Leptin: The link between overweight and primary hyperparathyroidism? Shih-Ping Cheng a , Gerard M. Doherty b , Yuan-Ching Chang a,c , Chien-Liang Liu a,c,⇑ a Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan b Department of Surgery, University of Michigan, Ann Arbor, MI, USA c Mackay Medicine, Nursing and Management College, Taipei, Taiwan article info Article history: Received 1 June 2010 Accepted 14 August 2010 summary Primary hyperparathyroidism is one of the most common causes of hypercalcemia. Most cases result from sporadic benign monoclonal adenomas or hyperplasia. Increased body weight is consistently pres- ent in cohorts of patients with primary hyperparathyroidism. It has been shown that fat mass is the major determinant of serum parathyroid hormone levels independent of vitamin D status. Leptin, an adipocyte- derived hormone with mitogenic activity, regulates energy homeostasis and mineral metabolism. Serum leptin levels increase in parallel to the amount of adipose stores. Interestingly, a positive association between leptin and parathyroid hormone levels is observed. Patients with primary hyperparathyroidism have higher serum leptin levels than healthy subjects. In addition, leptin administration in mice increases circulating levels of parathyroid hormone. We hypothesize that leptin involves pathogenesis of primary hyperparathyroidism and represents a link between hyperparathyroidism and increased body weight. Ó 2010 Elsevier Ltd. All rights reserved. Background Primary hyperparathyroidism (pHPT) is a common endocrine disorder characterized by autonomous overproduction of parathy- roid hormone (PTH). In a population-based screening, a prevalence of up to 2.1% was found in 5202 postmenopausal women [1]. The majority of pHPT cases occur sporadically, caused by a single ade- noma or multiglandular hyperplasia. A small proportion (<10%) are associated with familial genetic syndrome such as multiple endo- crine neoplasia syndrome type 1 and 2A, and hyperparathyroidism jaw-tumor syndrome [2]. External radiation and chronic lithium therapy are predisposing factors in a few sporadic pHPT [3,4]. Nonetheless, the pathogenesis of sporadic parathyroid disease in many cases remains unclear. Although pHPT predominantly affects postmenopausal women, the female–male ratio does not change significantly before and after menopause [5]. Thus, the disparity in the incidence of pHPT between women and men could not sim- ply be explained by estrogen and other hormonal changes. There is compelling evidence implicating increased body weight in the pathophysiology of pHPT. In a meta-analysis, most studies reported higher body weight or body mass index (BMI) in patients with pHPT [6]. However, the cause and effect relationship is un- known. It has been frequently reported that pHPT is associated with abnormalities of carbohydrate and lipid metabolism [7]. Patients with pHPT have a higher risk of developing impaired glu- cose tolerance or diabetes mellitus. Interestingly, diabetic patients with pHPT showed improvement in glucose control after parathyroidectomy [8]. Furthermore, Hagstrom et al. [9] demon- strated that dyslipidemia in pHPT patients was normalized after parathyroidectomy. The complex interactions of glucose and lipid metabolism are integrated in the regulation of feeding behavior and body weight [10]. A causal role for pHPT in overweight should not be extrapolated from unfavorable alterations in the carbohy- drate and lipid metabolism. To date, there is no study specifically addressing the effects of parathyroidectomy on body weight. Conversely, an alternative explanation for the association of in- creased body weight and pHPT is that overweight promotes the development of pHPT. In a small retrospective series, increased body weight preceded the onset of pHPT [11]. Pitt et al. [12] reported that morbidly obese patients undergoing parathyroidec- tomy for pHPT were younger than nonmorbidly obese patients, suggesting that increased fat mass may lead to the earlier develop- ment of disease. Further, they found that morbidly obese patients had significantly heavier resected parathyroid gland weights. It is relatively consistent across the studies that PTH levels are posi- tively correlated with BMI [12–14]. Notably, fat mass rather than lean mass is the independent determinant of serum PTH levels [14]. Taken together, these observations provide a plausible link between adipose tissue and pHPT. The physiologic and pathophysiologic role of the adipokines, a family of polypeptides mainly produced by adipose tissue, has aroused considerable interest in the recent years [15]. Among adipokines discovered until now, leptin is positively correlated BMI [15–17]. Leptin plays a pivotal role in regulating the energy balance, by decreasing appetite and increasing metabolism. 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.08.039 ⇑ Corresponding author at: Department of Surgery, Mackay Memorial Hospital, 92, Sec. 2, Chung-Shan North Road, Taipei 10449, Taiwan. Tel.: +886 2 2543 3535; fax: +886 2 2723 3897. E-mail address: surg.mmh@gmail.com (C.-L. Liu). Medical Hypotheses 76 (2011) 94–96 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy