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Editorial |
Division of Endocrinology, Columbia University College of Physicians & Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Shonni J. Silverberg, Department of Medicine, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, New York 10032.
Classical primary hyperparathyroidism was dubbed a disease of "stones, bones, abdominal groans and psychic moans". Along with nephrolithiasis, osteitis fibrosis cystica, and gastrointestinal complaints, psychological and neurological symptoms were prominent manifestations of the disease in the past. In primary hyperparathyroidism today, hypercalcemia is generally mild and is often an incidental finding on routine biochemical screening. Hyperparathyroid bone disease has also evolved, and overt skeletal involvement is rarely seen. Likewise, nephrolithiasis has become less frequent.
It remains unclear to what extent neuropsychiatric symptoms are present in the modern form of primary hyperparathyroidism. Many patients report nonspecific symptoms, including weakness, easy fatigability, depression, intellectual weariness, cognitive impairment, loss of initiative, anxiety, irritability, sleep disturbance, and somatization. However, these symptoms are difficult to quantify and may not be directly attributable to primary hyperparathyroidism. If patients such as these lack the classical findings of nephrolithiasis or bone disease, they are generally referred to as "asymptomatic."
In 2002, a group of experts met at the National Institutes of Health and, using an evidence-based approach, modified the recommended guidelines for surgery in patients with asymptomatic primary hyperparathyroidism. A number of prospective, nonrandomized studies had suggested that bone mineral density (BMD), renal function, serum calcium, and PTH levels remain stable in the majority of asymptomatic patients during periods of observation as long as 10 yr, whereas surgical cure leads to increased bone density at the lumbar spine and hip, but not at the radius (1, 2, 3). The revised National Institutes of Health guidelines recommend parathyroidectomy for patients with mild asymptomatic primary hyperparathyroidism in whom testing or other information indicates end-organ effects that are likely to be mitigated by intervention (i.e. greater renal or skeletal involvement), or a higher likelihood of disease progression (young age). Neuropsychiatric symptoms were not, however, added as an indication for parathyroidectomy because of inconsistent data on their precise nature, association with the underlying disease, and reversibility (4).
The biochemical alterations in primary hyperparathyroidism, i.e. elevations in serum calcium and PTH, clearly have the potential to produce neuropsychiatric symptoms. Calcium is critical to neurotransmitter function, and elevations in serum calcium concentrations have been postulated to have either a direct or indirect effect on cerebral function. PTH is also elevated in cerebrospinal fluid compared with controls (5), although this finding is of uncertain significance with respect to the pathogenesis of neuropsychiatric symptoms. Additionally, 25-hydroxyvitamin D deficiency, which has recently been associated with worse cognition and lower mood in older adults (6, 7), is a common finding in primary hyperparathyroidism (8, 9). Hypothetically, vitamin D deficiency could contribute to neuropsychiatric symptoms if present in primary hyperparathyroidism.
A number of studies have attempted to characterize the neuropsychiatric features that may accompany mild primary hyperparathyroidism, as well as the reversibility of such features with surgical cure (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Because of the difficulties inherent in performing studies of this nature, most are beleaguered by their observational design, small sample sizes, inclusion of subjects with symptomatic hyperparathyroidism, or lack of appropriate control groups. Others fail to use objective tests to assess symptoms or perform neuropsychiatric testing at short intervals after surgery. Most studies have investigated psychiatric symptoms or quality of life (QOL) rather than cognition. Some, but not all, suggest that there are psychological features of the disease that improve with surgery. Study design limitations, however, leave uncertainties about whether these findings result from nonspecific effects of surgery, selection bias, or confounding factors. Talpos et al. (21) performed a small, randomized controlled trial of the effect of surgery on QOL in asymptomatic primary hyperparathyroidism. Fifty-three patients were randomized to surgery or observation and assessed using the Short Form-36 general health survey (SF-36), which determines the degree to which disease affects physical, psychological, and social functioning. Patients followed without intervention for 2 yr had a decline in psychosocial functioning, whereas there was little change in the operative group. No absolute scores or comparison to norms were reported, so it is unclear whether those with primary hyperparathyroidism were actually abnormal (21).
The studies examining cognitive function (10, 16, 18, 19) have yielded inconsistent results that may be ascribed to variation in the aspects of cognition that were investigated as well as to differences in study design. Recently, there has been increasing interest in more subtle changes in cerebral function. More data will be forthcoming in intriguing studies of cerebral blood flow and cortical activation using single-photon emission computed tomography (22) or functional magnetic resonance imaging (23).
In this issue of JCEM, Bollerslev et al. (24) report on the interim analysis of a large, multinational, randomized, controlled trial of parathyroidectomy compared with observation in asymptomatic primary hyperparathyroidism. Although the study was intended to assess the effect of treatment on QOL and psychiatric symptoms, outcome parameters also included bone density and biochemistries. A total of 191 patients were randomized to medical observation or surgery. The SF-36 and Comprehensive Psychopathological Rating Scale (CPRS) were used to assess symptoms, and data are reported for 119 patients at 1 yr and 99 patients at 2 yr. The CPRS consists of 65 items and can be used to screen for the presence and severity of psychotic, mood, and neurotic disorders. At baseline, the patient population scored lower in all psychological domains, and the mental component summary of the SF-36 compared with a large, age- and sex-matched reference population. Those with primary hyperparathyroidism also had more psychiatric symptoms than controls as determined by the CPRS. SF-36-assessed physical function worsened in the observation group at 2 yr, although this parameter did not improve after parathyroidectomy. Similarly, surgery provided no consistent improvement in psychological domains of functioning or psychiatric symptoms.
Bollserslev et al. (24) also reported a significant increase in lumbar spine BMD 1 and 2 yr after surgery, whereas there was no change in the observation group. A similar but nonsignificant trend was seen at the femoral neck after surgery, although no changes were observed at the forearm. In patients followed without intervention, mean serum calcium, creatinine, and PTH levels remained stable over the 2-yr period, although four of 49 (8%) had an increase in serum calcium that led to parathyroidectomy.
The authors should be commended for this rigorous and sizable study. Randomized studies such as this have proved very difficult to perform in the United States, where most patients with asymptomatic primary hyperparathyroidism find randomization to surgery unacceptable. However, it should be noted that 7 yr, three countries, and at least 10 centers were necessary to yield the study population, raising concerns about how nonparticipants, who refused to be randomized, differ from participants in this study. For example, could the presence of psychiatric symptoms and impaired QOL at baseline be explained by the possibility that those who were willing to be randomized had more symptoms of depression or more concern about their mental health than those who were not? A comparison of demographic, biochemical, and skeletal features of the patients who enrolled in the study with those who declined enrollment would engender greater confidence about generalizing these results to all patients with primary hyperparathyroidism.
This report uses validated methods for evaluating QOL and psychiatric symptoms. The availability of the large national normative SF-36 database is another important strength. Normative data for the CPRS are provided by a control population (n = 102) similar in age but comprised only of women, which may limit its utility as a comparator. It is, however, important to consider that these assessment tools, while valid and reliable, may not necessarily identify problems specific to primary hyperparathyroidism. Observed QOL and psychiatric differences between those with and without primary hyperparathyroidism could be due to the burden of having any disease. Furthermore, the tests employed do not provide information on cognitive impairment.
This more rigorously designed study did not reveal the improvement in QOL with surgery reported in some previous studies (11, 12, 14, 15, 17, 20). The benefit of surgery seen in observational studies could be due to baseline differences between the surgical and observation groups, or to biases introduced by their unrandomized designs. In the current study, those randomized to surgery showed a trend toward fewer psychiatric symptoms and a trend to improve compared with baseline. However, it is unclear whether the psychological effect of being cured vs. the worry of still having a disease is significant in this regard. It is also important to remember that these data are the result of an interim analysis and may not be confirmed when final data on the entire study population are available.
In contrast to the neuropsychiatric data, other findings of this randomized trial of surgery in primary hyperparathyroidism validate the findings of previous observational studies. The biochemical profile of the observational group was generally stable, although 8% of asymptomatic patients developed hypercalcemia requiring surgery over the 2-yr period. It would be of interest to follow the observational group over a longer period of time to characterize the emergence of surgical criteria and clinical progression. The bone density findings confirm prior data on lumbar spine and forearm BMD changes following parathyroidectomy and provide further support for recommendations for surgery based on BMD. In contrast to previous observational studies, there was no significant increase in hip BMD after parathyroidectomy. The reasons for this are not clear, although prior studies may have included more individuals with more severely affected baseline bone density (the lower the BMD, the greater the increase after cure) (1). It would thus be of interest to know the range of participants’ T- and Z-scores. While a subset of patients (n = 28) were taking estrogens or bisphosphonates, the small numbers preclude any conclusions regarding the influence of these drugs on bone density changes after surgery. It is unfortunate that this study is underpowered to investigate the effect of cure on fracture incidence, given the paucity of prospective data in this area.
Although the preliminary results of this study suggest that impaired QOL and psychiatric symptoms are present in mild primary hyperparathyroidism, they do not demonstrate any clear benefit of surgery. Given these findings, it seems prudent not to add the presence of impaired QOL or psychiatric symptoms to the list of criteria for surgery at this time. This study adds considerably to the literature, but further investigation in this area is necessary. We await the final outcome of this important study, as well as others that may identify neuropsychological deficits that are specific to primary hyperparathyroidism.
Footnotes
Abbreviations: BMD, Bone mineral density; CPRS, Comprehensive Psychopathological Rating Scale; QOL, quality of life; SF-36, Short Form-36.
Received March 9, 2007.
Accepted March 14, 2007.
References
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