism (pHPT) is the third most common endocrine disease after diabetes mellitus and thyroid disease and gives rise to elevated serum calcium levels. It is difficult to detect because the symptoms are often non-specific and the severity of the symptoms does not correlate to the serum calcium level [1]. Patients with pHPT have an increased frequency of renal calculus [2], osteoporosis, and psychiatric diseases, as well as increased morbidity and mortality from cardiovascular disease [3], [4] and cancer [5].

In Sweden, pHPT patients with symptoms or with a high serum calcium level often undergo surgery. Symptoms of less than two years’ duration usually regress after surgery [6] and the risk of higher mortality seems to disappear after 5–15 years [7].

To increase detection of primary hyperparathyroidism (pHTP), increased serum calcium analyses are recommended by Swedish authorities. This study shows that:

• A high number of calcium analyses did not reveal more hypercalcaemic patients, but more patients with raised parathyroid hormone (PTH) levels are detected with an increase of PTH analyses.

• A similar rate of pHTP was found in the Tibro study compared with earlier population screenings.

• In 70% of patients, no underlying cause for the hypercalcaemia was found.

Analyses of serum calcium can be used in screening for pHPT. To detect more patients with pHPT, the Swedish authorities encouraged an increase in serum calcium analyses in primary care [8]. In the majority of patients serum calcium levels remain stable over decades [9], [10], but in a small proportion of patients levels increase rapidly [11]. Presently there is no way of predicting in which patients levels are prone to rapid increases.

Several population studies have been carried out in Scandinavia to detect pHPT (Table I). There are considerable differences regarding the actual cut-off points for serum calcium in screening surveys, ranging from 2.55 to 2.78 mmol/l [9], [10], [12–14]. The higher levels were used in older studies. There are also differences regarding the diagnostic criteria for pHPT. Some studies rely on PTH testing and others on pathoanatomical diagnosis of the parathyroid glands during surgery. Most of the literature on pHPT describes diagnostic procedures and treatment by specialists in endocrinology. There are very few studies of pHPT in primary care [13].

Table I.  Primary hyperparathyroidism in population surveys in Scandinavia according to serum calcium levels and mode of diagnosis.

Author, year	Ref. no.	Population	Selection	No. of subjects	Age (years)	Design	Ca test	Ca limit (mmol/l)	pHPT diagnostics	pHPT prevalence	Follow-up [year]
Christensson, 1976	12	Swedish Stockholm	Employees of Stockholm City and County Council	15 903	20–63	Health survey	Ca	>2.78	Operation	0.36%	–
Palmér, 1987	10	Swedish Gävle	People > 25 year in a district of Gävle	16 401	>25	Population survey	Ca albumin-corrected	>2.60	Operation	0.21%	14
Lindstedt, 1992	13	Swedish Mölnlycke	People > 75 year in Mölnlycke	368	75–95	Health survey	Ionized Ca	>1.3	PTH	2.2%	–
Lundgren, 1997	14	Swedish Uppsala	Mammography screening (women)	5 202	55–75	Health survey	Ca	>2.55	PTH	2.1%	–
Jorde, 2000	9	Norwegian Tromsö	Inhabitants in Tromsö	27 159	25–75	Population survey	Ca	>2.59	PTH	0.25%	3
Dalemo, 2006	Present study	Swedish Tibro	Patients at the health centre	11 000	7–96	Primary care survey	Ca albumin-corrected	>2.55	PTH	0.22%^a	–

^aRate of patients attending primary healthcare. pHPT = Primary hyperparathyroidism. PTH = Parathyroid hormone. Ca = calcium. Ref. no.=Reference number.

The primary aim of this study was to investigate whether the number of serum calcium analyses increased in Tibro's primary healthcare during the period 1992 to 2000. Does the number of serum calcium analyses correlate to the number of detected hypercalcaemia patients? The second aim was to characterize patients with hypercalcaemia during 1995 to 2000 retrospectively by examining the diagnoses in the patients, and to assess the rate of pHPT.

Material and methods

Tibro is a typical Swedish rural community 25 km from the nearest hospital in Skövde with approximately 11 000 inhabitants and a low migration. There is only one healthcare centre in the community, which the vast majority of the patients attend. A fully computerized medical record system has been in operation in Tibro since 1992. From 2000, the program used is ProfDoc Journal III (PDIII, ProfDoc AB; Uppsala). A search of the computerized medical records between 1992 and 2000 was performed to establish the total number of laboratory analyses, serum calcium, and PTH analyses related to the number of medical consultations in that period. Parameters were extracted using EpiInfo (EPI6, version 6.04d, Centre for Disease Control and Prevention, CDC, Atlanta in collaboration with WHO) from the laboratory files of the PDIII database. All patients with a serum calcium level above 2.55 mmol/l were filed separately, regardless of albumin level. This file was analysed using EP16.

A detailed evaluation was carried out for patients with calcium levels above 2.55 mmol/l recorded between 1995 and 2000 (n = 142). If serum albumin levels were ≤33 g/l, the serum calcium value was corrected by the formula S-Ca = 0. 02 (42-S-albumin) +S-Ca [18]. The diagnosis pHPT was based on a PTH test as a follow up to detection of a high serum calcium level.

The method that had been used to determine serum calcium and albumin was a spectrophotometric method for whole blood (Vision, Abbott, Solna) supervised by Capio Diagnostic Laboratory, Kärnsjukhuset, Skövde. PTH was measured in serum at Capio, Skövde (Elecsys 2010, Roche Diagnostics Scandinavia AB, Bromma).

The reference interval of the study for serum calcium was 2.15–2.55 mmol/l, for albumin 35–48 g/l, and for PTH 10–65 ng/l. Serum calcium levels > 2.55 mmol/l were corrected for albumin level by using the above-mentioned formula.

Results

The number of medical consultations at Tibro Medical Centre remained relatively constant at about 14 500/year, between 1992 and 2000. However, the total number of blood analyses during the same period increased from approximately 70 000 to 100 000 per year.

During 1992–2000, approximately 1% (n = 7364) of the analyses were for serum calcium levels and revealed 424 serum calcium levels > 2.55 mmol/l in 276 patients. Some 98% of the analyses were performed in order to detect disease. From 1992 to 2000 the number of serum calcium analyses increased from 51/1000 inhabitants in 1992 to 100/1000 inhabitants, but remained approximately constant in proportion to the total number of blood analyses (Figure 1). The number of serum calcium levels > 2.55 mmol/l was on average 50 per year regardless of the frequency of testing. The number of PTH analyses increased during the study period from 1 per year to > 25 per year while the number of patients detected with elevated PTH levels (>65 ng/l) increased from 0 to 10 per year (Figure 2). On average one third of PTH analyses showed pathological levels.

Figure 1.  Total number of serum calcium analyses and the number of detected raised calcium levels (>2.55mmol/l), during 1992–2000 at Tibro Primary Health Care Centre, Sweden.

Figure 2.  Total number of parathyroid hormone, PTH, analyses, and number of detected raised PTH levels (>65 ng/l) during 1992–2000 at Tibro Primary Health Care Centre, Sweden.

Patients with hypercalcaemia presented with a multitude of symptoms such as tiredness, vertigo, psychiatric illness, and indigestion. No single symptom dominated (data not shown). The serum calcium analyses were repeated in 70% (n = 107) of cases with elevated levels and in half of the patients with hypercalcaemia further investigation was performed with more detailed blood tests. One quarter of the hypercalcaemic patients, especially those with the highest serum calcium levels, were referred to specialists for further investigation (Table II).

Table II.  Albumin correction, parathyroid hormone analyses, further investigation, and diagnoses in 142 patients with different levels of hypercalcaemia found in Tibro primary care during 1995–2000.

