Hypoparathyroidism prevalence was reported by Underbjerg and colleagues in the first large-scale study to assess the prevalence of the disease worldwide, in Denmark between 1997 and 2012 [3]. The authors identified a total of 180 patients with nonsurgical hypoparathyroidism with a prevalence of 2.3 cases in 100,000 habitants. Compared with controls, mortality was not increased (HR 1.25; 95 % CI: 0.90–1.73), but patients had a significantly increased risk of renal insufficiency (HR 6.01), cardiovascular diseases (HR 1.91), neuropsychiatric complications (HR 2.45), infections (HR 1.94), seizures (HR 10.05), cataract (HR 4.21), and fractures at the upper extremities (HR 1.93). In contrast, patients had significantly reduced risk of malignant diseases (HR 0.44). Other studies estimated this prevalence between 0.7/100,000 in a Japanese study [5] and 5/100,000 in a study from Rochester in the US [6].

Hypoparathyroidism most commonly occurs after inadvertent damage or removal of parathyroid glands during neck surgery; the occurrence of this surgical complication ranges from 0.5 to 6.6 %, with higher rates after reoperations on the neck [7]. Edafe et al. performed a meta-analysis over a 20 years period including 115 observational studies (61 prospective) [8]. The reported incidence of transient hypocalcaemia was 27 % (interquartile range between 19 and 38 %) and the incidence of permanent hypoparathyroidism was 1 % (interquartile range between 0 and 3 %). They also identified that levels of preoperative calcium, perioperative parathyroid hormone, preoperative 25-hydroxyvitamin D, and postoperative magnesium were independent predictors of transient hypocalcaemia. Factors associated with transient hypocalcaemia in this meta-analysis were: inadvertent parathyroid glands excision (OR 1.90), parathyroid gland auto-transplantation (OR 2.03), Graves’ disease (OR 1.75), and female sex (OR 2.28). A calcium level lower than 1.88 mmol/L at 24 h after surgery, identification of fewer than two parathyroid glands at surgery, reoperation for bleeding, Graves’ disease, and larger thyroid specimens were identified as independent predictors of permanent hypocalcaemia in multivariable analysis.

The estimated incidence of primary hyperparathyroidism is approximately 25 cases per 100,000 persons per year in outpatients of Western countries [9], with a prevalence of one to four per 1000 persons [10]. The disease is probably underdiagnosed in most of the newly developed or developing countries, and the prevalence of the disease has been increasing around the world, with regional and national variations. Some publications suggest that about 1 % of the adult female population in North America and 3 % of postmenopausal women in Scandinavian countries have primary hyperparathyroidism [11–13]. Lower rates, however, have been reported in other regions of the world such as New Zealand (1 per 10,000 population per year) [14] and Hong Kong (3.7 per 100,000) [15].

Other studies showed that the prevalence of primary hyperparathyroidism depends on features of the targeted populations, as well as on the choice of the method employed to detect the disease. Using biochemical population screening, some reports found prevalence of 4.3 per 1000 (in Sweden), 3 per 1000 (Norway), 21 per 1000 (Finland, aged 55–75 years), 1 per 1000 (USA), and 90 per 100,000 (Austria, [16]). According to the number of patients undergoing parathyroid surgery, the prevalence of hyperparathyroidism in South Korea was 1.4 per 100,000 individual per year. Estimating the true incidence is difficult, but overall figures (UK, USA, and Sweden) are consistently between 27 and 30 per 100,000 person-years [8, 9, 17, 18].

Primary hyperparathyroidism occurs in 0.1–0.3 % of the population and is more common among women than men (1 in 500 compared to 1 in 2000) [19]. In another study, authors identified a female-to-male ratio of 2.8:1 of primary hyperparathyroidism in all age groups, with the incidence increasing after the age of 25 year-old in both sexes [20]. The female-to-male ratio does not change during the peri- and postmenopausal years. In addition, elderly men (69–81 years) had an incidence of primary hyperparathyroidism of 0.73 % in Sweden [21]. The prevalence varies between 0.36 and 13.4 % in postmenopausal women [22]. In Indian series, females were more commonly affected (1.7:1). 71.5 % of the cases were less than 40 years of age, whereas patients from developed nations are generally diagnosed in the fifth and sixth decades [23].

