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Original Article

Increasing incidence of primary hyperparathyroidism in Denmark

Ali Abood & Peter Vestergaard

1. feb. 2013
13 min.

Faktaboks

Fakta

Primary hyperparathyroidism (PHPT) is a common endocrine disorder. Over the past years, PHPT has experienced a dramatic change in epidemiology. The disease is often asymptomatic; hence, its incidence was previously often underestimated. With the increasing availability of plasma calcium measurements during the 1970s, the incidence of PHPT has risen significantly. In 1974, this resulted in the hitherto highest reported US incidence of 129 cases per 100,000 person-years [1]. In subsequent years, a significant decline in the US incidence of PHPT was seen. This was probably owed to the fact that the majority of prevalent cases had been detected prior to 1974, and after this point in time the incidence thus represented actual incident cases [2]. The latest available figures from the US show a continuing downward trend in incidence with an overall incidence rate of 21.6 per 100,000 person-years in the 1993-2001 period [1]. This downward trend was not observed in Denmark – in contrast, the incidence in Denmark was increasing. From 1980 to 1999, the incidence rose significantly among women (from 3.4 to 5.8 per 100,000 per year), while the increase for men was less pronounced [3]. It is worth noting that the large difference in incidence rates between Denmark and the United States probably reflects a large pool of undetected cases in Denmark. Similarly, in Switzerland, the incidence of parathyroidectomies was 3.8 per 100,000 per year between 2000 and 2004, i.e. low compared with the US [4]. There are thus considerable geographical differences, which underlines the importance of unknown aetiologic factors. This is also supported by a Scottish study on the incidence of PHPT in the 1997-2006 period, which reported a fluctuating and cyclical pattern [5]. In the Scottish study, the incidence was reported to have increased if annual incidence rates from 1997 and 2006, respectively, were compared. When comparing year-to-year incidence rates within the 1997-2006 period, large fluctuations were observed. Furthermore, unknown aetiologic factors were suggested as possible explanations [5]. The variations in the epidemiology of PHPT may, in part, be attributed to temporal components, but geographical/aetiologic factors also seem to play a role. These are not well documented and need to be clarified.

The incidence of PHPT in Denmark has not been assessed since 1999 [3]. The purpose of the present study was to evaluate incidence rates of PHPT in the 2000-2010 period to determine if the development in Denmark is similar to that seen in the rest of the world.

MATERIAL AND METHODS

Included were all patients who were registered in the National Hospital Discharge Register (Sundhedsstyrelsens Landspatientregister) [6] from 1977 to 2010 with a PHPT diagnosis. International Classification of Diseases (ICD) 8-codes: 252.00 (hyperparathyroidismus primarius, adenoma), 252.01 (hyperparathyroidismus primarius, hyperplasia), 252.03 (crisis hyperparathyroidismi), 252.04 (osteitis fibrosa cystica generalisata), 252.05 (nephrocalcinosis e hyperparathyroidismi), 252.08 (hyperparathyroidismus alia), 252.09 (hyperparathyroidismus), and ICD10 codes: E21.0 (primary hyperparathyroidism), E21.2 (secondary hyperparathyroidism), E21.3 (hyperparathyroidism without specification). The ICD 8 code system was used between 1977 and 1993, while the ICD 10 code system was applied from 1994 to 2010. Before 1990, only admissions were reported, but from 1990 to 1994 some departments started including reports from outpatient clinics and emergency rooms. From 1995 reports from all outpatient clinics and emergency rooms were included. It was determined when a diagnosis was initially confirmed and all patients who were diagnosed between 1977 and 2010 were included in the analysis. Incidence rates were calculated as the number of people with newly diagnosed PHPT in a given year divided by the population as per 1 January in that year obtained from Statistics Denmark (Danmarks Statistik, Statistikbanken). The mean and standard error of the mean (SEM) were used as the descriptive statistics, and t-tests for the two groups were used for statistical testing. All calculations were performed using SPSS for Windows 19 (IBM).

Trial registration: not relevant.

Results

Figure 1 shows the crude incidence rates of PHPT among men and women in the 1977-2010 period in Denmark. Throughout the whole period, incidence rates were higher among women than among men. Until about 1998, incidence rates among men remained relatively stable. Subsequently, a 3-fold increase was observed from 1998 to 2010. Among women, the incidence rates remained relatively stable until about 1990 after which year a 5-fold increase was seen from 1990 to 2010. Table 1 shows the age and sex of newly diagnosed patients with PHPT from 1977 to 2010. As a result of the rapid increase in the number of women with newly diagnosed PHPT the ratio of men versus women was gradually reduced from about 30% men in 1977 to around 23% men in 2010. The average age increased, so that newly diagnosed women were, on average, about 55 years in the 1980s, while they were around 65 years at the end of the period. In the 1980s, the mean age of newly diagnosed men was slightly above 50 years compared with slightly more than 60 years at the end of the period causing an increase in the average age for both men and women by ten years during the study period. Figure 2 shows the age-specific incidence for men and women. The largest increase occurred among women above 50 years of age, for whom incidence rates experienced a 5-fold increase. Among men aged 50 years or more, incidence rates increased by a factor of three. For women under 50 years of age, a factor three increase was observed, while men under age 50 years also saw a factor three increase.

