General Discussion

In view of the high prevalence figures for PHPT found in population studies, it is apparent that only a proportion of all subjects with PHPT are surgically treated.23,24 This is also true in the city of Göteborg, where the medical community has a liberal attitude toward PHPT surgery.

Subjects who are under medical care for other diseases are more likely to have PHPT diagnosed and treated. This means that a possible bias has been introduced in all three Scandinavian studies. In the Göteborg study, this possibility was considered.11 A selected series was formed by excluding 171 patients who had their PHPT diagnosed during treatment or follow-up for a disease that could cause increased mortality. These diseases were myocardial infarction, heart failure, arrhythmia, hypertension of more than 2 years' duration before detection of raised serum calcium concentrations, stroke, diabetes, and malignant tumors. In the selected series, the mortality was still significantly higher than expected (P < .001), as was the mortality from cardiovascular (P < .001) and malignant diseases (P < .01). The RR in the selected series was 1.43, with a CI of 1.23 to 1.64 (see Table 43-3). The increased mortality in the selected series during the observation period was 7.8% of the PHPT population, which was 5.4% less than in the total series (see Table 43-2). From the analyses of the selected series, it is obvious that PHPT by itself is associated with an increased risk of premature death from cardiovascular and malignant diseases.

Ninety-two percent of the exclusions had been made because of the very two diagnoses that in the selected series had been significantly linked to the increased mortality among PHPT patients. This suggests that when forming the selected series, some patients could have been incorrectly excluded and that the correct value for mortality from PHPT in the total series should be between 7.8% and 13.2%. The total series shows the risk of premature death in all patients who undergo surgery for PHPT. The selected series shows the minimum value for the increased risk of death caused by PHPT itself. The selected series proves that PHPT causes irreversible damage to the body. In a separate study, it was found that the parathyroid adenoma weight was a highly significant predictive factor for the risk of death. This finding was made in the PHPT series itself without using any control subjects. This independent observation strongly supports the association between PHPT and premature death.13 Premature aging could be a possible explanation for the premature deaths from cardiovascular and malignant diseases. The observation that women with PHPT on average experience menopause 4.5 years earlier than control subjects supports this hypothesis.25

The severity of PHPT is usually classified by the serum calcium concentrations. In a 1991 study, asymptomatic and symptomatic PHPT patients had similar preoperative serum calcium concentrations.26 These findings suggest that serum calcium alone is not responsible for the severity of PHPT. An increase in serum calcium concentrations over that found at diagnosis is seldom found in untreated PHPT patients, even if they are monitored for a long time.24,27 This means that the duration of the disease can differ considerably among patients with the same serum calcium concentrations. The possible role of duration of disease is seldom mentioned when discussing the morbidity of PHPT. A long-term, prospective, randomized study with two arms, surgery and nonsurgery, is needed to obtain more exact information about the impact of PHPT duration on morbidity and mortality. For ethical reasons, only asymptomatic patients can be included in such a study. In a previous study of patients with asymptomatic PHPT, there was a waning interest on the part of many patients, making it difficult to continue the study.27 The experience from that study suggests that a prospective, randomized study aimed at defining the influence of PHPT duration on long-term survival is not easily undertaken.

The Göteborg study covered 30 years." During the early part of this period, serum calcium determinations were not routinely done for ambulatory and hospitalized patients, and PHPT was considered a rare disease. Therefore, at that time, the duration of the disease before surgery was probably much longer than during the end of the period, when serum calcium determinations were routinely done. The longer duration of PHPT could have contributed to the higher mortality found during the early period of the study. However, the patients then usually had higher serum calcium concentrations than later, and we know that a high serum calcium concentration is a risk factor for mortality (see Table 43-5). Using a survival test, it was found that the relationship between calendar year and risk of death was significant even when the influence of the serum calcium concentrations had been eliminated.12 This suggests that calendar year of surgery was associated with another risk factor besides the high serum calcium concentration. From this reasoning, it seems logical to assume that the extra risk factor associated with early calendar year is long duration of PHPT.