Single gland adenoma is the most common cause (75–85 %), but multiglandular disease may occur, either hyperplasia of the 4 glands or double or triple adenomas (two glands in 2–12 % of cases, three glands in <1–2 %, and four or more in <1–15 %). Parathyroid carcinomas are very rare (~1 %) [4].

Ruda et al. performed a meta-analysis on the association of glandular diseases with primary hyperparathyroidism in 20,225 patients [24]. The authors identified that a solitary adenoma was the most frequent surgical pathology and occurred in an estimated 88.90 % of cases, followed by multiple gland hyperplasia with 9.84 % (multiple gland hyperplasia 5.7 % and double adenomas in 4.1 % of cases) and parathyroid carcinoma in 0.74 % of the patients.

The association between primary hyperparathyroidism and thyroid diseases, either benign or malignant, has long been described. Indeed, up to 65 % of patients with primary hyperparathyroidism have associated thyroid abnormality [25]. However, the association of hyperparathyroidism and Graves’ disease is extremely rare [26].

A study investigated the preoperative clinical symptoms and associated conditions of patients with primary hyperparathyroidism comparing two populations, one in San Francisco, USA and the other in Bursa, Turkey. The authors identified that more patients in the United States Group (15 %) had preoperatively persistent or recurrent hyperparathyroidism, whereas Turkish patients had higher serum parathyroid hormone levels and an increased incidence of osteoporosis. Moreover, the size of parathyroid adenomas was significantly greater in Turkish patients (25.2 vs. 17.5 mm) [12].

In the discussion of the article, the authors state that more information is needed regarding the etiology of primary hyperparathyroidism and differences among different races. For example, regional differences in the prevalence of vitamin D deficiency also may contribute to the frequency of primary hyperparathyroidism and its clinical manifestations. Another study reported that most cases of hyperparathyroidism in South Africa were symptomatic at presentation (92.9 %), usually associated with radiologic abnormalities (47.6 %) and significant morbidity [27]. These findings are in contrast with reports from developed countries where many asymptomatic cases were evident in the Western world with the introduction of routine calcium screening [17].

Parathyroid cancer is one of the rarest malignancies, with an incidence of approximately four per ten million persons per year [28]. Other series estimated a prevalence of 0.005 % of all cancers [29–32]. It is a rare cause of primary hyperparathyroidism, accounting for less than 1 % of patients with primary hyperparathyroidism [33]. However, there may be a geographic variation in the distribution of this disease, with reported incidence of about 1 % in Europe and the United States and about 5 % in Japan, Italy, and Korea [34–39]. Parathyroid carcinoma occurs with equal frequency in men and women [40].

Sadler et al. studied 1022 cases of parathyroid carcinoma assessing data from National Cancer Data Base that underwent surgery between 1998 and 2011 [41]. The authors identified that the 5-year overall survival was 81.1 %. The overall cohort was mainly non-Hispanic (96.5 %), white (77.4 %), and insured (94.3 %), with a median age of 57 years. Mean overall survival was lower and relative risk of death greater in older, African-American patients with a secondary malignancy, with more than two comorbidities, in surgical specimen with positive surgical margins or positive lymph nodes. Multivariate analysis demonstrated that positive lymph nodes (HR 6.47; 95 % CI, 1.81–23.11) and older age (HR 2.35; 95 % CI, 1.25–4.43) were associated with lower overall survival.

Multiple endocrine neoplasia type 1 (MEN-1) and type 2 (MEN-2a), which often include parathyroid neoplasia with primary hyperparathyroidism, occur in about two per 100,000 persons per year [42]. MEN1 represents the most common familial cause of primary hyperparathyroidism, accounting for 2–4 % of all cases, and it is characterized by a predisposition to develop endocrine tumors in pituitary, parathyroid, and pancreatic endocrine cells. Primary hyperparathyroidism, usually with multiglandular disease, is the most common endocrine component of MEN1, occurring in more than 90 % of individuals aged between 20 and 25 years [43, 44].

MEN2A is characterized by an increased risk of pheochromocytoma and parathyroid adenoma or hyperplasia. In MEN2a, primary hyperparathyroidism occurs in 20–30 % of cases. It is usually mild and asymptomatic. The average age of onset of primary hyperparathyroidism is 38 years, many years after the diagnosis of MTC [43, 45].