Figure 3 shows the seasonal variation in the incidence of PHPT for the 1977-2010 period. When comparing men and women, no seasonal variation was seen.

DISCUSSION

This study reveals a continuing increase in the incidence rates of PHPT in Denmark during the 2000-2010 period. The increase was seen in both men and women, especially above 50 years of age and it was more pronounced for women. It should be noted that incidence rates were only increasing when the entire period was considered, as the fluctuations in incidence from one year to the next were rather large. A similar pattern was seen in Scotland [5]. In the Scottish study [5], it was suggested that these fluctuations could be season-related, but there are still no studies that definitively confirms this. The reason for these fluctuations thus remains unclear. Unknown aetiologic factors probably play a role [5] and need to be clarified. In our study, there was no seasonal variation. Two months (July and December) had a lower incidence of newly diagnosed cases, but both are holiday months, and a lower activity in the health-care system may explain the lower frequency observed. For example, December was followed by a higher incidence of newly diagnosed cases in January. Among women, there were a few more new cases in the months of September through November than in the months of February through April. However, this could not be seen in men.

The incidence of 21.6 per 100,000 per year seen in the US [1] for the 1993-2001 period is close to but still well above the Danish incidence of 16 per 100,000 per year in 2010 demonstrated in this study. It is thus possible that the incidence will continue to increase in Denmark.

The general upward trend in the incidence of PHPT observed in this study may, in part, be attributed to the fact that more people are diagnosed as a result of more measurements being made. However, this cannot explain the cyclical pattern observed. Another reason for the increasing incidence of PHPT may be the prevailing obesity epidemic [7]. A metaanalysis has shown that on average PHPT patients are heavier than controls [8]. Their greater body weight can lead to resistance to parathyroid hormone (PTH) and resistance to thyroidstimulating hormone and insulin. Studies have also shown increasing PTH-levels with increasing body weight, possibly due to a declining level of 25-hydroxy-vitamin D, which is fat soluble [9, 10]. It is therefore perhaps possible to develop autonomy in the parathyroid glands and thus PHPT in obese patients. Consequently, with the increasing body weight in the population, a higher rate of PHPT is likely.

It should be underlined that neither the diagnostic criteria of PHPT nor the diagnostic tools have changed during the period evaluated, which makes incidence rates from different years comparable, which is a clear strength of this study.

The clear over-representation of women was also to seen in Scotland [5], Switzerland [4], USA [1] and Denmark before 2000 [3]. It seems probably that part of the explanation may be that women come into contact with the health-care system more frequently and therefore may have their plasma calcium levels measured more often, causing them to be diagnosed more frequently [3].

Oestrogen has an anti-resorptive effect resulting in a lower efflux of calcium from the skeleton, which lowers plasma calcium in primary hyperparathyroidism [11-17]. Another explanation may thus be that the decline in oestrogen levels in women after the menopause can unmask a mild hyperparathyroidism, whereby more women are detected and classified as incident [1]. This hypothesis is supported by the fact that the increase is more pronounced above 50 years of age.

In contrast to the development observed in Denmark and Scotland, the incidence of PHPT in the US is declining [1]. A complete and definitive explanation for this is still pending, but part of the explanation probably lies in a widespread use of therapeutic head/neck radiation in the 1930s and 1940s in the United States. It is known that excessive exposure to head/neck radiation may cause sporadic primary hyperparathyroidism [1, 18, 19]. This may also help explain the dramatic increase in the incidence in 1974. Over time a reduction in the incidence may be expected as the effects of radiation decreases. It should also be noted that when comparing incidence rates before 1974 (15.6 per 100,000 person-years) and from 1993-2001 (21.6 per 100,000 person-years), there is actually an increase in incidence in the US [1]. It should be noted that these numbers are not entirely comparable due to a more limited use of plasma calcium measurements before 1974.

In summary, the increase in incidence observed in Denmark may, in part, be attributed to more measurements being made. In addition, obesity may also play a role. The over-representation of women is, among others, due to the fact that women more often come into contact with the health-care system resulting in an unmasking a mild PHPT, especially after menopause where the antiresorptive properties of oestrogen are lost. The cyclic variations seen in our study are also observed in Scotland, and may be attributed to unknown aetiological factors.

CONCLUSION

A continuing increase was observed in the incidence of primary hyperparathyroidism in Denmark from 2000 to 2010. Part of the increase can be attributed to in creased diagnostic activity. A contributing reason for the increase may be the increasing body weight in the population.

Correspondence: Peter Vestergaard , Medicinsk-endokrinologisk Afdeling, Aalborg Universitetshospital, Hobrovej 18-22, 9100 Aalborg, Denmark.

Accepted: November 8 2012

Conflicts of interest:Disclosure forms provided by the authors are available with the full text of this article at www.danmedbul.dk.

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