It is impossible to estimate the exact duration of PHPT before diagnosis, but the size of a parathyroid adenoma must be related to the time of its growth and hence to the duration of PHPT. This should be true even if there are observations suggesting that both cell division and parathyroid tumor growth decline during the life span of the tumor.28 As mentioned, in the Göteborg studies, it was found that the parathyroid adenoma weight was a highly significant predictive factor for the risk of death after cure of PHPT.13 The adenoma weight and the serum calcium concentration were significantly correlated (P < .001). When the influence of the adenoma weight had been eliminated, the serum calcium concentration did not show any correlation with the risk of death. On the other hand, adenoma weight was significantly correlated with risk of death even when the influence of the serum calcium concentrations had been eliminated (P < .01). These calculations show that the parathyroid adenoma weight is a more powerful predictive factor for increased mortality than the serum calcium concentration.13 A plausible hypothesis to account for this observation is that patients with heavier adenomas had a longer duration of PHPT before they were operated on and were, therefore, subjected to more severe and more lasting damage. In the Göteborg study, a shift from an increased risk of death to a normal risk occurred as time passed after surgery.12 This positive effect of surgery was most apparent in recent years, when there was a more positive attitude to the diagnosis and treatment of PHPT. For 65-year-old patients operated on in 1980, it took about 5 years for the survival curve to return to normal. Thus, in untreated patients with PHPT, the risk of death increases with time, whereas after surgical cure of PHPT the risk decreases with time. These observations are strong arguments for early surgery in patients with PHPT.

The risk of increased cardiovascular morbidity and premature death in PHPT has also been discussed in several other studies. Grey and colleagues found that postmenopausal women with mild asymptomatic PHPT had increased body weight and total body fat mass and also a more android fat distribution than age-matched control subjects. They thought that these findings could be relevant to the increased incidence of cardiovascular disease in PHPT.29 A large Danish study showed that patients operated on for PHPT had an increased incidence of myocardial infarcts up to 10 years before surgery. This risk fell to a normal level after surgery. In this study, mortality after surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997.30 In a German series, 383 patients with PHPT were observed prospectively after surgery during a period of 10 years. It was found that the mortality in the study population was significantly higher than in the control subjects. The prevalence of patients with symptomatic PHPT in this series was 94%.31 In an interesting study, it was found that increased cardiovascular mortality was found in patients with mild hypercalcemia followed up for 25 years.32 In another study, it was found that higher serum calcium by itself was associated with increased risk for premature death. The mortality rate in relation to a single serum calcium value was examined in a large population during a mean follow-up of 10.8 years. It was found that men who were younger than 50 years and had serum calcium values greater than 2.45 mmol/L had an increased mortality of 20% compared with those with lower serum calcium levels; those with serum calcium greater than 2.60 mmol/L had a doubled risk rate. The excess mortality was largely attributable to cardiovascular diseases but also to a significant excess mortality because of malignant disease.33

In Europe, several studies have shown an increased risk of premature death in patients operated on for PHPT. Such results were not obtained in studies conducted in the United States at the Mayo Clinic. The patients in the Mayo Clinic series were operated on from 1980 to 1984, and 43% of the 1052 patients in the series had symptomatic PHPT.34 In 1974, a screening program was started at the Mayo clinic, for the early detection of patients with PHPT using routine measurements of serum calcium levels. This program was still ongoing when the 1052 patients referred to above were diagnosed with PHPT. In any 3-year period, more than 90% of Olmsted County residents had at least one measurement of serum calcium level.35 The patients in the Göteborg series had surgery from 1953 to 1982. Clinical data for the first 274 patients in this series were published in 1973.36 Eighty-seven percent of these patients had PHPT with classic symptoms, and 20 of the 200 patients with renal stones recalled that they had their first renal colic more than 20 years before the diagnosis of PHPT. This means that, in these patients, the actual onset of PHPT predated the clinical recognition by more than 2 decades. In this early series, 29 patients were diagnosed with "hypercalcemic crises." These patients from the 1950s and 1960s did not represent our current patients, but their inclusion in the analyses made it possible to define a number of risk factors for premature death and to study the impact of surgery on survival.

Mild hypercalcemia in patients followed for more than 2 decades is accompanied by premature cardiovascular death.32 The exemplary screening program at the Mayo Clinic, with early diagnosis and operations, seems to eliminate the risk for premature death in patients with PHPT.

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