Secondary hyperparathyroidism is a frequently observed complication in patients with chronic renal failure. The prevalence of secondary hyperparathyroidism is around 45 % among chronic kidney disease patients undergoing hemodialysis, and increases across declining estimated glomerular filtration rate levels [46]. Hyperplasia of the four glands with autonomous disease is the must see in these patients.

The high prevalence of chronic kidney disease patients with secondary hyperparathyroidism with indication of surgical treatment has been recognized in several countries [47]. In Japan, 10 % of the patients on hemodialysis for over 10 years and 30 % of those on hemodialysis for over 20 years, need parathyroidectomy. In 1982, the European Dialysis and Transplantation Association Registry reported 5/1000 patients/year incidence of parathyroidectomy during the second or third year on dialysis, but a rate of over 40/1000 patients/year among those on dialysis for more than 10 years [48]. The Dialysis Outcomes and Practice Pattern Study (DOPPS) , which assessed the hemodialysis status and quality from 1996 to 2001 in European countries, the United States, and Japan, revealed that surgical treatment is less frequent in Japan than in Europe (4.1 % prevalence, with a 0.6/100 patients/year parathyroidectomy incidence) [49].

A recent published meta-analysis [50] identified that across Europe and Australia, the prevalence of secondary hyperparathyroidism within dialysis populations ranged from 30 to 49 %; prevalence within dialysis populations in the North America (US, Canada) was estimated at 54 %. Within Asia, prevalence estimates were only identified for India (28 %) and Japan (11.5 %). The results of this study are summarized in Table 45.1.

A Brazilian study [47] evaluated the status of secondary parathyroid patients and their need of parathyroidectomy. The prevalence of the disease was 10.7 % when PTH levels were higher than 1000 pg/mL (the cut-off value was one of the limitations of the study). The authors wrote that in Brazil, 68 services perform parathyroidectomy, of which 36 (53 %) are in the south-eastern region. If we consider that Brazil has approximately 92,000 patients on dialysis, and that the estimated prevalence of secondary hyperparathyroidism with indication of parathyroidectomy is 10.7 %, about 9800 patients should be operated on. Three hundred and fifty to five hundred parathyroidectomies are estimated to be performed every year in Brazil, which allows a projection of 20 years before all present surgical indications are met. It is well known that, unfortunately, the access for surgical treatment is also not easy in other developing countries.

Another important cause of hyperparathyroidism is hypovitaminosis D. Recent studies suggest that the prevalence of subclinical vitamin D deficiency is continuously increasing worldwide [51]. The prevalence of vitamin D deficiency depends on the cut-off point used, as well as the type of population studied [52] Therefore, vitamin D deficiency was found in almost all geriatric patients [53], and in 57 % of the American acute symptomatic patients [54]. The prevalence of vitamin D deficiency was 36 % of men and 47 % of women in the European elderly population. Surprisingly, the most southern countries showed the lowest levels [55], and, in women with postmenopausal osteoporosis, the deficiency prevalence ranged from 0 % in Singapore to 3.5 % in the US, and slightly above 10 % in France and Spain [56].

Gomés-Alonso et al. conducted a study evaluating vitamin D levels and secondary hyperparathyroidism in Spain [52]. The authors found that serum 25-hydroxyvitamin D levels were “deficient” (<10 ng/mL) in 27 % of subjects, “borderline” (10–18 ng/mL) in 40 % of subjects, and “normal” (>18 ng/mL) in 33 % of subjects. The prevalence of secondary hyperparathyroidism (PTH>65 pg/mL) according to 25-hydroxyvitamin D levels was 33 % (<10 ng/mL), 16 % (10–18 ng/mL), and 12 % (>18 ng/mL), respectively. There were no cases of secondary hyperparathyroidism with 25-hydroxyvitamin D levels >40 ng/mL. The independent predictors for PTH were 25-hydroxyvitamin D and serum creatinine in both sexes, but age was a predictor only in men. The prevalence of secondary hyperparathyroidism was similar to that found in another study [57] and increased with age, most likely due to the deterioration of renal function and the decrease of 25-hydroxyvitamin D levels. The relationship found between 25-hydroxyvitamin D and PTH was similar to that found in other studies [56] with normal renal function or chronic hemodialysis [58].