Calcium (mmol/l)	Group I 2.56–2.60 n = 87		Group II 2.61–2.65 n = 27		Group III >2.65 n = 28		Total n = 142
	m	(SD)	m	(SD)	m	(SD)	m	(SD)
Age (years)	54	(±21)	61	(±22)	68	(±17)	58	(±21)
Serum calcium (mmol/l)	2.58	(±0.013)	2.63	(±0.015)	2.84	(±0.36)	2.64	(±0.19)
	n	(%)^a	n	(%)^b	n	(%)^c	n	(%)^d
Albumin
Controlled patients	57	(66)	24	(89)	26	(93)	107	(75)
Levels ≤ 33 g/l	0	(0)	0	(0)	9	(32)	9	(6)
Parathyroid hormone (PTH)
Controlled patients	15	(17)	10	(37)	8	(29)	33	(23)
Raised PTH levels > 65ng/l	6	(7)	4	(15)	4	(14)	14	(10)
Further investigation
Referred patients	13	(15)	6	(22)	14	(50)	33	(23)
No investigation	37	(43)	5	(19)	6	(21)	48	(34)
Diagnoses
PHPT	9	(10)	5	(19)	8	(29)^e	22	(15)^e
Cancer	1	(1)	–		3	(11)^e	4	(3)^e
Hypervitaminosis D	3	(3)	–		–		3	(2)
Sarcoidosis	–		1	(4)	–		1	(1)
Kidney disease	–		–		5	(18)	5	(3)
Lithium treatment	1	(1)	–		–		1	(1)
Thyroid disease	1	(1)	–		–		1	(1)
Skeletal disease	1	(1)	4	(15)	2	(7)	7	(5)
Unknown	71	(82)	17	(63)	11	(39)	99	(70)

^aPercentage of 87; ^bpercentage of 27; ^cpercentage of 28; ^dpercentage of 142; ^eone patient had both cancer and pHPT.

During 1995–2000 there were 142 patients (96 females and 46 males) with raised serum calcium level, in at least one analysis. Sixteen patients with hypercalcaemia were below the age of 25. All patients with low albumin levels were females with a mean age of 78 years. The patients were divided into three groups according to their serum calcium level (albumin corrected): ≤2.60 mmol/l, 2.61–2.65 and > 2.65 mmol/l (see Table II).

In total, 15% of the patients with raised serum calcium levels (22 patients) had pHPT and the frequency of patients diagnosed with pHPT increased with increased degree of hypercalcaemia (see Table II). Even so, 40% (n = 9) of the patients with pHPT were in group I (≤2.60 mmol/l) with only slightly raised serum calcium levels. None of the patients with pHPT had calcium levels above 3.0 mmol/l. Almost 90% (n = 16) of the females with pHPT were 60–80 years old while the majority of males were between 50 and 59. Half of the patients with pHPT were treated surgically or were on a waiting list for surgery. The rate of pHPT was 0.22% in the Tibro population during the time of the survey.

In 70% (n = 99) of the cases of hypercalcaemia, no diagnosis was presented in patient records. After pHPT, the second most common diagnosis in hypercalcaemic patients was skeletal disease (fractures, immobilization, and osteoporosis), followed by kidney disease (see Table II). Patients with malignant diseases were most frequently detected in the group with highest serum calcium levels. The patients with D hypervitaminosis were on vitamin D or analogous medication due to injury to parathyroid glands when surgically treated for thyroid diseases.

Discussion

The main result of this study was that an increase in the number of serum calcium analyses did not result in an increased detection rate of raised calcium levels. The frequency of serum calcium analyses was high in Tibro primary care. As early as 1994, the number of serum calcium analyses was twofold (61/1000 inhabitants) compared with a study from primary care in southern Stockholm (29/1000 inhabitants) [19].

This study shows that the rate of pHPT seen in Tibro primary healthcare centre (0.22%) is the same as the prevalence in observed population screenings for serum calcium in Tromsö (0.2%), Gävle (0.21%), and Stockholm (0.36%) (see Table I). A limitation of this study is that a true prevalence cannot be calculated, as this is a clinical sample. The figure probably represents a mixture of prevalence and incidence during the six years included in this study. However, because many patients with pHPT have symptoms that make them more likely to attend the primary care centre the rate of pHPT in this study is likely to be near the population prevalence. The age of the subjects in the population studies varied from 20 to 96 (see Table I). Studies limiting the subject population to retirees or females 55 to 75 years of age detected a prevalence of about 2% (see Table I). The lower age limit in the Tromsö, Gävle, and Stockholm [9], [10], [12] studies was 20–25 years while the rate in Tibro was calculated for a population aged 7 years and older, as this was the age of the youngest patient with hypercalcaemia. With a lower age limit of 45 years, a rate of 0.43% would have been registered in this study. None of the patients with pHPT was under 50 years of age.

In this study only 23% (n = 33) of patients with hypercalcaemia had a PTH test taken and nearly half of the patients diagnosed with pHPT had only marginally raised calcium (2.55–2.60 mmol/l). It therefore seems to be a step in the right direction to lower the upper reference limits for serum calcium level to about 2.50 mmol/l following the Nordic Reference Interval Project (NORIP) [20]. To analyse PTH in patients with only slightly raised calcium levels seemed to detect more cases of pHPT.

In as many as 70% (n = 99) of the cases of hypercalcaemia detected in Tibro, it was not possible to make a definitive diagnosis from the patient record, even among patients with the highest serum calcium levels (>2. 65 mmol/l). Some could be suffering from pHPT. Ten patients in this study were very old (≤85 years) and further investigation may therefore not have been carried out.

Hypercalcaemia is a common finding in patients with malignancy. In over half of the patients in the studies performed at hospital clinics, malignancy was the cause of hypercalcaemia, while in primary care the frequency is considerably lower (Table III). In Tibro 2% (n = 4) of the patients with hypercalcaemia had cancer, comparable with the figure found in Stockholm (Table III).

Table III.  Distribution of diagnoses (%) in studies of hypercalcaemia in health surveys, hospitals, and primary care.

Country	Norway	Sweden	Sweden	USA	UK	USA	Sweden
Reference	9	14	12	15	16	17	Present study
Decade	90s	90s	70s	60s	70s	60s	90s
S-Ca level mmol/l	2.6	2.55	2.78	NI	2.7	NI	>2.55
Population	HS	HS	HS	PC	H	H	PC
Number	366	188	95	61	469	57	142
PHPT	17	58	60	51	27	21	15
Cancer	–	–	2	31	54	65	2
Hypervitaminosis D	–	–	–	8	2	5	2
Sarcoidosis	–	–	1	–	–	–	1
Kidney disease	–	1	–	–	15	–	3
Lithium treatment	–	–	–	–	–	–	1
Milk alkali syndrome	–	–	–	7	–	–	–
Thyreoidea disease	–	–	4	3	1	–	1
Addison′s disease	–	–	–	–	–	2	–
Thiazide treatment	–	–	4	–	–	–	–
Skeletal disease	–	–	–	–	–	–	5
Unknown	83	41	29	–	1	7	70
	100%	100%	100%	100%	100%	100%	100%

HS = health survey; PC = primary care; H = hospital; NI = no information.

In conclusion, the data in this study suggest that doubling the number of serum calcium analyses did not increase the detection rate of hypercalcaemia. On the other hand, increasing PTH analyses led to increased detection of pHPT. Therefore PTH analyses should be used more in patients with diffuse symptoms and mild hypercalcaemia. The rate of pHPT among patients in this study was comparable to the prevalence found by population screening. An important finding in this investigation was that a majority of patients with hypercalcaemia were undiagnosed. It is essential that these patients are kept under surveillance as they might have curable diseases. A prospective follow up of the prognosis for these patients in Tibro is therefore planned.

This research was funded by the Region Västra Götaland. The authors are most grateful to Magnus Dalemo, PhD for statistical advice. Thanks are offered to Robert Eggertsen MD PhD and Lennart Welin MD PhD for valuable viewpoints. The authors also wish to thank Mrs Birgitta Lindberg for valuable technical assistance.